Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cccnc2)n1
Yield: 1.07 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(3-pyridyl)-1,3-thiazole-4-carboxylic acid (0.285 g, 1.381 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.3 g, 1.151 mmol). The product was purified by triturated using DCM. Yield 1.065%. 1H-NMR (400 MHz; CDCl3): δ 1.31 (d, 3H), 4.34 (dd, 1H), 4.48 (dd, 1H), 4.60-470 (m, 1H), 6.63 (d, 1H), 7.37 (dd, 1H), 7.50-7.54 (m, 2H), 7.80 (dd, 1H), 7.88 (d, 1H), 7.98 (d, 1H), 8.13-8.18 (m, 2H), 8.73 (dd, 1H), 9.16 (d, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:20][C:19]1[C:14]([N:4]2[CH2:5][CH2:6][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([OH:1])[CH2:3]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1cccnc1Br
Reactant: CCOC(=O)C1CCNCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1CCN(c2ncccc2Cl)CC1O
Temperature: 90 °C

Procedure:
Ethyl 3-hydroxy-4-piperidinecarboxylate, 2-bromo-3-chloropyridine (700 mg, 3.6 mmol), and potassium carbonate (1.0 g, 7.2 mmol) were and heated at 90° C. for 2 days. Standard work-up gave the title compound.
Reaction SMILES: C1[O:3]C1.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16](O)=[CH:17][CH:18]=1>>[CH2:12]([C:13]1([OH:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C1CO1
Product: CCCCCCCCCC1(O)CCCCC1

Procedure:
The same procedures as the first ethylene oxide addition step of Example 29 were carried out except that the amount of ethylene oxide was changed to 61 g (1.38 moles). That is, 0.69 mole of ethylene oxide was reacted with 1 mole of nonylphenol. Colorless liquid thus obtained was analyzed with liquid chromatography. The liquid contained 27.3% by weight of nonylphenol, 72.7% by weight of one molar ethylene oxide adduct, and trace amount of two molar ethylene oxide adduct of nonylphenol, respectively. The reaction product unfavorably formed a large amount of nonylcyclohexanol in the next hydrogenation step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[O:10].[Cl-].[NH4+].O1CC[CH2:15][CH2:14]1>>[OH:10][CH:9]([CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:14]#[CH:15]
Reactant: O=CCOC1CCCCO1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Acetylene gas was bubbled into tetrahydrofuran (30 ml) for 30 minutes. Ethyl magnesium bromide (25 ml) was added. 2-(Tetrahydro-2-pyranyloxy)-acetaldehyde (5.0 g, 0.035 mole) in tetrahydrofuran (25 ml) was then added. The reaction mixture was warmed to room temperature and stirred overnight. Saturated ammonium chloride aqueous solution (30 ml) was added to quench the unreacted acetylide and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography eluted with n-hexane/ethyl acetate (5:2) to give colorless oil (4.5 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:20]([O-])=O>CCO.[Fe]>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH2:1])=[C:3]([NH2:20])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Product: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1N
Yield: 64.9 %

Procedure:
Iron dust reduction of 7-amino-4-(3-bromoanilino)-6-nitroquinazoline (0.5 g, 1.4 mmol) in 65% aqueous EtOH containing sufficient aqueous HCl to ensure solubility gives 4-(3-bromoanilino)-6,7-diaminoquinazoline (0.30 g, 65%). 1H NMR (DMSO) δ9.14 (1H, s), 8.27 (1H, s), 8.23 (1H, brs), 7.85 (1H, d, J =8.0 Hz), 7.31-7.14 (2H, m), 7.29 (1H, s), 6.79 (1H, s), 5.73 (2H, brs), 5.13 (2H, brs).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=2)=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (4.89 g, 12.66 mmol), 3-chlorophenylboronic acid (2.97 g, 18.99 mmol), Pd(PPh3)4 (1.463 g, 1.266 mmol) and 2 M aqueous Na2CO3 (12.66 ml, 25.3 mmol) in 1,2-dimethoxyethane (100 ml) is allowed to stir at 95° C. under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and quenched with brine. The two phases are separated. The mixture is extracted twice with ethyl acetate from the aqueous layer. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 70:30) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (3.33 g); HPLC retention time=1.44 minutes (condition B); MS (ES+)=318.26 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.2 Hz, 3H) 1.41 (s, 9H) 2.47 (A of ABX, Jab=15.8 Hz, Jax=5.9 Hz, 1H) 2.52 (B of ABX, Jab=15.8 Hz, Jbx=5.4 Hz, 1H) 2.83-2.89 (m, 1H) 2.95-3.00 (m, 1H) 4.17 (q, J=7.2 Hz, 2H) 4.18 (br s, 1H) 5.07 (br s, 1H) 7.26-7.37 (m, 4H) 7.43-7.51 (m, 3H) 7.55 (br t, J=1.8 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12]C)[C:8](=[O:14])[CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCc2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 5,6-dimethoxy-indan-1-one (40.0 g, 0.208 mol) in CH2Cl2 (800 mL) at −78° C. was added BBr3 (59.0 mL, 0.624 mol) dropwise. The dry ice bath was removed after the addition. The mixture was stirred at room temperature for 1 hour and poured into a large amount of ice/water and stirred vigorously. The pink solid was filtered, washed with water, and vacuum oven dried to give 33.3 g (98%) of the desired product. MS (DCI/NH3) m/z: 165.0 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 2.58-2.61 (m, 2H) 2.98 (t, J=5.55 Hz, 2H) 6.85 (s, 1H) 7.04 (s, 1H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:42])[CH:19]([O:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:12][C:11]=1[OH:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.[H][H]>[Ni].O1CCCC1>[C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:42])[CH:19]([O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:12][C:11]=1[OH:43])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Agent: [Ni]
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(Oc1ccc(N)cc1)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl

Procedure:
An amount of 670 g (1.10 mol) of 2-benzamido-4-chloro-5-[2-(p-nitrophenoxy]-myristamido]-phenol in the presence of 2370 ml of tetrahydrofuran, 47.8 g of morpholine, and 22 ml of Raney nickel is reduced in an autoclave at an initial hydrogen pressure of 10 MPa and a temperature of 40° C. After 90 min the theoretical amount of hydrogen is found to be taken up. The catalyst is filtered off. The filtrate is concentrated by evaporation to a volume of 1 l and then poured out in 4 l of ethanol. The precipitate is filtered off and dried.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[O:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M45) (0.20 g, 0.37 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (131 mg, 84%).
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:21][N:20]([C:22](=[O:39])[CH2:23][N:24]([CH2:32][CH2:33][C:34]3[N:35]=[N:36][NH:37][CH:38]=3)C(=O)OC(C)(C)C)[CH2:19][CH2:18][C:16]=2[N:17]=1>ClCCl.CO>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:21][N:20]([C:22](=[O:39])[CH2:23][NH:24][CH2:32][CH2:33][C:34]3[N:35]=[N:36][NH:37][CH:38]=3)[CH2:19][CH2:18][C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)N(CCc1c[nH]nn1)CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(CNCCc1c[nH]nn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Add hydrogen chloride (1M in ethyl ether; 2.55 mL; 8 equiv; 2.55 mmoles) to a 0° C. solution of tert-butyl {2-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-oxoethyl}[2-(1H-1,2,3-triazol-4-yl)ethyl]carbamate (0.165 g; 1.0 equiv; 0.318 mmoles) in dichloromethane (2 mL) and methanol (1 mL). After stirring for 1 hour at 0° C., concentrate the mixture. Redissolve the crude product in a 10:1 mixture of dichloromethane:methanol and wash with saturated sodium bicarbonate. Extract the aqueous layer with additional 10:1 mixtures of dichloromethane:methanol (4×). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-{[2-(1H-1,2,3-triazol-4-yl)ethyl]amino}ethanone (0.136 g; 102%) as a brown foam: MS (m/z): 419 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([C:13]([CH2:20][CH3:21])([C:17](Cl)=[O:18])[C:14](Cl)=[O:15])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[CH2:11]([C:13]1([CH2:20][CH3:21])[C:14](=[O:15])[C:6]2[C:5](=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH3:1])[C:7]=2[CH3:8])[C:17]1=[O:18])[CH3:12]
Reactant: COc1cccc(C)c1C
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CCC1(CC)C(=O)c2cc(OC)c(C)c(C)c2C1=O
Temperature: 0 °C

Procedure:
A stirred mixture of 2,3-dimethylanisole (6.8 g., 0.05 mole) and 2,2-diethylmalonyl chloride (10 g., 0.051 mole) in hexane (75ml.) is cooled to 0°C. and treated with aluminum chloride (13.5 g., 0.11 mole) in several portions over a 15 minute period. The reaction is heated at reflux for 2 hours, the hexane is distilled at reduced pressure, the product treated with cold 1N-hydrochloric acid, extracted into ether, washed with water, 5% sodium hydroxide, water then dried over magnesium sulfate. Evaporation of the ether at reduced pressure affords 6.3 g. of 2,2-diethyl-4,5-dimethyl-6-methoxy-indan-1,3-dione which melts at 80°-81°C. after recrystallization from petroleum ether.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]=2)[CH3:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N1CCOCC1)C>C(Cl)Cl.CCOCC>[C:1]([N:13]1[CH2:12][CH2:11][N:10]([CH2:16][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=3)[CH:20]=2)[CH3:18])[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(C(C)CN3CCNCC3)ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2cc(C(C)CN3CCN(C(=O)c4ccccc4)CC3)ccc2c1
Reaction time: 3 h

Procedure:
Benzoyl chloride (0.58 ml, 5 mmols) is added, at 0° C., to a solution of 2-(2-piperazino-1-methylethyl)-6-methoxynaphthalene (1.42 g, 5 mmols) and N-ethylmorpholine (0.65 ml, 5 mmols) in 15 ml of methylene chloride. The mixture is allowed to return to ambient temperature and stirred for 3 hours. The reaction medium is washed with water and dried over sodium sulphate. Concentration of the mixture yields an oily residue which dissolves in ether and crystallises. The compound is recrystallised from ethyl acetate (15 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:16]([C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]=O)=[CH:24][NH:25]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:27]=[C:26]2[C:22]([C:23](/[CH:28]=[CH:14]/[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])=[CH:24][NH:25]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Product: COc1cc(C(=O)/C=C/c2c[nH]c3cc([N+](=O)[O-])ccc23)cc(OC)c1OC
Yield: 1.1 %

Procedure:
Substantially the same procedure as in Example 21 was repeated using 3',4',5'-trimethoxyacetophenone (1.25 g) and 6-nitroindole-3-carboxaldehyde (1.13 g) except that the obtained product was further purified by preparative HPLC, that the eluting solution was cooled, and that the precipitated crystals were collected by filtration, to give Compound 34 (26 mg).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[F:15])=O.C(N(CC)CC)C.C([O:43][C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])C>CCOCC>[F:15][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:6]=1[NH:5][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:46][C@H:45]([C:44]([OH:48])=[O:43])[CH3:47])=[O:11]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1F

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-3-fluoro-4-(hexadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the N-[3-fluoro-4-(hexadecylamino)benzoyl]alanine as a white, crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccccc1
Yield: 69.8 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (400 mg), 10% palladium carbon (100 mg), methanol (5 ml) and THF (5 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:13][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: O=Cc1ccccc1Cl
Product: CC(C)NCc1ccccc1Cl

Procedure:
Synthesized according to typical procedure J from 2-chlorobenzaldehyde and isopropylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:5]=[C:4]([Cl:19])[N:3]=1.Cl.[F:21][C:22]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>>[Cl:19][C:4]1[CH:5]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:7]=[C:2]([N:24]2[CH2:25][CH2:26][C:22]([F:27])([F:21])[CH2:23]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(Cl)c2)C1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)C1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl 3-(2,6-dichloro-4-pyridyl)azetidine-1-carboxylate (1-a, 472 mg, 1.557 mmol), 3,3-difluoropyrrolidine hydrochloride (1.12 g, 5.0 equiv., 7.784 mmol) in NMP (3.0 mL, 31 mmol) in a microwave vial was added DIPEA (1.90 mL, 7.0 equiv., 10.90 mmol)), and the reaction was maintained at 140° C. for 30 min and then at 150° C. for 30 min in the microwave machine. LCMS showed more than 95% conversion. The crude was used without further treatment. LCMS: m/z 374 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=[S:24])[CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared by heating under reflux overnight a stirred mixture of 3-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluorobenzonitrile and an equal weight of phosphorus pentasulfide in pyridine and workup as in the previous example gave a yellow solid: mp. 240-242° C. dec.; 1H-NMR (DMSO-d6) δ 12.37 (s, 1H), 8.13 (s, 1H), 7.98 (dt, 1H, J=10.4 and 5.4 Hz), 7.81 (d, 1H, J=8.4 Hz), 7.7 (d, 1H, J=1.8 Hz), 7.68 (dd, 1H, J=8.3 and 1.9 Hz), 7.22 (d, 1H, J=8.3 Hz), 2.85 (s, 2H), 1.27 (s, 6H); MS m/z 309 [M−H]− Anal. Calc. For C18H15FN2S 0.10 H2O: C, 69.25, H, 4.91, N, 8.97. Found: C, 69.15, H, 4.74, N, 8.75.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[C:13]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[CH3:14].[H-].[Na+].Cl>C1COCC1>[C:13]([O:16][CH2:17][CH2:18][O:19][CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6])(=[O:15])[CH3:14]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Reactant: CC(=O)OCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCCOCc1cc(Cl)cc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a soln. of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.3 mmol) (A.2.2.1.) and 2-hydroxyethyl acetate (1.43 mmol) in 7 mL THF was added NaH (1.95 mmol, 60% suspension in oil). The reaction mixture was stirred at RT overnight and then poured into a 1M HCl soln. The mixture was extracted twice with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4 and conc. in vacuo. Purification with CC (0-25% EtOAc/Hept) gives the desired compound as orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]2[N:13]([CH:20]3[CH2:22][CH2:21]3)[CH:14]=[CH:15][C:16]=2[C:17]([OH:19])=O)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[C:17](=[O:19])[C:16]3[CH:15]=[CH:14][N:13]([CH:20]4[CH2:21][CH2:22]4)[C:12]=3[CH:11]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Cn1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)ccn2C2CC2)cc(Cl)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(N2C(=O)c3ccn(C4CC4)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 240.2 but using 2-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylic acid (Step 243.3) and stirring the reaction mixture for 2 hr. tR: 0.99 min (LC-MS 6); ESI-MS: 414.1 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 95:5): Rf=0.32.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.Cl.[CH3:37]O>>[CH3:37][O:34][C:33](=[O:35])[CH2:32][C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: 80 °C

Procedure:
To [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (0.5 g, 1.0 mmol) in MeOH (20 mL) was added hydrogen chloride (4N in 1,4-dioxane; 2 mL), and the reaction was heated to 80° C. for 2 hours. The mixture was then concentrated and worked-up with EtOAc and saturated aqueous NaHCO3 to give the title compound.