Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCNCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
22.2 g(0.2 mol) of 4-aminomethyl piperidine was dissolved in 250 ml of toluene and 21.2 g(0.2 mol) of benzaldehyde was added thereto. The reaction mixture was heated to reflux for 3 hours with Dean-stack and then cooled down to 0° C. 34.2 g(0.2 mol) of benzyl chloroformate was added dropwise while stirring. The reactants were stirred for 3 hours and 220 ml of 1N KHSO4 was added at room temperature. The reaction solution was extracted with 200 ml of diethylether 3 times and the aqueous layer was basified with sodium hydroxide. After the aqueous solution was treated with saturated sodium chloride solution, it was extracted with 100 ml of dichloromethane 3 times. and the organic layer was dried over magnesium sulfate. Removal of dichloromethane under reduced pressure provided 38 g of the title compound(Yield 91%, MW 248).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([CH3:24])[CH:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[C:11]([C:10]1[C:9]([CH3:24])=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:13]=1)#[N:12]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)c(Sc2ccc(F)cc2F)cc1C#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (2.2 ml) was added dropwise to an ice-cooled solution of 4-amino-5-(2,4-difluorophenylthio)-2-methylbenzonitrile (3.9 g) and triethylamine (3.9 ml) in pyridine (40 ml). The mixture was stirred overnight at room temperature and concentrated to dryness. To the residue were added pyridine (10 ml) and 5% aqueous solution of sodium hydroxide (50 ml). The resulting mixture was stirred for 2 hours and washed with toluene (50 ml). The aqueous layer was acidified with hydrochloric acid, and the precipitates obtained were recrystallized from a mixture of ethanol and ethyl acetate to give a pale brown powder of 4'-cyano-2'-(2,4-difluorophenylthio)-5'-methylmethanesulfonanilide (2.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Cl-].[Zn+2].[Cl-].C(=O)(OCC)OCC>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:32][CH2:31][C@:29]([CH2:28][CH2:27][CH2:26][C@@H:24]([CH2:23][CH2:22][CH2:21][C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33][C:3]=2[C:2]=1[CH3:1]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(=O)OCC
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 35 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To a mixture consisting of 69.9 g (0.460 mol) of 2,3,5-trimethylhydroquinone, 52.5 g (0.386 mol) of zinc chloride, 150 ml of diethyl carbonate and 7.5 g of concentrated hydrochloric acid, 138.3 g (0.459 mol) of isophytol (purity: 98.3%) was added dropwise under stirring at 30-40° C. over 3 hours. At the same temperature, the reaction mixture was stirred for an additional 2 hours. After the reaction mixture was washed with 30 ml of water, the solvent was distilled off. Toluene (300 ml) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturate aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 201.2 g of the title compound was obtained as a brown oil (yield: 99.2%), GLC purity: 97.5%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[OH:28])[CH2:22][CH2:23][NH2:24].C(O)CCC>O>[ClH:13].[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([NH:6][CH2:5][CH:4]2[C:25]3[C:21](=[CH:20][C:19]([OH:18])=[C:27]([OH:28])[CH:26]=3)[CH2:22][CH2:23][NH:24]2)=[CH:12][CH:11]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CNc1ccc(Cl)cc1)OCC
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Oc1cc2c(cc1O)C(CNc1ccc(Cl)cc1)NCC2

Procedure:
p-Chloroanilinoacetaldehyde diethyl acetal (486 mg) and 3,4-dihydroxyphenethylamine hydrochloride (378 mg) were added to a mixture of n-butyl alcohol (4 ml) and water (0.4 ml) and then the mixture was refluxed for 3.5 hours. The above-mentioned acetal (0.24 g) was further added thereto and the resultant mixture was refluxed for 3 hours. The reaction mixture was treated in a conventional manner to give 1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This product was identified by thin-layer chromatography on silica gel [Developing solvent: (n-butyl alcohol:acetic acid:water=8:1:1)] with an authentic sample, mp 91° to 93° C., which was obtained by reacting 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride obtained in Example 1(D) with conc. hydrochloric acid and acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[O:14][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A solution of methyl 5-nitrosalicylate (10.0 g, 50.7 mmol) and imidazole (3.8 g, 55.8 mol) in DMF (50 mL) at 0° C. was treated with t-butylchloro-dimethyl-silane and stirred 16 h at room temperature. The reaction mixture was poured into water (100 mL) and extracted with ether (3×50 mL). The combined extracts were washed with water (4×100 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated. The crude residue was purified by flash chromatography (silica gel, 4×15 cm, eluted with 95/5 hexanes/EtOAc) to yield 2-(tert-butyl-dimethyl-silanyloxy)-5-nitro-benzoic acid methyl ester as a white solid (4.9 g, 31%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][N:20]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(S(C)(=O)=O)C1
Yield: 43 %

Procedure:
Using a similar procedure to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-6-[(3S)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (210 mg) was reacted with methane sulfonyl chloride to give the title product (100 mg, 43%); 1H NMR Spectrum: (DMSO d6) 2.18-2.37 (m, 2H); 2.93 (s, 3H); 3.38-3.52 (m, 3H); 3.69 (dd, 1H); 3.92 (s, 3H); 5.17 (m, 1H); 7.15-7.35 (m, 2H); 7.40-7.60 (m, 2H); 7.80 (s, 1H); 8.38 (s, 1H); 9.58 (s, 1H); Mass Spectrum: (M+H)+ 467.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[H-].[Na+].[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32].C>CN(C=O)C.O>[C:31]([NH:35][C:36]([NH:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine (0.48 g) from Example 20 in DMF (5 mL) was added 60% sodium hydride suspension (46 mg), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added t-butyl isocyanate (0.113 g), and the mixture was stirred for 18 hours. The reaction mixture was diluted with water and the insoluble material was collected by filtration. The solid was suspended in water (20 mL) and acidified with 1.ON HCl to form a solution. Activated charcoal was added to the solution, and the suspension filtered through celite, washing with water. The filtrate was made basic with 1.0 N NaOH, and the insoluble product was collected by filtration and washed with water. A 180-mg sample of the product was further purified by reverse phase preparative HPLC on a C18 reverse phase column, eluting with a solvent gradient starting from 86% of 0.1% trifluoroacetic acid in water/14% acetonitrile to 14% of 0.1% trifluoroacetic acid in water/86% acetonitrile over a 22-minute time period to afford 165 mg of 1-tert-butyl-3-[6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea, mp dec >80° C.
Reaction SMILES: [H-].[Na+].[O-:3][CH2:4][CH3:5].[Na+].[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2I)=[O:23])=[CH:17][C:16]=1[F:39]>C1COCC1.CCO>[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2[O:3][CH2:4][CH3:5])=[O:23])=[CH:17][C:16]=1[F:39]
Reactant: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2Cl)c(F)c1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a suspension of NaH (1.87 g, 77.9 mmol) in THF (26 mL) under nitrogen was slowly added EtOH (80 mL, Aldrich>99.5%, 200 proof) and the resulting homogeneous solution was stirred for 10 minutes. The sodium ethoxide solution was then added to a mixture of 3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide (37.3 g, 59.9 mmol) in THF (100 mL) and EtOH (46 mL), and the resulting mixture was stirred at room temperature for 1 h before being concentrated in vacuo. The residue was suspended in water (500 mL) and the mixture was sonicated and stirred for about 1 h at room temperature until the remaining solid became a filterable powder. The resulting powder was collected, triturated with ethyl ether (50 mL) and dried under high vacuum for 48 h to afford 3-Chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (30.8 g, 95%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.94 (dd, 1H, J=12.4, 2.4 Hz), 7.80 (d, 1H, J=8 Hz), 7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J=5.6 Hz), 6.61 (d, 1H, J=7.2 Hz), 4.34 (q, 2H, J=7.2 Hz), 1.45 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 541.11 (M+H)+.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([NH:21][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: O=C(NCc1ccccc1)C12CC3CC(CC(C3)C1)C2

Procedure:
Dissolve 2.0 g. of (10 mmoles) of 1-adamantane carboxylic acid chloride in 20 ml. of ethyl ether and add to 3.0 ml. (28.0 mmoles) of benzylamine and repeat the process of Example 11 to obtain the product of this example, m.p. 170°-172° C.
Reaction SMILES: B(Cl)(Cl)Cl.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.ClC(Cl)(Cl)[C:16]#[N:17].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[C:16]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[NH:5][CH2:6][CH2:7]2)#[N:17]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCN2
Agent: C[O-]
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1cccc2c1NCC2
Temperature: 55 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
22 g of BCl3 (187.8 mmol) in 120 ml of toluene (dried) was dissolved in a 750 ml round flask at -20°. 15.9 g of indoline (133.4 mmol) in 100 ml of toluene was added within 25 minutes and the temperature rose to 10°. This suspension was refluxed for 1 hour, then 110 ml of toluene was distilled off and the reaction mixture was cooled to 55° C. Then 38.4 g of trichloroacetonitrile (266 mmol) was added within 20 minutes and the resulting red solution was stirred for 20 hours at 60° C. After addition of methanol (110 ml) the reaction mixture was mixed within 1.5 hours with 60 g of a 30 percent methanolic sodium methanolate solution. After 1 hour of stirring the methanol was distilled off in a vacuum and then toluene (300 ml) and water (300 ml) were added. The aqueous phase was extracted several times with 200 ml of toluene. The combined toluene extracts were then washed with a 0.12N HCl (91 ml) and with water to remove the not reacted indoline. After concentration by evaporation of toluene 20.12 g of a brownish oil was obtained. The latter was then recrystallized in a hexane/pentanol mixture (80 ml; mixture ratio of hexane: pentanol=9:7) to obtain 11.47 g of a light brownish product with a purity of 99.4 percent corresponding to a yield of 60.5 percent relative to feedstock used. Other data concerning the product was:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])N.[K+].O>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-fluoro-2-methylnitrobenzene (2 g), 1,2,4-triazole (0.9 g) and anhydrous potassium carbamate (1.78 g) was stirred and heated in dimethylsulphoxide (50 ml) at 90° C. for 24 hours. The reaction mixture was cooled, poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to give an orange solid which was purified by chromatography on silica using pentane/ethyl acetate as eluant, (1.8 g, 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO>[OH:16][N:15]=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[C:10]([F:13])([F:11])[F:12]
Reactant: NO
Reactant: Cc1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
An oven-dried 20 mL reaction vial containing a stir bar was cooled under a stream of dry nitrogen. The vial was charged with 4-methyl-2-(trifluoromethyl)benzonitrile (1000 mg, 5.40 mmol), hydroxylamine hydrochloride (469 mg, 6.75 mmol), sodium bicarbonate (681 mg, 8.10 mmol), and methanol (6 mL). The vial was flushed with nitrogen, sealed, stirred at room temperature for 30 minutes, and then placed in a sand bath set to 75° C. and stirred overnight. The crude reaction material was purified by reverse phase preparative HPLC. The collected product fractions were evaporated under vacuum to afford N′-hydroxy-4-methyl-2-(trifluoromethyl)benzimidamide (0.54 g, 2.45 mmol, 45% yield). MS M+1=219.0.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:6]=1[NH2:7].[CH3:19]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]([C:3]1[C:2]([CH3:19])=[C:6]([NH2:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)c(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(C(C)(C)C)c(C)c1N
Temperature: 155 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 4-bromo-3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate J, 800 mg, 2.60 mmol) in DMF (5 mL) was added trimethylboroxine (0.73 mL, 5.19 mmol), [1,1′-bis(diphenylphosphino)-butane]palladium (II) dichloride (157 mg, 0.26 mmol), and potassium carbonate (1.08 g, 7.79 mmol). The reaction mixture was stirred for 18 h at 155° C. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using hexane/EtOAc (1:9, v/v) to afford the product (243 mg, 38%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.97 (s, 3H), 2.03 (s, 3H), 4.48 (s, 2H) 7.14-7.32 (m, 4H). ES-MS m/z 244.2 (MH+); HPLC RT (min) 1.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:21]=[CH:22][C:23](=[O:27])[N:24]([CH3:26])[CH:25]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=O.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:21]=[CH:22][C:23](=[O:27])[N:24]([CH3:26])[CH:25]=1)[CH2:9]/[C:10](/[C:12]1[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)=[N:29]\[OH:30]
Reactant: Cn1cc(C(=O)CC(c2ccc(=O)n(C)c2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(=O)n(C)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5,5′-[1-(2-chlorophenyl)-3-oxopropane-1,3-diyl]bis(1-methylpyridin-2(1H)-one) was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=398.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:42])[CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][C:22]([NH:24][C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:14][CH:13]=1)=[O:10].C1COCC1.[Li+].[OH-]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:42])[CH:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:34][CH:35]=2)=[O:23])=[CH:16][CH:17]=1)=[O:10]
Reactant: CCOC(=O)c1ccc(NC(=O)CC(C(=O)Nc2ccc(NC(=O)Nc3ccccc3C)cc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(NC(=O)C(CC(=O)Nc2ccc(C(=O)O)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 4-[(4-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]amino}-4-oxo-3-phenylbutanoyl)amino]benzoate (160 mg, 0.28 mmol) was dissolved in water:THF (10 mL; 1:1; v:v) and LiOH (27 mg, 1.13 mmol) was added at 0° C. and the reaction mixture was stirred at r.t. for 24 h. The reaction mixture was acidified, the product was isolated by filtration and purified by flash chromatography (CH2Cl2/MeOH/AcOH; 10/1/0.5) (11 mg, 0.02 mmol). M.p. 169° C. TLC (DCM/MeOH 9/1) Rf 0.27, ESI-MS: 537[M+H]+.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2ccc(N)cc2)c2ccccc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(NS(C)(=O)=O)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
To a mixture of 2-methyl-4-(4-aminophenyl)-1-(2H)-phthalazinone (8.77 g, 34.9 mmol), CH2Cl2 (300 mL) and pyridine (3.11 mL, 38.4 mmol) at 0° C. was added dropwise methanesulfonyl chloride (2.97 mL, 38.4 mmol) in CH2Cl2 (20 mL) over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 12 hours. Additional pyridine (0.5 mL) and methanesulfonyl chloride (0.5 mL) was added and the mixture was stirred as such for 2 hours. The reaction mixture was poured into 2N HCl, the organic layer was separated and then washed with water and dried over Na2SO4. The solvent was removed in vacuo and the residue was azeotroped with toluene and CH2Cl2 to afford 9.0 g (78%) of 2-methyl-4-(4-methylsulfonylaminophenyl)-1-(2H)-phthalazinone as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].O1CCO[CH:13]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C(=O)C>[F:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]3([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=1)[NH:6][C:4]2=[O:5]
Reactant: OC1(c2ccc(C3OCCO3)cc2)CCCC1
Reactant: NC(=O)c1cc(F)ccc1N
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2ccc(C3(O)CCCC3)cc2)nc2ccc(F)cc12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A suspension of 2-amino-5-fluorobenzamide (135 mg, 0.88 mmol), 1-(4-[1,3]dioxolan-2-yl-phenyl)-cyclopentanol (206 mg, 0.88 mmol) and sodium disulfite (170 mg, 0.89 mmol) in N,N-dimethylacetamide (2 ml) is heated to 150° C. and stirred at this temperature for 3 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration and washed with water. It is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 6-fluoro-2-[4-(1-hydroxy-cyclopentyl)-phenyl]-3H-quinazolin-4-one as white solid; HPLC/MS 1.80 min (A), [M+H] 325;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].C([Li])(C)(C)C.CCCCC.CN(C)[CH:25]=[O:26]>C1COCC1>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:25]=[O:26])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CCc1n[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCc1n[nH]c2ccc(C=O)cc12

Procedure:
A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example 7A) in THF (300 ml) was cooled to −78° C. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (63.1 ml, 107 mmol) was slowly added. The mixture was stirred at −78° C. for 30 minutes before N,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath was removed, and stirring was continued until room temperature was reached. Then, water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.5 g (84% of th.) of the crude title compound which was used in the next step without further purification.