Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:38][C:39](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:40]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][N:31]([CH:39]([CH3:40])[CH3:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 27 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpyrrolidin-3-yloxy)picolinamide (30 mg, 27%) was prepared using a procedure analogous to that described Example 20, substituting N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 507 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.58 (br. s., 1H), 8.89 (br. s., 1H), 8.33 (br. s., 1H), 8.08 (d, J=8.48 Hz, 1H), 7.81 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.67 Hz, 1H), 7.42 (d, J=8.29 Hz, 2H), 6.50 (s, 1H), 5.05 (br. s., 1H), 2.84-2.95 (m, 1H), 2.69-2.84 (m, 2H), 2.21-2.47 (m, 3H), 1.69-1.87 (m, 1H), 1.30 (s, 9H), 1.03 (d, J=5.65 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH2:32][CH3:33])[C:25]([F:26])([F:28])[F:27])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (100.5 mg, 0.235 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (14.1 mg, 0.353 mmol) at 0° C. After 30 min, to the mixture was added ethyl iodide (94 μL, 1.175 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (80.7 mg, 0.177 mmol, 76%).
Reaction SMILES: C[Al](C)C.[CH3:5]CCCCC.Br[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])[CH:20]=1)[C:15]([OH:17])=[O:16].O>C1COCC1.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>[CH3:5][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])[CH:20]=1)[C:15]([OH:17])=[O:16]
Reactant: CCCCCC
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 150 °C

Procedure:
1.15 ml (2.29 mmol) of a 2 M solution of trimethylaluminium in a hexane fraction were added to a solution of 250 mg (0.764 mmol) of the compound of Example 15A and 27 mg (0.023 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.5 ml of anhydrous THF, and the mixture was then, under an argon atmosphere, heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 150° C. for 120 min. After cooling to RT, about 10 ml of water were added, and the reaction mixture was extracted three times with in each case about 10 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness on a rotary evaporator. The product was isolated by preparative HPLC (Method 9). Concentration of the product fractions and drying of the residue under high vacuum gave 98 mg (47% of theory, 95% pure) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39]1([NH2:42])[CH2:41][CH2:40]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH:42][CH:39]3[CH2:41][CH2:40]3)=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NC3CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 47.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.2 g, 0.36 mmol), cyclopropylamine (0.05 g, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.18 g, 0.72 mmol) were dissolved in 20 mL of dichloromethane under stirring, and triethylamine (0.36 g, 3.6 mmol) was added to the solution at room temperature. The reaction mixture was reacted at room temperature for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-cyclopropylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 15a (0.1 g, yield 45%) as an oil.
Reaction SMILES: C(OC([N:8]([CH2:24][C:25]1([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27][CH2:26]1)[C:9]1[N:14]=[N:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([O:22]C)=O)[O:17][N:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[NH4+:37]>CO>[F:35][C:34]1[C:29]([C:25]2([CH2:24][NH:8][C:9]3[N:14]=[N:13][C:12]([C:15]4[CH:19]=[C:18]([C:20]([NH2:37])=[O:22])[O:17][N:16]=4)=[CH:11][CH:10]=3)[CH2:28][CH2:27][CH2:26]2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)no1
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)no1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 36 %

Procedure:
Methyl 3-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)isoxazole-5-carboxylate (0.53 g, 1.1 mmol), methanol (5 mL) and concentrated ammonium hydroxide (8 mL) were combined in a microwave reactor and heated to 100° C. for 60 min. The reaction mixture was then concentrated and diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Resultant oil was diluted in 10 mL of DCM and TFA (6 mL) was added and the reaction was stirred for 35 min. The reaction mixture was then concentrated and purified by reverse phase chromatography to give the title compound as a white solid (144 mg, 36%), (m/z [M+H]=369.1).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:34])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][C:21]=2[F:33])[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:4][C:5]([CH3:36])([CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:34])([CH3:1])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][C:21]=2[F:33])[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1
Reactant: C[Mg]Br
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2ccc(F)cn2)cc1F
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2ccc(F)cn2)cc1F
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (28 μL, 0.08 mmol) was added to a 0° C. solution of 4-(2,2-dimethylpropyl)-2-{[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (20 mg, 0.04 mmol) in tetrahydrofuran (3 mL). After warming slowly to ambient temperature, the reaction was quenched with a few drops of water and concentrated in vacuo to afford 4-(2,2-dimethylpropyl)-2-{2-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11](Br)[CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14]>C1COCC1.CCCCCC>[O:4]=[C:3]([CH2:5][CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (225 μL, 2.1 mmol) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension, prewashed with hexane) (100 mg, 2.1 mmol) in anhydrous THF (5 mL) at 0° C. under an Argon atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6M solution (1.3 mL, 2.1 mmol) of n-butylithium in hexane over 2 minutes. The yellow solution was stirred 15 min at 0° C. and then treated dropwise with farnesyl bromide (545 μL, 2.0 mmol). The cloudy orange solution was stirred at 20° C. for 11/2 hours and then quenched by dropwise addition of saturated aqueous NH4Cl solution. The resulting mixture was diluted with ethyl acetate and washed with water, dried, filtered and evaporated to give the crude product which was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](OB(O)O)[CH:22]=[CH:23][CH:24]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(OB(O)O)c1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2ccccc2n(-c2cccc(OC)c2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 205.6 %

Procedure:
2.0 g (9.2 mmol) of ethyl 2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in dichloromethane (100 mL), and 2.8 g (1.8 mmol) of 3-methoxyphenylboric acid, 3.3 g (1.8 mmol) of anhydrous copper (II) acetate and 1.4 g (1.8 mmol) of pyridine were added thereto. The mixture was stirred for 72 hours at room temperature. After completion of the reaction, the inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (developing solvent:ethyl acetate:hexane=1:1), to obtain 1.2 g (yield: 42%) of ethyl 1-(3-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17](Cl)=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.[F-:23].[K+].S1(CCCC1)(=O)=O>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]([F:23])=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nsc3cc(Cl)c([N+](=O)[O-])cc23)cc1C
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(-c2nsc3cc(F)c([N+](=O)[O-])cc23)cc1C
Temperature: 154 °C
Reaction time: 19 h
Yield: 30.1 %

Procedure:
A mixture of 3-(6-methoxy-m-tolyl)-6-chloro-5-nitro-1,2-benzisothiazole (7.30 g, 0.0218 mol), potassium fluoride (6.33 g, 0.109 mol) 18-crown-6 (2.31 g, 0.0872 mol) and sulfolane is stirred 19 hours at 154° C., cooled to room temperature, and poured into ice water. The resultant solid is filtered and chromatographed on silica gel with methylene chloride to afford a solid which is recrystallized from acetonitrile to afford a tan powder. The powder is recrystallized from ethyl acetate to give the title compound as a tan solid (2.09 g, 29.9%) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:17]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=3[S:19][CH:20]=2)[C:6]=1[C:26]([OH:28])=[O:27])(O)=[O:2].FC1C=C2[C:36](=CC=1)[N:35](CC1C3C=C(F)C=CC=3SC=1)[C:34]1C(=O)OC(=O)CC2=1.CNC>>[CH3:34][N:35]([CH3:36])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[C:17]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=3[S:19][CH:20]=2)[C:6]=1[C:26]([OH:28])=[O:27])=[O:2]
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccc(F)cc12
Reactant: O=C1Cc2c(n(Cc3csc4ccc(F)cc34)c3ccc(F)cc23)C(=O)O1
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
3-Carboxymethyl-5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid (from Example 60) was converted to 6-fluoro-9-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was reacted with dimethyl amine as described in Example 68.2. to give the title compound as a white solid. MS: 427.2 ([M−H]−).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]2[CH2:23][O:22]2)=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([OH:22])[CH2:23][NH:12][CH:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: CC(N)CO[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: COc1ccc(OCC(O)CNC(C)CO[Si](C)(C)C(C)(C)C)cc1
Yield: 58.2 %

Procedure:
A procedure similar to that described in Preparation 10 was repeated, except that 3.22 g of 2-t-butyldimethylsilyloxy-1-methylethylamine, 3.00 g of 4-methoxyphenoxymethyloxirane and 30 ml of ethanol were used, to give 3.58 g of the title compound having an Rf value of 0.15 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)C=Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, cinnamoyl chloride, and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white solid after removal of the solvent: m.p. 126°-140° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH:17]([O:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1)([CH3:19])[CH3:18]
Reactant: OCc1cccc(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(CO)c1
Temperature: 90 °C

Procedure:
To a mixture of 3-(hydroxymethyl)phenol (10 g) and potassium carbonate (27.2 g) in DMF (100 ml) was added 2-bromo-propane (14.8 g), the reaction was heated to 90° C. overnight. The reaction mixture was filtered and the filtrate was concentrated and purified by chromatography on silica gel, eluting with petrol:ethyl acetate=5:1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([O:33][CH2:34][CH3:35])=[N:28]2>>[CH2:34]([O:33][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[NH:22][CH2:11][C:10]([C:13]([F:14])([F:16])[F:15])([OH:17])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:20][CH3:21])([CH3:18])[CH3:19])[N:28]=1)[CH3:35]
Reactant: CCOc1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Product: CCOc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Yield: 44 %

Procedure:
Analogously to Example 20, 500 mg (1.6 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 363 mg (1.9 mmol) of 5-amino-2-ethoxyquinoline are reacted to form 338 mg of the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][CH:26]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:29]=1[C:30](O)=[O:31])[CH3:27]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:30]([C:29]1[C:28]([CH:26]([CH3:25])[CH3:27])=[CH:36][CH:35]=[CH:34][C:33]=1[CH:37]([CH3:39])[CH3:38])=[O:31]
Reactant: CC(C)c1cccc(C(C)C)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C(C)C)cccc1C(C)C

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[2,6-bis-(1-methylethyl)phenyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2,6-bis-(1-methylethyl)benzoic acid using the general procedure described in example 3. LR MS: 555 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Br[CH2:11][CH2:12][F:13].C(N(C(C)C)CC)(C)C>CCOCC>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:11][CH2:12][F:13])[CH3:6]
Reactant: CCOC(CN)OCC
Reactant: FCCBr
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNCCF)OCC

Procedure:
A solution of 3.1 ml (21.5 mmol) of 1-amino-2,2-diethoxyethane, 3.0 g (23.6 mmol) of 1-bromo-2-fluoroethane and 5.56 g (43 mmol) of diisopropylethylamine was heated at 100° C. in a closed vessel for 6 hours. The reaction mixture was diluted with ether and washed with 1N NaOH and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was distilled in vacuo. 1.3 g of substance were obtained as a clear liquid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1)#[N:35].C(O)C(N)(CO)CO.CN(C=O)C>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:43]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)=[O:44])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)Nc3ccc(C#N)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 132.1 %

Procedure:
To a solution of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate (37 mg, 0.084 mmol) in anhydrous DCM (2 ml) was added 4-cyanophenyl isocyanate (Aldrich, 45 mg, 0.31 mmol) and the reaction mixture was stirred at rt for 18 hrs. Then PS-trisamine resin (75 mg, Novabiochem, 3.5 mmol/g) and DMF (1 mL) were added and the resulting mixture was stirred at rt for 5 additional hrs. Removal of the resin by filtration followed by evaporation of the solvents gave 65 mg (97%) of the title compound as a pale yellow oil. HPLC, Rt: 5.7 min (purity: 74.1%).
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(CCCc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.3 g--see EP-A-0178947), 1-bromo-3-phenylpropane (0.238 g), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.4g.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[F:7][C:8]([F:12])([F:11])[CH:9]=[CH2:10]>C1(C)C=CC=CC=1>[F:7][C:8]([F:12])([F:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CC(F)(F)F
Reactant: O=C(O)CCS
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 20 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with 3-mercaptopropionic acid (3.67 g, 34.6 mmol), toluene (30.26 g), and 2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.543 g, 1.76 mmol) and the reactor was cooled with a dry ice/acetone bath, purged with nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.20 g, 33.3 mmol) was added via transfer cylinder and the reaction was allowed to warm to 20° C. After 24 hours, the reaction was heated to 50° C. for 1 hour to decompose any remaining V-70 initiator. The reaction was allowed to cool to room temperature. The solution was concentrated by rotary evaporation to provide the title compound (6.80 g, 77.5 wt % linear isomer by GC internal standard assay, 5.27 g active, 76%, 200:1 linear:branched by GC, 40:1 linear:branched by fluorine NMR)