Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:23]4[C@@H:19]([O:20]C(C)(C)[O:22]4)[C@H:18]([O:26]C)[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.FC(F)(F)C(O)=O>O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:23]([OH:22])[C@@H:19]([OH:20])[CH:18]([OH:26])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: CO[C@@H]1O[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)[C@H]2OC(C)(C)O[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3OC(O)[C@H](O)[C@@H]3O)c21
Temperature: 80 °C

Procedure:
To a suspension of 4-Amino-5-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (Example 265b) (15 mg, 0.038 mmol) in water (1 mL) was added trifluoroacetic acid (0.2 mL) and the mixture was heated overnight at 80° C. The reaction mixture was evaporated to dryness to furnish the title compound as a white solid in quantitative yield (mixture of diastereomers ˜10/1). 1H NMR (400 MHz, DMSO-d6): δ 3.71 (m, 4H), 4.12 (m, 3H), 4.35 (m, 1H), 5.02 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 8.03 (br s, 1H), 8.31 (br s, 1H), 10.96 (br s, 1H), [11.00 (br s, 0.1H)].
Reaction SMILES: OS(O)(=O)=O.[C:6]([NH:9][C@@H:10]([CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[O:34])=[O:17])[C:11]([OH:13])=[O:12])(=[O:8])[CH3:7].O.[CH3:46]O>>[C:6]([NH:9][C@H:10]([C:11]([O:13][CH3:46])=[O:12])[CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)=[O:34])=[O:17])(=[O:8])[CH3:7]
Reactant: CO
Reactant: COc1ccc(COC(=O)c2cc(-c3ccc(F)cc3F)ccc2OC(=O)SC[C@H](NC(C)=O)C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](CSC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCc1ccc(OC)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
H2SO4 (0.04 mL, 0.750 mmol) was added to a solution of (R)-2-acetamido-3-((2′,4′-difluoro-3-((4-methoxybenzyloxy)carbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid (160 mg, 0.286 mmol) in MeOH (25 mL). The reaction mixture was stirred at r.t. for 2 days, poured into H2O (100 mL) and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (5→80% EtOAc/hexanes) to furnish (R)-4-methoxybenzyl 4-((2-acetamido-3-methoxy-3-oxopropylthio)carbonyloxy)-2′,4′-difluorobiphenyl-3-carboxylate (white solid, yield: 30%).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1)([OH:4])=[O:3]>O>[ClH:1].[C:2]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])[CH2:9][CH2:10]1)([OH:4])=[O:3]
Reactant: O=C(O)c1ccc(N2CCN(c3ccc(C4CCNCC4)cc3)C2=O)cc1
Agent: Cl
Solvent: O
Product: O=C1N(c2ccc(C3CCNCC3)cc2)CCN1[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
1-(4-carboxyphenyl)-3-[4-(4-piperidinyl)phenyl]imidazolidin-2-one-hydrochloride×H2O
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[CH2:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cn1nc(C#CCCCc2ccccc2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (86 mg, 60%); 1H NMR δ (CDCl3): 7.31-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.64 (s, 1H), 3.98 (s, 3H), 2.78 (t, J=7.44 Hz, 2H), 2.42 (t, J=7.04 Hz, 2H), 1.95 (p, J=7.33 Hz, 2H); LCMS m/z: 292.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:41](=[O:42])[N:18]3[CH:19]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH:20]([CH:23]=O)[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C.O>[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:41](=[O:42])[N:18]3[CH:19]([C:25]([O:27][CH:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:26])[C:20](=[CH:23][O:3][C:1](=[O:4])[CH3:2])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: O=CC1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
Sodium acetate (0.23 g.) was added to a solution of diphenylmethyl 7-(2-phenylacetamido)-3-formylcepham-4-carboxylate (0.5 g.) in acetic anhydride (2 ml.), and stirred at 50° C. for 1.5 hours. The resultant solution was added to ethyl acetate (60 ml.) and water (50 ml.) and adjusted to pH 7.2 with sodium bicarbonate. The organic layer was separated, washed with aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was evaporated in vacuo to give diphenylmethyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (0.4 g.).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[N:20]1[CH:19]=[CH:24][C:23]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:22][CH:21]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Clc1ccncn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccncn1)\c1ccccc1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 4-chloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]>C(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (61.1 mg, 0.223 mmol) in CH2Cl2 (2 mL) was added 3,4-difluorophenyl isocyanate (0.30 μL, 0.256 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 136 as a colorless solid (53.3 mg, 56%). LCMS m/z (%)=430 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (bs, 1H), 8.72 (bs, 1H), 7.71-7.61 (m, 1H), 7.49-7.42 (m, 2H), 7.37 (d, J=2.68 Hz, 1H), 7.35-7.28 (m, 1H), 7.14-7.06 (m, 1H), 7.09 (d, J=8.96 Hz, 1H), 6.23 (d, J=1.82 Hz, 1H), 3.97 (t, J=6.37 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH2:8]([NH:12][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: CCCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Butylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-butylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:20][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Product: CCN(CC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16 %

Procedure:
125 ml of this crude solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were treated with 11.3 ml (0.109 mol) of diethylamine and stirred at room temperature for 20 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over silica gel with ethyl acetate/methanol 17:3 as the eluent and recrystallized from hot ethyl acetate. There was obtained 0.75 g (16%) of 3-(5-diethylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as light beige crystals; m.p. 182-184°. A further 0.39 g of yellowish crystals was obtained from the mother liquor.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][S:6]([O-:9])(=O)=[O:7])=[O:4].[Na+].P(Cl)(Cl)([Cl:13])=O>>[CH3:1][O:2][C:3]([CH2:5][S:6]([Cl:13])(=[O:9])=[O:7])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CS(=O)(=O)[O-]
Agent: [Na+]
Product: COC(=O)CS(=O)(=O)Cl
Yield: 65.7 %

Procedure:
The sodium methoxycarbonylmethylsulfonate salt was added in small portions to a stirred solution of 840 ml (9.14 mols) phosphorus oxychloride. The resulting mixture was then heated at 80°-100° C for about 5 hours and allowed to cool overnight. The reaction mixture was filtered, the filtered solid was washed with dichloromethane and the filtrate distilled under reduced pressure to remove the dichloromethane and excess phosphorus oxychloride. The resulting oil residue was distilled through a short Vigreaux column to give 226.8 g (65.7% yield) of methoxycarbonylmethylsulfonyl chloride, as a yellow oil, b.p. 79°-80° C. (0.5 mm Hg).
Reaction SMILES: [Br:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH:3]1Br.N12CCCC1=NCCC2.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH:3]=1
Reactant: NC(=O)N1c2ccccc2C(Br)C(Br)c2ccccc21
Agent: C1CN=C2CCCN2C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)N1c2ccccc2C=C(Br)c2ccccc21
Reaction time: 2 h

Procedure:
With cooling at 5°-10° C, 12 g (app. 0.03 mole) of the crude 10,11-dibromo-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide obtained according to (a) are suspended in 35 ml of dimethyl formamide. With stirring, 10 g (app. 0.08 mole) of 1,5-diazabicyclo[4.3.0]non-5-ene are added dropwise at 5°-10° C. Stirring is continued for 2 hours at 25° C and a new precipitate forms. The reaction mixture is then heated for 10 minutes to 90°-100° C and, after it has cooled, poured onto a mixture of water and ice and the organic phase is dissolved in ethyl acetate. The aqueous phase is then separated and the organic phase is washed with water, dried over calcium chloride and evaporated in a water jet vacuum. The residue is crystallised from 30 ml of acetonitrile to yield light green 10-bromo-5-H-dibenz[b,f]azepine-5-carboxamide of m.p. 168°-170° C.
Reaction SMILES: [C:1]([Cl:7])(=[O:6])[O:2][CH:3]([CH3:5])[CH3:4].[N:8]1[CH:13]=CC=[CH:10][CH:9]=1.C(OCC)(=[O:16])C>>[ClH:7].[C:1](=[O:6])([O:16][CH2:10][CH2:9][NH:8][CH3:13])[O:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOC(C)=O
Reactant: c1ccncc1
Product: CNCCOC(=O)OC(C)C
Product: Cl

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (3.50 g) obtained in Reference Example 1 and ethyl acetate (20 mL) were added isopropyl chlorocarbonate (1.35 g) and pyridine (1.94 mL) under ice-cooling. After stirring under ice-cooling for 3.5 hrs., isopropyl chlorocarbonate (1.84 g) was added, and the mixture was stirred at room temperature for 2.5 hrs. Ethyl acetate (120 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hrs., the precipitated solid was collected by filtration. The solid was washed with ethyl acetate (15 mL), and dried under reduced pressure at 60° C. to give the title compound (1.38 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([OH:11])[CH:3]=1.Cl[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=[O:15].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([CH3:9])=[C:13]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[O:15])[O:11][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Temperature: 90 °C
Reaction time: 38 h
Yield: 44.1 %

Procedure:
To a stirred solution of 1-(4-Bromo-2-hydroxy-phenyl)-ethanone (2.81 g, 13.1 mmol, from step 1) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (6.88 g, 30.8 mmol, 2.3 eq) in anhydrous N,N-dimethylformamide (50 mL) was added K2CO3 (7.42 g, 53.7 mmol, 4.0 eq). The dark brown reaction mixture was stirred at 90° C. for 38 h. The reaction was poured into ethyl acetate (100 mL) and water (100 mL) after cooled down to rt. Extracted with ethyl acetate (3×50 mL). The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The crude product was washed by hexane (2×30 mL) followed by ethyl ether (2×30 mL) to provide 2.22 g (44%) of the desired compound as light yellow solid. 1H-NMR (CDCl3) δ 7.64 (d, J=1.9 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 7.45-7.36 (m, 3H), 2.57 (s, 3H); MS LC-MS (MH+=385).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH2:32]([O:34][C:35](=[O:40])[C:36](Br)([CH3:38])[CH3:37])[CH3:33]>CCCCCCC.C(OCC)(=O)C>[CH2:32]([O:34][C:35](=[O:40])[C:36]([O:30][C:26]1[CH:25]=[C:24]([Cl:31])[C:23]([O:22][C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][CH2:6]2)=[O:15])=[CH:28][C:27]=1[Cl:29])([CH3:38])[CH3:37])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)C(C)(C)Oc1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 58, from (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) and 2-bromo-2-methyl-propionic acid ethyl ester (commercially available, CAS RN 600-00-0) after a reaction time of 23 hours at room temperature and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light brown foam (30%). MS (ESI): m/z=570.156 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-furan-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G7) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a beige powder (271 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 124 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1.[ClH:33].CCOCC>O1CCOCC1>[ClH:33].[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[O:23][CH2:22][CH2:21][NH:20][CH2:19]4)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc3c(NC(=O)c4ccc(F)cc4)n[nH]c3c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Nc1n[nH]c2cc(C3CNCCO3)ccc12)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Tert-butyl 2-(3-(4-fluorobenzamido)-1H-indazol-6-yl)morpholine-4-carboxylate (40 mg, 0.09 mmol) was dissolved in dioxane (0.2 ml) and a solution of HCl in dioxane (4M, 0.34 ml, 1.36 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. After cooling ether (2 ml) was added, the mixture was stirred for 30 min and the solid was filtered off. It was washed with ether and dried in vacuo to afford 4-fluoro-N-(6-(morpholin-2-yl)-1H-indazol-3-yl)benzamide hydrochloride (22 mg, 66%) as an off-white solid. MS (ISP): 341.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]1([C:24]2([C:30]#[N:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:30]([C:24]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26][N:27]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:28][CH2:29]1)#[N:31]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCC(C#N)(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-piperidine-4-carbonitrile in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-(4-cyano-4-phenyl-piperidin-1-yl)-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=408.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:39]=[CH:38][N:37]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C(C)C)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(C)C)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 41 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 3.5 days at 35° C., from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(propane-2-sulfonyl)-piperazin-1-yl]-methanone (example 15) and 2-chloropyridine-4-boronic acid to afford the desired product as a light-brown foam (41%). MS (ISP): 601.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:15]1([O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[O:13][CH3:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC2CCCC2)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-hydroxy-3-methoxybenzoate (7.17 g), cyclopentyl bromide (4.7 ml) and potassium carbonate (7.6 g) in N,N-dimethylformamide (70 ml) was stirred at 80° C. for 3 hours. Then the mixture was poured into water and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 4:1) to give ethyl 4-cyclopentyloxy-3-methoxybenzoate (8.58 g) as an oil.