Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]C(=O)C)=O)=[C:3]([C:5](=[O:15])[NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[OH-].[K+].Cl>C(O)C.O>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:3]([CH3:4])=[C:2]([CH3:1])[N:16]=1
Reactant: CC(=O)Oc1ccccc1C(=O)NC(C)=C(C)C(=O)NCCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccccc2O)n(CCc2ccccc2)c(=O)c1C
Yield: 37 %

Procedure:
Acetic acid 2-(1-methyl-2-phenethylcarbamoyl-propenylcarbamoyl)-phenyl ester of Example 1f (220 mg, 0.59 mmol) was dissolved in the mixture of ethanol (8 mL) and water (8 mL) which contained 85% potassium hydroxide (0.80 g, 1.2 mmol). The mixture was refluxed overnight. After cooling, the reaction mixture was acidified with hydrochloric acid to pH=1 and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. After concentration, the product was purified by flash chromatography on silica gel (39 g) eluting with hexanes-ethyl acetate (1:1) to give 2-(2-hydroxy-phenyl)-5,6-dimethyl-3-phenethyl-3H-pyrimidin-4-one (70 mg, 37%) as a white solid.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:30][C:31]1[C:36]([Pb+3])=[C:35]([CH3:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][C:31]1[C:36]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[C:35]([CH3:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: O=C1CC(=O)C2CCC1C2
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C

Procedure:
To a mixture of bicyclo[3.2.1]octane-2,4-dione (0.553 g, 4 mmol) in dry chloroform (12 ml) is added 4-dimethylaminopyridine (2.44 g, 20 mmol), and the mixture is stirred at room temperature until all the solid is dissolved. To this solution is then added dry toluene (8 ml), and 3,5-dimethylbiphen-4-yllead triacetate (0.5 M solution in dry chloroform, 10 ml, 5 mmol), and the mixture is heated under reflux for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH=1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 3-(3,5-dimethylbiphen-4-yl)bicyclo[3.2.1]octane-2,4-dione as a white powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:10]2[C:11]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH:29]=3)=[N:12][C:13]([C:16]([NH:18][C:19]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])=[CH:14][CH:15]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.S(Cl)(Cl)=O.[CH3:46]O>CCOCC>[ClH:2].[Cl:2][C:3]1[C:4]([C:10]2[C:11]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH3:41])[CH:29]=3)=[N:12][C:13]([C:16]([NH:18][C:19]3([C:25]([O:27][CH3:46])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:17])=[CH:14][CH:15]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CO
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)CCCCC3)ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C1(NC(=O)c2ccc(-c3ncc(Cl)cc3Cl)c(-c3ccc(Cl)c(OCCCN(C)C)c3)n2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 300 mg (0.47 mmol) of 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclo-hexanecarboxylic acid hydrochloride in 10 mL of methanol and cooled to 0° C. is added 0.07 mL (0.93 mmol) of thionyl chloride. The reaction mixture is warmed to room temperature and stirred for 20 hours, and then concentrated under reduced pressure. The residue obtained is taken up in 20 mL of ether and solidified. After drying under reduced pressure, 268 mg of methyl 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylate hydrochloride are obtained in the form of a white powder.
Reaction SMILES: [C:1](=[O:37])([O:6][C:7]([CH3:36])([CH3:35])[CH2:8][NH:9][C:10]([NH:12][C@H:13]([CH:32]([CH3:34])[CH3:33])[C:14]([N:16]1[CH2:21][CH2:20][C@@:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([OH:22])[C:18]([CH3:31])([CH3:30])[CH2:17]1)=[O:15])=[O:11])[O:2][CH2:3][CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[C:1](=[O:37])([O:2][CH2:3][CH2:4][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[O:6][C:7]([CH3:36])([CH3:35])[CH2:8][NH:9][C:10]([NH:12][C@H:13]([CH:32]([CH3:34])[CH3:33])[C:14]([N:16]1[CH2:21][CH2:20][C@@:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([OH:22])[C:18]([CH3:31])([CH3:30])[CH2:17]1)=[O:15])=[O:11]
Reactant: CC(C)[C@@H](NC(=O)NCC(C)(C)OC(=O)OCCBr)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)NCC(C)(C)OC(=O)OCCN1CCOCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 2-bromoethyl 1-(3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)ureido)-2-methylpropan-2-yl carbonate (780 mg, 1.289 mmol) and K2CO3 (356 mg, 2.58 mmol) in DMF (3 mL) was added morpholine and the reaction was stirred at rt overnight. After drying the crude product overnight under high vacuum, the residual glass was purified via column chromatography (50% EA/hep to 100% EA to 5% MeOH/EA) to furnish 1-(3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)ureido)-2-methylpropan-2-yl 2-morpholinoethyl carbonate (620 mg, 1.014 mmol, 79% yield) as a foam. 1H NMR (CDCl3, 400 MHz, rotameric) δ 7.40-7.24 (m, 4H), 5.44 (dd, J=21.9, 8.8 Hz, 1H), 5.13 (dt, J=21.1, 5.7 Hz, 1H), 4.82 (m, 1H), 4.65 (br d, 0.5H), 4.20 (t, J=6.2 Hz, 2H), 3.95 (m, 0.5H), 3.71 (t, J=4.8 Hz, 4H), 3.58 (m, 1H), 3.43 (m, 3H), 3.15 (dt, J=13.1, 2.6 Hz, 0.5H), 3.05 (d, J=12.7 Hz, 0.5H), 2.64 (t, J=5.7 Hz, 2H), 2.51 (t, J=4.4 Hz, 4H), 1.96 (m, 1H), 1.54 (m, 1H), 1.47-1.43 (m, 6H), 1.06 (d, J=6.6 Hz, 1.5H), 0.97-0.76 (m, 10.5H). HPLC Purity: >99%, rt 3.23 min (Chromalith Speedrod, C18, 4.6×50 mm, 10% MeOH/water to 90% MeOH/water with 0.2% H3PO4, 4 min gradient, 4 mL/min) LCMS: 611.38 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1ncc[nH]1
Product: O=C(Nc1ncc[nH]1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-aminoimidazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1H-imidazol-2-yl)terephthalamide. MS (Q1) 452 (M)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:60]=[C:61]([CH:64]=[CH:65][CH:66]=2)[C:62]#[N:63])[CH2:54][CH2:53]1>CN(C=O)C.O>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([N:52]2[CH2:53][CH2:54][CH:55]([O:58][C:59]3[CH:66]=[CH:65][CH:64]=[C:61]([C:62]#[N:63])[CH:60]=3)[CH2:56][CH2:57]2)=[O:21])=[CH:14][CH:15]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: N#Cc1cccc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1
Reaction time: 0.03 h
Yield: 20.5 %

Procedure:
DIPEA (135 mg, 11.0 mmol) was added to a stirred solution of N-biphenyl-4-yl-malonamic acid (64 mg, 0.3 mmol) in DMF (2.0 mL) followed by HOBt (61 mg, 0.45 mmol) and EDCI.HCl (85 mg, 0.45 mmol). After 2 minutes of stirring, 3-(piperidin-4-yloxy)-benzonitrile hydrochloride (60 mg, 0.3 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 27 mg (19.7% Yield) of N-biphenyl-4-yl-3-[4-(3-cyano-phenoxy)-piperidin-1-yl]-3-oxo-propionamide. LC/MS [M+H]+: 440.2, 98.14%, 1H NMR (300 MHz, DMSO-d6): δ10.2 (s, 1H), 7.7 (m, 5H), 7.5 (m, 5H), 7.3 (m, 2H), 4.8 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 3.3 (m, 2H), 2.0 (m, 2H), 1.7 (m, 1H), 1.6 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[CH3:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=[CH2:25])[CH:23]=1.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:22]3[CH:21]=[N:20][CH:19]=[C:18]([CH3:17])[CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: C=Cc1cncc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cncc(CCn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)c1
Temperature: 90 °C
Yield: 3 %

Procedure:
The title compound was prepared by following general procedure 4. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.85 mmol), tetra n-butyl ammonium chloride (11 mg, 0.043 mmol), 3-methyl-5-vinylpyridine (121 mg, 1.02 mmol) were taken into 50% NaOH (6 mL) and the reaction mixture was heated overnight at 90° C. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was extracted with ethyl acetate and water, the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by preparative TLC to obtain 9 mg of 9-chloro-3-methyl-6-(2-(5-methylpyridin-3-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, isolated as its oxalate salt. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 8.40 (s, 1H), 8.0 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.18 (d, 1H), 7.0 (d,1H), 4.40 (t, 2H), 3.70 (t, 2H), 3.30 (s, 3H), 3.20 (m, 5H), 3.0 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:2][CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.P(Br)(Br)[Br:19]>C(Cl)(Cl)Cl>[Br:19][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOCCCCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)CCOCCCCBr
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 6.4 g (0.4 mol) of 4-isopentyloxy-butanol and 0.32 g (0.004 mol) of pyridine in 40 ml of chloroform are added over a period of 15 minutes with stirring at 0° , 1.42 ml (0.015 mol) of phosphorus tribromide. The mixture is stirred for a period of one hour at 20° and then for 20 hours at 60°C. After cooling to room temperature, the reaction mixture is poured into an ice cold saturated aqueous sodium bicarbonate solution and the reaction product is extracted with chloroform. The chloroform extract is then first washed with water and then with saturated aqueous sodium chloride solution and afterwards dried with sodium sulphate. The chloroform is then evaporated off under reduced pressure. The residue is chromatographed on a silica gel column with hexane/ethyl acetate (99:1 to 98.2) as eluent. After fractional distillation of the practically pure chromatographic fractions, pure 1-bromo-4-isopentyloxy-butane is obtained, as a colourless oil. (Boiling point 40° to 46° 0.03 mm Hg).
Reaction SMILES: Cl[S:2]([C:5]1[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=1)(=[O:4])=[O:3].Cl.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(CC)CC)C>C(OCC)(=O)C>[CH:20]12[N:23]([S:2]([C:5]3[N:9]=[CH:8][N:7]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[N:6]=3)(=[O:4])=[O:3])[CH:16]([CH2:22][CH2:21]1)[CH2:17][CH2:18][CH2:19]2
Reactant: CN(C)C(=O)n1cnc(S(=O)(=O)Cl)n1
Reactant: C1CC2CCC(C1)N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)n1cnc(S(=O)(=O)N2C3CCCC2CC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 54-a) (470 mg), 8-azabicyclo[3.2.1]octane hydrochloride (350 mg), triethylamine (0.7 ml), and ethyl acetate (10 ml) was stirred overnight at room temperature. The reaction solution was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 50 to 100% ethyl acetate/hexane to yield the title compound (150 mg).
Reaction SMILES: O[CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[N:43][CH:44]=1>C(Cl)Cl.O>[CH3:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][CH:46]2[CH2:51][CH2:50][N:49]([CH2:10][C:9]34[CH2:2][CH:3]5[CH2:12][CH:7]([CH2:6][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:4]5)[CH2:11]3)[CH2:8]4)[CH2:48][CH2:47]2)=[N:43][CH:44]=1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Reactant: COC(=O)C12CC3CC(CC(CO)(C3)C1)C2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C12CC3CC(CC(CN4CCC(Nc5ccc(C)cn5)CC4)(C3)C1)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
After dissolving methyl 3-hydroxymethyltricyclo[3.3.1.1 3,7]decane-1-carboxylate (0.1648 g, 0.735 mmol) and pyridine (0.0829 g, 1.05 mmol) in methylene chloride (5 mL), trifluoromethanesulfonic anhydride (0.185 mL, 1.11 mmol) was added dropwise while cooling on ice and the mixture was stirred for 1 hour. Water (10 mL) was added to the reaction mixture, and after extraction with ethyl acetate (20 mL), the extract was washed with 1N HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL) in that order and dried over anhydrous magnesium sulfate, and then 4-(5-methylpyridin-2-yl)aminopiperidine (0.2995 g, 1.57 mmol) was mixed therewith and the solvent was distilled off under reduced pressure. The obtained yellow oil was heated at 60° C. for 1 hour. It was then subjected to chromatography (50 g Merck Art. 9385, methylene chloride:methanol:ammonia water=97:3:0.2) to obtain the title compound as a white solid (0.2398 g, 0.603 mmole) (82% yield).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].CI>CS(C)=O>[Cl:7][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccncc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
Potassium carbonate (36.3 g, 263 mmol) was added to 3-chloroisonicotinic acid (10.35 g, 65.7 mmol) in DMSO (50 mL). After 30 min, MeI (8.22 mL, 131 mmol) was added. The mixture was stirred at room temperature for 2 h, quenched with saturated NH4Cl (300 mL) and water (200 mL), and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine (2×50 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 10-30% ethyl acetate in hexanes, gave methyl 3-chloroisonicotinate as a colorless liquid (6.275 g, 56% yield). MS (ES+) m/z: 172 (M+H); LC retention time: 2.45 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].C.[OH-].[NH4+:11]>>[NH2:11][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCCC=CC(=O)O
Reactant: [NH4+]
Agent: C
Agent: [OH-]
Product: CCCC(N)CC(=O)O
Temperature: 150 °C

Procedure:
A mixture of 2 hexenoic acid (7.0 g, 0.06 mol) and concentrated aqueous ammonium hydroxide (70 ml) is heated for 24 hours in an autoclave at 150° C. The cooled mixture is treated with carbon black and filtered. After evaporation of the solvent the crude product is recrystallized from ethanol to give the title compound m.p. 203° C. (compound 1.21, Table 2). Following an analogous procedure, the compounds 1.8, 1.9, 1.12 and 1.18-1.20 of Table 1 are obtained.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][N:5]=1)=O.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>B(F)(F)F.CCOCC>[NH2:15][C:13]1[S:14][C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([I:22])[CH:24]=3)[N:9]=2)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: CS(=O)c1nccc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: Nc1cccc(I)c1
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(I)c3)n2)s1

Procedure:
A mixture of 5-(2-methylsulfinyl-pyrimidin-4-yl)-4-phenyl-2-amino-thiazole (2.0 g, 6.3 mmol) and m-iodoaniline (7.0 g, 31.6 mmol) is heated at +100° C. After the addition of boron trifluoride diethyl etherate (3 drops) the solution is heated at +150° C. for half an hour. On cooling the product starts to crystallize. The N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-phenyl)-amine after chromatography (eluent: 2:1 mixture of ethyl acetate/hexane) has a m.p. of 243–244° C.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[C:27]([F:35])[CH:26]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.O1CCCC1.Cl>CO.O>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[C:27]([F:35])[CH:26]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium hydroxide, monohydrate (13 mg, 0.31 mmol) was added to a solution of methyl 3′-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate made above (0.030 g, 0.062 mmol) in methanol (0.2 mL)/tetrahydrofuran (0.2 mL)/water (0.09 mL). The reaction was stirred at room temperature for 1.5 h, then treated with conc. HCl (60 uL) to adjust pH to 2, The solvent was removed to provide the crude product which was used in next step without further purification. LCMS calculated for C23H22ClFN5O3 (M+H)+: m/z=470.1; Found: 470.2
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[CH:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:13]3[CH3:28])=[CH:7][N:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>COCCOC>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]3[CH3:28])=[CH:7][N:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC1c2cc(OC)ccc2N(c2cnnc3cc(Cl)ccc23)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: COCCOC
Product: COC(=O)Cc1c(C)n(-c2cnnc3cc(Cl)ccc23)c2ccc(OC)cc12

Procedure:
A solution of methyl 1-(7-chlorocinnolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetate (7.9g.) in dry 1,2-dimethoxyethane [80ml.; dried over sodium alumino-silicate (molecular sieve type 4A; obtainable from BDH Chemicals Ltd., Poole, England)] was mixed with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.5g.) in dry 1,2-dimethoxyethane (30ml.). The solution was heated under reflux for 20 minutes and then evaporated in vacuo. The residue was extracted with chloroform (5 × 50ml.). Evaporation of the extracts gave an oil, which was purified by chromatography on silica gel (350g.), using ether as eluant, to give methyl 1-(7-chlorocinnolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate as a red syrup, homogeneous by thin layer chromatography (ether: silica gel) [hereinafter referred to as system C], and having a satisfactory NMR spectrum (5-OCH3, τ6.13).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([NH:31][CH2:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCCC(=O)OC(C)(C)C)c2nc1OC
Reaction time: 2.5 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and β-alanine tert-butyl ester hydrochloride 153 mg (0.80 mmol). Reaction was continued for 2.5 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 230 mg (68%), mp 140-142° C., Rf 0.47 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3): δ 8.31 (s,1H), 6.37 (br s, 1H), 4.08 (s, 3H), 3.97 (s, 3H), 3.74 (q, 2H, methylene protons, J=6.1 Hz), 2.57 (t, 2H, J=6.3 Hz, J=6.1 Hz), 2.55 (s, 3H), 1.42 (s, 9H); MS (APCI): m/z 421 (M+H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C([O-])(O)=O.[Na+]>Cl>[N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: COCOc1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(-c2ccncc2)cc1
Yield: 78.9 %

Procedure:
A solution of 4-(4-(methoxymethoxy)phenyl)pyridine (240 mg, 1.11 mmol) in aqueous HCl (1N, 2.8 mL) was stirred at rt overnight. The reaction was neutralized with saturated NaHCO3 and the precipitate was collected by filtration to yield the desired compound as a white solid (150 mg). NMR (MeOH-d4): 8.49 (d, 2H), 7.65 (m, 4H), 6.92 (d, 2H).