Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH2:12]1.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:12]2[C:13](=[O:21])[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:11]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C1COc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C=C2Oc3ccccc3NC2=O)cc1
Reaction time: 8 h

Procedure:
4-Cyanobenzaldehyde (1.98 g, 0.015 mol) was added to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0.01 mol), acetic anhydride (4 ml) and triethylamine (2 ml). The reaction mixture was refluxed for 7 h, left overnight at room temperature and poured into crushed ice. The precipitated solid was collected by filtration and washed with acetonitrile. The crude product was purified by recrystalization from DMF:ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:10]2[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Cl)c1
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2cccc(Cl)c2)c1

Procedure:
Following the procedure of Example 11, except for use of two 50 ml. quantities of dimethylformamide, 3-chlorothiophenol (4.52 g., 31.4 mmoles) was reacted with 5-bromofuran-3-carboxylic acid to yield crude product (1.9 g.). Recrystallization from hot hexane gave purified 5-(3-chlorophenylthio)furan-3-carboxylic acid (1.0 g., m.p. 98°-102° C., m/e 254).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[N:10]2[S:40]([CH3:39])(=[O:42])=[O:41])=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(S(C)(=O)=O)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (260 mg, 500 μmol) was initially charged in dry THF (10 ml), and sodium hydride (60% in mineral oil; 28 mg, 700 μmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (80 mg, 700 μmol; 1.4 eq.) in THF (2 ml) was then slowly added dropwise. After a reaction time of 20 h, the reaction mixture was concentrated and the residue was subjected to flash chromatograpy on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 55:45). The title compound was obtained as a colorless solid (288 mg, 96% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:35]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]([CH:40]([CH:37]2[CH2:38][CH2:39][C@H:35]([N:34]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36]2)[OH:41])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Reactant: O=CC1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A round-bottomed flask was charged with 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.5 g, 8.05 mmol, Adesis) in THF (161 mL) to give a colorless solution. The solution was cooled to about −78° C. and n-BuLi (1.6 M in hexanes, 6.54 mL, 10.46 mmol) was added drop-wise over about 15 min. After addition of the n-BuLi solution was complete, (35)-3-(dibenzylamino)cyclopentanecarbaldehyde (2.48 g, 8.45 mmol) in THF (10 mL) was added drop-wise over about 5 min. The reaction mixture was stirred for about 4 h at about −78° C. Saturated aqueous NH4Cl (40 mL) was added slowly and the mixture was stirred for about 5 min. The organic solvent was removed under reduced pressure and EtOAc (100 mL) was added. The layers were separated and the organic layer was washed with brine (3×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil that was purified by silica gel chromatography eluting with a gradient of 5-10% EtOAc in heptane. The product containing fractions were combined and concentrated to give (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanol (3.5 g, 72%): LC/MS (Table 2, Method n) Rt=2.97 min; MS m/z: 603 (M+H)+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[N+:14]([O-])=O>[Ni].C1C=CC=CC=1>[CH2:12]1[O:13][C:8]2[CH:7]=[C:6]3[C:5]([CH:4]=[CH:3][NH:14]3)=[CH:10][C:9]=2[O:11]1
Reactant: CN(C)/C=C/c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Ni]
Solvent: c1ccccc1
Product: c1cc2cc3c(cc2[nH]1)OCO3
Yield: 50 %

Procedure:
A solution containing 11.83 g. of trans-β-dimethylamino-4,5 -methylenedioxy-2-nitrostyrene in 250 ml. of benzene was shaken with 1 teaspoonful of Raney nickel under an initial hydrogen pressure of 3.5 atm. until hydrogen absorption ceased. The catalyst was removed by filtration and washed several times with benzene. The filtrate and washings were washed with 1M sulfuric acid (2 × 100 ml.), 100 ml. of water, and 100 ml. of 10% sodium bicarbonate. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 5.52 g. of a brown solid. A solution of the residue in benzene was percolated through a column of alumina. The eluate, after evaporation of the solvent, was sublimed at 110°/0.2 mm. to give 5.2 g. of a white solid which, upon crystallization from methylene chloride-hexane, yielded 4.50 g (50%) of 5,6-methylenedioxyindole as white needles having a melting point of 109.5°-110.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14](F)[C:13]([F:17])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[SH:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([S:22][C:23]3[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)[C:13]([F:17])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cn1)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: Cn1ccnc1S
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1ccnc1Sc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])cc1F
Temperature: 130 °C
Yield: 71.7 %

Procedure:
A mixture of N-(5-bromo-pyridin-2-yl)-4,5-difluoro-2-nitro-benzamide (236 mg, 0.66 mmol), 2-mercapto-1-methylimidazole (83 mg, 0.73 mmol) and triethylamine (0.18 mL, 1.32 mmol) in 2 mL CH3CN was microwave heated to 130° C. for 10 min and the resulting solid was collected by filtration, rinsed with CH3CN, and dried under high vacuum to provide 214 mg (72%) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 3.70 (s, 3H), 6.91 (d, 1H, J=7 Hz), 7.20 (d, 1H, J=1 Hz), 7.58 (d, 1H, J=1 Hz), 8.07 (br s, 2H), 8.24 (d, 1H, J=10 Hz), 8.47 (br s, 1H), 11.39 (s, 1H); LCMS (m/z): 452/454 [C16H11BrFN5O3S+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cu][C:16]#[N:17]>CN(C=O)C.O.CCOC(C)=O>[OH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[CH:3][C:2]([C:16]#[N:17])=[CH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: N#C[Cu]
Reactant: OC1CCN(c2ncc(Br)cn2)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N2CCC(O)CC2)nc1
Temperature: 140 °C

Procedure:
A mixture of 1-(5-bromopyrimidin-2-yl)piperidin-4-ol (5 g, 19.37 mmol) and copper(I) cyanide (6.94 g, 77 mmol) in DMF (48.4 mL) was heated at 140° C. for 18 h. The mixture was diluted with water (100 mL) and EtOAc (50 mL) and filtered through celite. The filtrate was extracted with EtOAc (3×20 mL). The combined organic fractions were washed with 1N HCl (20 mL) then dried over Na2SO4. The solvent was evaporated and the product was recrystallized from CH2Cl2/hexanes, filtered and washed with hexanes to afford the title compound.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:12]=[C:11]([C:13](=[O:17])[CH:14]=[N+]=[N-])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CCOCC>[Br:1][CH2:14][C:13]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([Cl:2])[CH:12]=1)=[O:17]
Reactant: COC(=O)c1ccc(C(=O)C=[N+]=[N-])cc1Cl
Reactant: Br
Solvent: CCOCC
Product: COC(=O)c1ccc(C(=O)CBr)cc1Cl
Yield: 79 %

Procedure:
Hydrogen bromide gas was bubbled through a suspension of 2-chloro-4-(diazoacetyl)benzoic acid, methyl ester (400 mg, 1.7 mmol) in ether (30 mL) for 10 min. The solvent was evaporated and the residue was triturated with ether/hexane and filtered to give 4-(bromoacetyl)-2-chlorobenzoic acid, methyl ester (385 mg, 79%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.Br[C:28]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:29]=1[C:30]([O:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:31].C([O-])(=O)C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.O>[NH2:26][C:8]1[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:28]3[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:29]=3[C:30]([O:32][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[O:31])[CH:14]=2)[N:9]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(C(=O)OC2CCCC2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)OC2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 145 °C

Procedure:
3-Morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.15 g, 0.422 mmol, prepared as Example 2, Step 1-2), cyclopentyl 2-bromo-3-methylbenzoate (0.133 g, 0.470 mmol), potassium acetate (0.079 mL, 1.267 mmol), 2-dicyclohexylphosphino-2′,4′,6′,-triisopropylbiphenyl (0.020 g, 0.042 mmol), palladium(II) acetate (4.74 mg, 0.021 mmol), water (0.3 mL) and ethanol (2 mL) were combined in a microwave vial and heated to 145° C. for 30 min. The crude material was partitioned between water (40 mL) and DCM (50 mL). The organic layer was dried on magnesium sulfate, filtered and concentrated. The crude material was purified by silica chromatography (0-10% methanol in DCM gradient) to give cyclopentyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzoate. MS (ESI, pos. ion) m/z: 432 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]1[C:25](O)=[O:26])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]1[CH2:25][OH:26])=[O:15])[CH:28]([CH3:30])[CH3:29])[CH3:31])[CH3:32])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2CC1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2CC1CO
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
To a stirred solution of 1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionyl amino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 1) (3.8 g, 8.48 mmol) in THF (65 mL) were added N-methylmorpholine (1.11 mL, 10.17 mmol) followed by the addition of isobutyl chloroformate (1.32 mL, 10.17 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 10 min and the white precipitate of N-methylmorpholine hydrochloride salt was removed by filtration. The filtrate was cooled to −20° C., NaBH4 (483 mg, 12.72 mmol) was added followed by cold water (30 mL) at −20° C. After 30 min the reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (80 mL×2). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 28% EtOAc in hexanes) to give {(S)-1-[(S)-1-(2-hydroxymethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (2.7 g), m/z=435 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][C@H:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:34].[H-].[Na+]>CN(C=O)C.[Cl-].[NH4+]>[CH2:1]([O:8][C:9]([N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C@@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][C:14]([CH3:34])([C:25]([O:27][CH3:28])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)C[C@H](N(CC(C)C)C(=O)OCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-{[(benzyloxy)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (430 mg) and iodomethane (90 μl) were dissolved in DMF (5 ml), sodium hydride (50% contained, 70 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38](Cl)(=[O:41])[CH2:39][CH3:40].[Na]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:38](=[O:41])[CH2:39][CH3:40])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Agent: [Na]
Product: CCC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using propanoyl chloride in place of trimethylacetyl chloride in Step B. Anal. C, H, N for sodium salt·1H2O Calc. C 66.61; H 5.42; N 4.71 Found C 66.87; H 5.45; N 4.69.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[NH:29][CH2:28][CH2:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[CH:34]=2)=[CH:16][CH:15]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH:1]=[O:3])[CH2:28][CH2:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[CH:34]=2)=[CH:18][CH:19]=1)[CH3:9]
Reactant: CC(=O)O
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.25 ml) was added formic acid (0.13 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling, a solution of methyl 7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g) in THF (10 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) as colorless crystals.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.NCC1C=CC=CN=1.[H][H]>[Pd].CO>[OH:10][CH2:9][C:3]1[CH:2]=[CH:1][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: O=Cc1ccc(C=O)cc1
Agent: [Pd]
Agent: NCc1ccccn1
Solvent: CO
Product: O=Cc1ccc(CO)cc1
Yield: 78 %

Procedure:
Terephthaldicarboxaldehyde (30.02 g, 224 mmol), methanol (200 mL), palladium on activated carbon, (10%, 3.02 g) and 2-(aminomethyl)pyridine (2.3 mL, 22 mol, 0.01 mol equiv) were combined in a hydrogenation vessel and the reaction mixture was shaken on a Parr hydrogenator for 2.5 hours at 40 psi of hydrogen. The mixture was filtered through celite, the cake washed with methanol and the solvent from the eluent removed in vacuo. Purification of the crude product by column chromatography on silica gel (EtOAc/Hexanes, 1:1) afforded the title compound (23.8 g, 78%) as a white solid. 1H NMR (CDCl3) δ 4.80 (s, 2H), 7.53 (d, 2H, J=9 Hz), 7.87 (d, 2H, J=9 Hz), 10.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[CH2:17][CH:16]1[CH3:34].C1CCN2C(=NCCC2)CC1.[CH3:46][O:47][C:48](=[O:51])[CH2:49]Br.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH3:46][O:47][C:48](=[O:51])[CH2:49][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:32])([F:31])[F:30])=[CH:21][CH:22]=4)[CH2:17][CH:16]3[CH3:34])[N:4]=2)=[CH:12][CH:11]=1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Reactant: COC(=O)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)COc1ccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40 mg (0.083 mmol) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-phenol (example 99) in 0.5 mL of DMF was treated with 0.01 mL of DBU and 0.01 mL (0.1 mmol) of methylbromoacetate. The mixture was stirred overnight at RT and distributed between Et2O and a saturated aqueous solution of NH4Cl. Drying of the combined organic phases, evaporation of the solvent and chromatography on silica gel with n-heptane/EtOAc 1:1 gave (4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-phenoxy)-acetic acid methyl ester, off-white foam, MS: 559 (MH+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH:16]=[O:17])=[C:11]([CH:13]3[CH2:15][CH2:14]3)[N:12]=2)[N:9]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH2:16][OH:17])=[C:11]([CH:13]3[CH2:14][CH2:15]3)[N:12]=2)[N:9]=1
Reactant: O=Cc1c(C2CC2)nc2ccc(Cl)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(C2CC2)nc2ccc(Cl)nn12
Reaction time: 1 h
Yield: 93 %

Procedure:
Sodium borohydride (5.62 mg, 6.62 mmol, 1.3 eq) is added dropwised, at room temperature, to a solution of 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde x110 (958 mg, 4.32 mmol) in methanol (100 ml). After 1 hour, the reaction is quenched by water (100 ml) and the crude product is extracted by dichloromethane (2×100 ml). The organic layers are dried over MgSO4, filtered and condensed under reduced pressure to afford (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 which is used without any further purification.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[C:17]3[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]=3[O:15][C:14]([CH3:25])([CH3:24])[CH:13]=2)[CH:4]=1)#[N:2]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:22]([C:19]1[CH:20]=[CH:21][C:16]2[O:15][C:14]([CH3:25])([CH3:24])[CH2:13][CH:12]([N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:3]([C:1]#[N:2])=[CH:4]3)[C:17]=2[CH:18]=1)#[N:23]
Reactant: CC1(C)C=C(n2cc(C#N)c3ccccc32)c2cc(C#N)ccc2O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CC(n2cc(C#N)c3ccccc32)c2cc(C#N)ccc2O1
Reaction time: 48 h

Procedure:
4-(3-Cyano-1H-indol-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (25 mg, prepared according to Example 1) in methanol/ethyl acetate (3:1) was treated with an equal weight of palladium hydroxide catalyst and shaken under an atmosphere of hydrogen at 55 psi over 2 days, recharging the catalyst midway, to provide a 53:30 mixture of the desired compound and the starting material along with minor amounts of by-products. Another 250 mg of starting material was treated in an identical manner. Purification of the desired product from the combined reaction mixtures was effected by preparative reverse phase chromatography on a C-18 column, eluting with 85% of 90:10 MeOH:H2O with 0.1% trifluoroacetic acid and 15% of 10:90 MeOH:H2O with 0.1% trifluoroacetic acid at a flow rate of 49 mL/min. and injections of 75 mg. Product-containing fractions were concentrated to remove methanol and extracted twice with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue of 50 mg. Final hexane trituration (decanted) gave the title compound (45 mg), m.p. 175°-178° C.: 1H NMR (CDCl3) δ 7.80-7.88 (m, 1H), 7.48-7.65 (m, 2H), 7.25-7.40 (m, 2H), 7.10-7.30 (m, 1H), 6.95-7.05 (m, 2H); 13C NMR (CDCl3) δ 157.8, 134.0, 133.8, 133.7, 133.6, 132.2, 124.7, 123.1, 120.8, 120.7, 119.6, 118.6, 115.4, 111.0, 110.9, 104.3, 77.4, 51.0, 39.4, 29.7, 24.7.