Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[O:10][C:11](=[O:28])[C:12]([O:26][CH3:27])([CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:1]([NH:8][C:22]([CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12]([O:26][CH3:27])([CH3:25])[C:11]([OH:28])=[O:10])=[CH:19][CH:18]=1)=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: COC(=O)C(C)(Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCCCCNC(=O)COc1ccc(CC(C)(OC)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethoxy-phenyl)-2-methoxy-2-methyl-propionic acid methyl ester heptyl amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][C:6]([CH3:10])=[N:5]1)[CH:2]=[CH2:3].[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(O)(C)C>[CH2:1]([N:4]1[C:8]([OH:9])=[C:7]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=2[Cl:14])[C:6]([CH3:10])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1N=C(C)CC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: C=CCn1nc(C)c(C(=O)c2ccc(Cl)cc2Cl)c1O
Reaction time: 1.5 h
Yield: 40.7 %

Procedure:
A suspension of 1.4 g. of 1-allyl-3-methyl-2-pyrazolin-5-one and 0.74 g. of calcium hydroxide in 20 ml. of isopropanol is heated under reflux with stirring for 1.5 hours. After cooling, to the resulting mixture is added dropwise 2.3 g. of 2,4-dichlorobenzoyl chloride. After completion of the dropwise addition, the resulting mixture is heated under reflux for 5.5 hours. After completion of the reaction, the solvent is distilled off from the reaction mixture and to the residue is added 3 ml. of 2 N hydrochloric acid to adjust pH to 3.0. Then, the mixture is extracted with chloroform and the extract solvent is distilled off from the extract. The residue is dissolved in a small amount of benzene and the solution is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off. The resulting residue is recrystallized from isopropyl ether containing a small amount of methylene chloride to give 1.18 g. of the desired product as white crystals melting at 161°-163° C. Yield 40.7%.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Li].Cl[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32])(=[O:22])=[O:21]>C1COCC1.[Cl-].[Na+].O>[F:32][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:23]=1[S:20]([NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1)(=[O:22])=[O:21])[C:27]([OH:29])=[O:28]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)c(F)c1
Agent: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)c(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 26, 500 mg, 2.1 mmol, 1.0 eq) was dissolved in THF (10 ml) and cooled to −78° C. 1,1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 4.2 ml, 4.19 mmol, 2.0 eq) was added dropwise and the reaction mixture stirred for a further 10 minutes. A solution of 4-(chlorosulfonyl)-3-fluorobenzoic acid (Preparation 9, 500 mg, 2.1 mmol, 1 eq) in THF (3 ml) was added dropwise and the reaction mixture stirred at −78° C. for 1 hour then at room temperature for 18 hours. The reaction mixture was diluted with brine, extracted into ethyl acetate, dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was passed through a SCX cartridge to remove remaining amine. The material was redissolved in 4M HCl in dioxane and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with diethylether to yield the title compound (100 mg, 0.33 mmol, 16%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH:8]=O.Cl.[CH3:17][C:18]([CH3:20])=[O:19]>C(O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:17][C:18](=[O:19])[CH3:20])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15]
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C=CC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
10% sodium hydroxide aqueous (40 ml) was added under stirring to a solution of 3-methoxy-4-ethoxybenzaldehyde (9.09 g, 50 mmol) in acetone (25 ml), 95% ethanol (25 ml) and water (200 ml). The reaction mixture was stirred for 24 hr at room temperature, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7.0. The precipitated solid was collected by filtrating and washed with water and ethanol successively, dried, and then recrystallized from 95% ethanol to give 7.38 g of a pale yellow solid, mp: 95-97° C., yield: 66.5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:33]([C:37]1[N:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:40]=[C:39]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:38]=1)([CH3:36])([CH3:35])[CH3:34].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12]([N:46]1[CH2:47][CH2:48][N:43]([C:41]2[CH:40]=[C:39]([CH:49]3[CH2:52][CH2:51][CH2:50]3)[N:38]=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:42]=2)[CH2:44][CH2:45]1)=[O:14])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCCC(=O)N1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
6 g of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (27.6 mmol) and 5.53 g of triethylamine (54.6 mmol) were dissolved in 100 ml of dimethylformamide. 4.1 g of hydroxybenzotriazole (HOBt, 30.35 mmol), 7.6 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (27.7 mmol), and 5.8 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodimide hydrochloride (EDCl, 30.26 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane. Fractions containing the product were combined and the solvent evaporated to yield 13.1 g of the title compound.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][SiH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][SiH:13]([Br:1])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(C2CC[SiH2]CC2)cc1
Reactant: BrBr
Solvent: ClCCl
Product: Fc1ccc(C2CC[SiH](Br)CC2)cc1

Procedure:
Subsequently, 11.8 g of bromine was added to a solution of 14.0 g of 4-(p-fluorophenyl)-1-silacyclohexane in 100 ml of dichloromethane to obtain 4-(p-fluorophenyl)-1-bromo-1-silacyclohexane. The reaction solution was concentrated and the resultant residue was dissolved in 50 ml of diethyl ether, followed by dropping in 100 ml of a THF solution of 1 mole/liter of n-heptylmagnesium bromide at room temperature. The reaction mixture was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The resultant ethyl acetate solution was washed with brine, dried and concentrated, followed by purification through silica gel chromatography to obtain 19.0 g (yield: 90%) of the intended product. The results of IR and NMR analyses are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[S:26])=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(COc2ccc(C#N)cc2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To the solution of 4-(p-methoxybenzyl)oxybenzonitrile (7.18 g) in pyridine (100 ml) was added triethylamine (20 ml), and hydrogen sulfide gas was streamed 30 minutes. The mixture was stirred at room temperature for 3 hours followed by 50° C. overnight. After the solvent was evaporated under reduced pressure, the residue was taken into ether, and crystals were collected by filtration and dried to give 8.05 g of 4-(p-methoxybenzyl)oxythiobenzamide (yield, 98%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:28]2
Reactant: OCc1cccc2c1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3cccc(CO)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 58.5 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 250 mg of the target compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](/[C:10](=[CH:16]/[N:17]([CH3:19])C)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.[NH2:21][CH2:22][CH2:23]C#N>C(O)C.C(OCC)C>[Cl:20][C:4]1[N:3]=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[CH2:19][CH2:23][C:22]#[N:21])=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccc(Cl)nc1Cl
Reactant: N#CCCN
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cn(CCC#N)c2nc(Cl)ccc2c1=O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 81A (20 g) and 3-aminopropionitrile (4.9 mL) in 1:1 ethanol/diethyl ether (400 mL) was stirred for 15 minutes, diluted with hexanes (1 L), and filtered. The filtrant was dissolved in acetonitrile (400 mL), and the resulting solution was treated with potassium carbonate (17.4 g), heated at 75° C. for 18 hours then cooled, diluted with water (1.5 L), stirred for 1 hour, and filtered.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[C:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>O>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2
Reactant: COCCO
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1c2ccccc2c(C=O)c2ccccc12
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of KOtBu (MCB, 18.2 g, 0.162 mol)) in 2-methoxyethanol (1 L) was treated with 10-chloro-9-anthraldehyde (Aldrich, 25 g, 0.104 mol) and refluxed for 2 h. The cooled reaction mixture was diluted with H2O (5 L), and the resulting oil stirred for 2 h until solidification occurred. The filtered solid was chromatographed on a plug of SiO2 (500 g) using CH2Cl2 as the eluting solvent to afford 26.9 g (92%) of 10-(2-methoxyethoxy)-9-anthracenecarboxaldehyde mp 87°-88°, (C, H), (CH2Cl2 /hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: COc1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccccc2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[(2-methoxy-4-phenylphenyl)methyl]piperazine-1-carboxylate (850 mg, 2.22 mmol, 1.00 equiv), dichloromethane (15 mL), trifluoroacetic acid (1.50 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to provide 600 mg (crude) of 1-[(2-methoxy-4-phenylphenyl)methyl]piperazine as yellow oil. LCMS (ESI, m/z): 283 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]3)=[N:16][CH:15]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCC(O)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C
Reaction time: 1.6 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (2.5 mL) was added 3-pyrrolidinol (0.029 mL, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 120° C. and stirring continued for 1.6 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)pyrrolidin-3-ol as a yellow solid. Mass Spectrum (ESI) m/e=376.1 (M+1).
Reaction SMILES: FC1C=C(C2C=C(F)C=CC=2OC)C=CC=1C(N[S:11]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][N:17]([CH3:19])[CH:18]=1)(=[O:13])=[O:12])C.[Cl:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][C:45]([C@H:48]([NH2:50])[CH3:49])=[C:44]([O:51][CH3:52])[CH:43]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1>>[Cl:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][C:45]([C@H:48]([NH:50][S:11]([C:14]3[C:15]([C:20]([F:23])([F:21])[F:22])=[N:16][N:17]([CH3:19])[CH:18]=3)(=[O:13])=[O:12])[CH3:49])=[C:44]([O:51][CH3:52])[CH:43]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1
Reactant: COc1cc(-c2cc(Cl)cnc2OC)ccc1[C@@H](C)N
Reactant: COc1ccc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)c(F)c1
Product: COc1cc(-c2cc(Cl)cnc2OC)ccc1[C@@H](C)NS(=O)(=O)c1cn(C)nc1C(F)(F)F

Procedure:
A mixture of 4-bromo-2-hydroxyacetophenone (0.460 g, 2.0 mmol), titanium tetraethoxide (1.0 g, 4.0 mmol) and (R)-2-methyl-2-propanesulfinamide (0.266 g, 2.2 mmol) in dichloromethane (3.0 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was cooled in ice and added to a stirred mixture of sodium borohydride (0.30 g, 8.0 mmol) in tetrahydrofuran (50 ml). This mixture was stirred for 1 h at ambient temperature, treated with brine (30 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated The residue was flash chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide. A mixture of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide (0.130 g, 0.4 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid (0.150 g, 0.8 mmol), tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.02 mmol), 2M aqueous sodium carbonate solution (2 ml), toluene (1 ml) and ethanol (1 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent evaporated and the residue dissolved in methanol. This solution was treated with 2M hydrogen chloride in diethyl ether solution. After standing for 2 hours, the mixture was poured onto an SCX column, washed with methanol and then eluted with 1M ammonia in methanol solution. The solvent was evaporated and the residue flash chromatographed on silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol to give (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine. The title compound was prepared in a similar manner to 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 30) using (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine instead of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. MS (ESI) m/z: 505.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.[Cl:25][C:26]1[N:31]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][N:27]=1.N#N>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:26]1[N:31]=[C:30]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=3)[N:14]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1ccnc(Cl)n1)nn2C1CCCCO1
Temperature: 90 °C
Yield: 52.1 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 14 (0.2 g, 0.45 mmol) and 2-Chloro-4-tributylstannanyl-pyrimidine 20a (0.27 g, 0.68 mmol) in DMF was bubbled N2 for 15 min and added CuI (0.052 g, 0.54 mmol) and Pd(PPh3)4 (0.1 g, 0.025 mmol). The reaction mixture was heated at 90° C. for 2 h and cooled to RT. The reaction mixture was quenched with water and precipitate was formed. The resulting precipitate was collected by filtration, washed with water, and dried to yield crude product. Purification by silica gel column chromatography, eluting with 5-10% EtOAc and hexanes to obtain the title compound (0.1 g, 38%). MS (ESI, pos. ion) m/z: 427.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].[Cl:22]Cl.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:18])([CH3:19])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:20][CH3:21])[Cl:22]
Reactant: CCC1Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: ClCl
Solvent: O
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
2-(1-Oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-2-methylpropionic acid (4.7 g., 0.0014 mole) is dissolved in warm acetic acid (170 ml.) and treated with a solution of chlorine (1.06 g., 0.015 mole) in acetic acid (20 ml.) at 20° C. with stirring. The reaction mixture is kept at 20° C. for one hour and then at 80°0 C. for one hour. The reaction mixture is cooled and added to water (1 1.) with stirring. The white powder that separates is recrystallized from acetic acid-water (4:3) to obtain 3.0 g. of 2-(1-oxo-2-ethyl-2,67-trichloro-5-indanyloxy)-2-methylpropionic acid, m.p. 164.5°-165° C.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[S:8][C:9]([CH3:23])=[C:10]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:11]=1)=[O:6].Cl>CO.O>[CH3:23][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][C:10]=1[NH:12][C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)c1cc(NC(=O)NCc2ccccc2)c(C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1sc(C(=O)O)cc1NC(=O)NCc1ccccc1

Procedure:
A 2N aqueous potassium hydroxide solution (16 mL) was added to a stirred solution of 5-methyl-4-(3-benzyl-ureido)-thiophene-2-carboxylic acid methyl ester from Step 2 of Example 16 below (0.4 g, 1.3 mmol) in warm methanol (4 mL), and the mixture was heated under reflux. After 1 hour the mixture was cooled, diluted with water (100 mL), and acidified with aqueous HCl. The precipitate was filtered off, rinsed with water, then ethanol, then ether, and dried to afford 0.29 g of 5-methyl-4-(3-benzyl-ureido)-thiophene-2-carboxylic acid; mp 259-260° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:10][NH:11][CH2:12][CH2:13][NH:14][CH3:15]>C1C=CC=CC=1>[CH3:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:15])[CH:7]1[C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CNCCNC
Solvent: c1ccccc1
Product: Cc1ccc(C2N(C)CCN2C)cc1

Procedure:
Using the method of Birch and Dastur, Austral. J. Chem., 26, 1364 (1973), a solution of 48 g of p-tolualdehyde in 185 ml of benzene was added dropwise to a stirred solution of 25 g of sym-dimethylethylenediamine in 95 ml of benzene, and heated at 60° for 2 hrs. Evaporation and distillation at 52° (0.1 mm) afforded 48 g, identified by nmr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=O)[NH:32][CH:33]=2)=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:26][C@H:24]1[NH:25][C@@H:20]([CH3:19])[CH2:21][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:32][CH:33]=2)=[O:28])[CH2:23]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (74 mg, 63%).