Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH:5]([N:6]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][S:9][CH3:10]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CCSC)N=Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A suspension of methionine methyl ester hydrochloride (3.8 g, 19 mmol) and freshly distilled benzaldehyde (2 g, 19 mmol) in dichloromethane (60 mL) was cooled to 0° C. and magnetically stirred. A solution of triethylamine (1.92 g, 19 mmol) in solution in dichloromethane (30 mL) was added slowly thereto. The resulting solution was allowed to stand overnight at room temperature, with stirring. After removal of the solvent, the residue was taken up in anhydrous diethyl ether, with the insoluble material being filtered off. The filtrate was washed with water (3×30 mL), brine (2×40 mL), dried over sodium sulfate, and concentrated, to provide a crude material which was purified by distillation (bp 144° C., 4 mm) providing methyl-2-(benzylideneamino)-4-(methylthio)butyrate (3.62 g) at a yield of 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH:13]=[CH:14]3)=[CH:5][CH:4]=1.[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH2:13][CH2:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@H]2CCC[C@H]3C=CCC(=O)N32)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc([C@H]2CCC[C@H]3CCCC(=O)N32)cc1
Yield: 81.5 %

Procedure:
Platinum oxide (2 mg) was added to a solution of (6R*,9aS*)-6-(4-methoxyphenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (28 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for 13 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 23 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[OH:36][CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][C:40]1=[O:46].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:42]3[CH:43]=[CH:44][N:39]([CH2:38][CH2:37][OH:36])[C:40](=[O:46])[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)ccn1CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(CCO)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 26.8 %

Procedure:
A mixture of compounds (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (72 mg 0.150 mmol), 1-(2-hydroxyethyl)-4-iodopyridin-2(1H)-one (48 mg 0.181 mmol), Pd(PPh3)2Cl2 (14 mg, 0.020 mmol), and Cs2CO3 (2 mL) in 1,4-dioxane (8 mL) was stirred at reflux for 2 h. After the reaction was finished, the mixture was washed with water, and extracted with EtOAC. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to get the crude product, which was purified by TLC to provide compound (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (19.7 mg, 28%). LC-MS Method 2 tR=1.065 min, m/z=491.2; 1H NMR (CDCl3): δ1.10 (d, 6H), 1.50 (d, 3H), 2.20 (m, 5H), 2.35 (m, 1H), 3.50 (m, 1H), 3.90 (m, 2H), 4.10 (m, 2H), 5.60 (m, 1H), 6.40 (m, 1H), 6.70 (s, 1H), 6.95 (d, 2H), 7.35 (m, 8H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]#[C:8]Br.[N:10]1([C:19](=[O:34])[CH2:20][C:21]2[NH:26][C:25](=[O:27])[CH:24]=[C:23]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>O1CCOCC1>[N:10]1([C:19](=[O:34])[CH2:20][C:21]2[N:26]([C:8]#[N:7])[C:25](=[O:27])[CH:24]=[C:23]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccccc21
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cn1c(CC(=O)N2CCc3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 40 °C

Procedure:
330 mg of cesium carbonate and 404 mg of cyanogen bromide are successively added to a solution of 1 g of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one (which can be obtained according to example 41d, step 1d) in 40 ml of dioxane with 4 Å molecular sieve. The reaction mixture is heated at 40° C. for 2 hours and then cooled to ambient temperature. The suspension is filtered through sintered glass and then rinsed with dioxane, and the filtrate is concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05). The fractions of interest containing the product are combined and then evaporated under reduced pressure. The residue is taken up with a mixture of 3 ml of methanol and 10 ml of ethyl ether. After stirring and filtration, the precipitate obtained is rinsed with ethyl ether (3×2 ml) and 22 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-4-(morpholin-4-yl)-6-oxopyrimidine-1(6H)-carbonitrile are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:5]([NH2:4])[C:6]1=[O:15]
Reactant: COC(=O)CBr
Reactant: NC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(N)Cc2ccccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
Sodium hydride (60% in oil, 2.52 g, 63.0 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985, 1511–16; 5.0 g, 25.2 mmol), in anhydrous DMF (100 mL) at 0° C. over a period of 5 min keeping the internal temperature at <10° C. The reaction was stirred for a further 30 min before addition of methyl bromoacetate (2.85 mL, 30.2 mmol), then stirred for a further 60 min. The reaction was quenched by addition of 1M aqueous HCl (5 mL) and the volatiles were removed by evaporation. The residue was dissolved in DCM (250 mL) and washed with sat. aqueous NaHCO3 (100 mL) and the organic layer was dried (MgSO4), filtered and evaporated to yield the title compound (5.89 g, 25.2 mmol) as yellow paste which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([C:18]([OH:20])=O)=[C:16]([C:21]#[N:22])[CH:15]=[N:14]1.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([C:18]([Cl:25])=[O:20])=[C:16]([C:21]#[N:22])[CH:15]=[N:14]1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(=O)O
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(=O)Cl
Yield: 58.5 %

Procedure:
A slurry of 12.0 g (0.0343 mole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyano-1H-5-pyrazolylcarboxylic acid in 30 mL (49 g, 0.41 mole) of thionyl chloride was heated at gentle reflux for approximately 62 hours, after which it had become a dark solution. This solution was cooled, and the excess thionyl chloride was evaporated under reduced pressure, leaving a residue. Petroleum ether was added to this residue, causing a precipitate, which, upon filtration, yielded 7.4 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyano-1H-5-pyrazolylcarboxylic acid chloride as a solid, mp 100°-102° C. The NMR spectrum was consistent with the proposed structure. A second crop of tacky crystals was obtained by chilling the filtrate obtained when the product was isolated by filtration. The NMR spectrum of the second crop of crystals was consistent with the proposed structure, but showed also that it was contaminated with some starting material.
Reaction SMILES: [OH:1][C@@H:2]([C:13]([O:26][CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(O)(=O)[CH2:29][OH:30]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:20]1([C:13]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@@H:2]([C:3]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[O:1][C:29](=[O:30])[CH2:27][O:26]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)OCc1ccccc1
Reactant: O=C(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C1COC(c2ccccc2)(c2ccccc2)[C@@H](C(=O)OCc2ccccc2)O1
Yield: 54 %

Procedure:
38 g (100 mmol) of the benzyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate were added to 9.8 g (130 mmol) of glycolic acid, and the mixture was stirred with 300 mg of anhydrous para-toluenesulfonic acid at 70° C. on a rotary evaporator under reduced pressure for 20 minutes. The content of the flask was taken up in dichloromethane, the acid was separated off using sodium hydrogen sulfate solution, the organic phase was separated off and dried and the solvent was distilled off. The residue was recrystallized from ether, and 21 g (54 mmol) of product were isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:17]([O:21][C:22]([N:24]1[CH2:31][CH:30]2[O:32][CH:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:5]=[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH2:3][CH2:2][N:28]1[CH2:27][CH:26]2[O:32][CH:30]([CH2:31][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25]2)[CH2:29]1
Reactant: N#Cc1ccc2c(c1)CCN2C(=O)CCCl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCC(=O)N3CCc4cc(C#N)ccc43)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(3-Chloropropionyl)-2,3-dihydro-1H-indole-5-carbonitrile (3.07 g, 0.031 mol; see step (v) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (3 g, 0.031 mol; see WO 01/28992) and potassium carbonate (6.43 g, 0.0465 mol) were taken in dry acetonitrile (30 mL) and stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to provide a crude product. This product was then purified by column chromatography using methanol in DCM as eluent to yield the sub-title compound as pale yellow solid. Yield: 5 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]2)[CH:3]=1.Cl>CO.C1COCC1.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]2)[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC(O)C3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(O)C3)c12

Procedure:
Methyl 4-(4-fluoro-2-(3-hydroxycyclopentyloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (150 mg) in methanol (2.0 ml), THF (2.0 ml) and 2M aq. sodium hydroxid (0.9 ml) was stirred at reflux for 40 min. After addition of 2 M aq. HCl (8.0 ml) the reaction mixture was concentrated in vacuo. The aqueous layer was filtered and washed with water. The crude was re-evaporated from EtOH to give the desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2].[CH2:19]([OH:21])C>[C].[Pd]>[CH2:1]([N:3]1[C:19](=[O:21])[NH:10][C:9]2[C:4]1=[N:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7][CH:8]=2)[CH3:2]
Reactant: CCO
Reactant: CCNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Product: CCn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-ethylamino-5-nitro-2-phenylpyrimidine (2.7 g), palladium-carbon (0.3 g), and ethanol (50 ml) is stirred at room temperature under hydrogen atmosphere for five hours, and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, and to the resulting residue is added urea (1.4 g). The mixture is stirred at 200° C. for two hours. After cooling, water is added to the reaction mixture, and the precipitates are collected by filtration, washed with water, and washed with ethanol to give the desired compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(Cl)cc1
Solvent: O
Product: O=C1CCCc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 92.1 %

Procedure:
4-(4-Chlorophenyl)butyric acid (26.62 g) was added to 150 g of hot polyphosphoric acid (90° C.); the mixture was maintained at 90°-95° C. for 0.33 hour. After cooling to room temperature, the reaction mixture was added to 400 mL of ice-cold stirred water. The solution was allowed to warm to room temperature; and the resulting precipitate was filtered, washed (water) and air dried to give a pale yellow solid (22.3 g). The solid was recrystallized from toluene (50 mL) at -10° C. The crystals were collected and washed with cold toluene and then hexanes to give the tetralone as pale yellow crystals (18.18 g); mp 100.3°-101.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@H:25]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][C@H:25]3[CH2:30][CH2:29][CH2:28][O:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1O[C@H]1CCCOC1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCOC3)c2c1C

Procedure:
Prepared analogously to example 1.1 from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-4-fluoro-2-(tetrahydro-2H-pyran-3yloxy)aniline (Intermediate XIII).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH2:9][C:8]2[CH2:28][C:18]3[C:23]([C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1=CC(c2ccccc2)c2ccccc21
Agent: C=O
Solvent: Cc1ccccc1
Product: c1ccc(C2=C(CC3=C(c4ccccc4)c4ccccc4C3)Cc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 246.7 %

Procedure:
In a 500 mL flask equipped with magnetic stirring bar were introduced 4.46 g (0.023 moles) of 1-phenyl-indene, 0.35 g (0.0117 moles) of formalin and 0.88 g (0.0046 moles) of para-toluenesulphonic acid in 200 ml of toluene; the mixture was heated to 80° C. and was maintained under stirring for 6 hours at 80° C. Then the reaction was quenched with water/NaHCO3; the organic layer was separated, washed with water and brought to dryness under reduced pressure. The crude product was crystallized upon standing at room temperature, and then was further purified by washing with pentane or MeOH, thus isolating 4.5 g of bis(3-phenyl-2-indenyl)methane (purity of 97.3% by G.C.; yield=95.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>>[Br:20][C:21]1[N:22]=[CH:23][N:24]([C:2]2[N:3]=[C:4]([CH3:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=3)[N:7]=2)[CH:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example A.40) (0.40 g, 1.4 mmol) and commercially available 4-bromo-imidazole (0.31 g, 2.1 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.54 g, 97%). MS (ISP) 399.0 [(M+H)+]; mp 157.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.S(O)(O)(=O)=O.[CH3:18][C@H:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:27][C@@H:19]([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[C@H](N)Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CN[C@@H](C)Cc2ccccc2)cc1OC
Reaction time: 16 h
Yield: 65.7 %

Procedure:
A solution of 3,4-dimethoxybenzaldehyde (1.06 g, 6.4 mmol), (S)-1-methyl-2-phenylethylamine sulfate (1.18 g, 6.4 mmol) and triethylamine (0.89 ml, 6.4 mmol) in 1,2-dichloroethane (50 ml) was stirred at room temperature under argon for 15 min. Sodium triacetoxyborohydride (2.97 g, 14 mmol) was added over 5 min. then stirring was continued for a further 16 h. The reaction mixture was diluted with MDC (50 ml) then washed with saturated aqueous K2CO3. The aqueous phase was extracted with MDC and the combined organics washed with brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0–100% EtOAc-pentane) to afford the title compound as a colourless oil (1.20 g, 67%).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([NH:20][C:21]4[CH:29]=[C:28]5[C:24]([CH:25]=[N:26][NH:27]5)=[CH:23][CH:22]=4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[N:4]([CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:3]1.C=O.[BH3-][C:41]#N.[Na+]>CCO>[CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[NH:20][C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[CH:23][CH:22]=3)=[CH:8][CH:9]=2)[N:4]([CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:41])[CH2:33][CH2:32]2)[CH2:3]1
Reactant: CC1(C)CN(CC2CCNCC2)c2cc(NC(=O)c3cccnc3Nc3ccc4cn[nH]c4c3)ccc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(CN2CC(C)(C)c3ccc(NC(=O)c4cccnc4Nc4ccc5cn[nH]c5c4)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[3,3-Dimethyl-1-(4-piperidylmethyl)indolin-6-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide (140 mg, Example 41) was dissolved in 10 mL EtOH. Formaldehyde (10 mL, 37%) was added, followed by 100 mg of NaCNBH3. The mixture was stirred at RT overnight, and concentrated in vacuo. The crude was extracted between saturated NaHCO3 solution and EtOAc, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a yellow solid. This material was further purified by preparative HPLC to yield a white solid. MS: 510 (M+1). Calc'd. for C30H35N7O—509.6.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[O:19])=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[O:19])=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc(C=CC=CC=O)c2CC1
Agent: O=[Pt]
Solvent: CCO
Product: CN1CCc2c(Cl)ccc(CCCCC=O)c2CC1
Yield: 16.4 %

Procedure:
A solution of 5-(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)-2,4-pentadienal (3 g) in ethanol (100 ml) and platinum oxide was shaken under hydrogen (50 psi) for 2 hours, filtered, concentrated and the residue chromatographed on silica gel eluted with a gradient of methanol-methylene chloride (3:97°-7:93) to give 0.5 g of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-pentanal.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10](#[N:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:12][CH2:11][C:10]#[N:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=CC#N
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCC#N
Yield: 84.1 %

Procedure:
150 g (1 mol) of butyl ethylphosphonite (produced as in Example 2) and 64 g (1.2 mol) of acrylonitrile in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% solution of Wako V65 in toluene are added by metered addition. The solvent is distilled off in vacuo to leave 171 g (84% of theory) of butyl ethyl(2-cyanoethyl)phosphinate.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>C(O)C.O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Cl)c1
Reactant: C=O
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)c(Cl)c1

Procedure:
2-Phenylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (34.0g) was dissolved in ethanol (300 ml) and paraformaldehyde (6.0g) in water (600 ml) added. The mixture was refluxed 4 hours, cooled and worked up as in Example 2(c) to yield 20 g m.p. 206°
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>C(OCC)(=O)C.CCCCCC>[F:30][C:31]1[CH:32]=[C:33]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])[CH:34]=[CH:35][CH:36]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(F)c1)OCC2c1ccc(C(C)C)cc1
Yield: 67 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-fluorophenyl)boronic acid, the title compound was synthesized in the same manner as in Example 107. Yield: 67%. Melting point: 182-183° C. (ethyl acetate-hexane).