Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1.C(Cl)(Cl)Cl.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:9][CH2:10]2)=[O:28])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)CC1CCCN(C(=O)c2ccc(N)cc2)c2ccccc21
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a mixture of 5-ethoxycarbonylmethylene-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (671 mg) and nickel chloride hexahydrate (419 mg) in a mixture of methanol (25 ml) and tetrahydrofuran (25 ml) was added sodium borohydride (601 mg) in portions at 0° C. and the mixture was stirred at the same temperature for 30 minutes. The solution was filtered through a bed of celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform and the solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a crude oil and the oil was subjected to silica gel column (30 g, 1% methanol in chloroform) to give 1-(4-aminobenzoyl)-5-ethoxycarbonylmethyl-2,3,4,5-tetrahydro -1H-1-benzazepine (500 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:40]([CH2:41][CH2:42][OH:43])=[C:39]([CH3:44])[NH:38][N:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:43][CH2:42][CH2:41][C:40]3[C:36]([CH3:35])=[N:37][NH:38][C:39]=3[CH3:44])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: Cc1n[nH]c(C)c1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1n[nH]c(C)c1CCOc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Reaction time: 18 h
Yield: 11.2 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (50 mg, 0.107 mmol), 2-(3,5-dimethyl-1H-pyrazol-4-yl)ethanol (74.8 mg, 0.533 mmol) and Ph3P-resin (139 mg, 0.533 mmol) in THF (2 mL) was added DIAD (0.104 mL, 0.533 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (2 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(2-(3,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (7 mg, 0.012 mmol, 11.66% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.19 (d, J=8.4 Hz, 1H), 7.09-6.86 (m, 3H), 5.81 (br. s., 1H), 4.11-3.94 (m, 2H), 3.29 (br. s., 1H), 3.17 (s, 3H), 2.78-2.74 (m, 2H), 2.42 (s, 3H), 2.13 (s, 5H), 2.04 (s, 3H), 1.48 (br. s., 1H), 1.28 (br. s., 1H), 1.23 (br. s., 1H), 1.19 (br. s., 1H), 1.11 (s, 9H), 1.03 (br. s., 1H), 0.84 (br. s., 3H), 0.61 (br. s., 3H). LCMS (M+H)=563.4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:14]=[C:15]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[CH:14]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2nc3ccccc3o2)cc1-c1cccc(C#N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-cyano-phenylboronic acid (183 mg, 1.3 mmol), 2-(3-bromo-4-methylphenyl)-1,3-benzoxazole (300 mg, 1.04 mmol), dichlorobis(triphenylphosphine)palladium(II) (36.5 mg, 0.052 mmol), triphenylphosphine (27 mg, 0.104 mmol), and potassium carbonate (287 mg, 2.08 mmol) in degassed DME/H2O (5:1, 18 mL) was heated to 80° C. for 18 h. The mixture was cooled to rt and the two layers were separated and the aqueous layer was extracted with EtOAc (3×). The organics were combined, dried over Na2SO4, and evaporated to dryness to give a clear solid. Purification of the crude by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30 min: 0 to 20% EtOAc) afforded 5′-(1,3-benzoxazol-2-yl)-2′-methyl-1,1′-biphenyl-3-carbonitrile a colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.C1COCC1>CCOCC>[CH2:7]([CH:15]([CH2:16][OH:17])[CH2:21][OH:22])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCC(CO)CO
Yield: 65 %

Procedure:
250 ml of ether and 19.0 of lithium aluminum hydride were put in a 1-liter four-necked flask, and a solution obtained by dissolving 72.1 g of the thus prepared diethyl octylmalonate in 50 ml of ether was put therein dropwise at such a rate that ether is gently refluxed. After the dropwise addition, the mixture was refluxed with heating for 3 hours, and after allowing it to cool, a mixture of water-THF was added to decompose excess lithium aluminum hydride. The resultant solid was removed by filtration, and the filtrate was washed with saturated saline and dried over anhydrous sodium sulfate. The crude crystal obtained by distilling away the solvents was recrystallized from isooctane to give 32.4 g of colorless crystals. Yield 65%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[C:18]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:17]=[CH:16][N:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[CH:38]([O:37][C:35]([N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:18]2[CH:19]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:15]=[CH:16][N:17]=2)[CH2:22][CH2:23]1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 4b (0.12 mmol) and triethylamine (0.2 mL, 12 eq) in 1 mL of DCM, was added the isopropyl chloroformate (1.3 eq). The mixture was stirred at room temperature for 22 h and the solvent volume was reduced to 0.7 mL under a stream of nitrogen. The residue was purified by preparative HPLC to afford 4-1, LCMS 461.2 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@@H:16]1[CH2:21][OH:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C(OCC)C>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@@H:16]1[CH:21]=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add triethylamine (1.1 mL, 7.79 mmol) and sulfurtrioxide-pyridine complex (0.63 g, 3.89 mmol) to an ice-cold solution of 4-(S)-fluoro-2-(R)-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (0.426 g, 1.95 mmol) in DMSO (2 mL). Stir 30 min, warm to room temperature and stir 30 min. Dilute with diethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[CH:30][CH:29]=4)[C:21]4[N:22]([CH:24]=[CH:25][N:26]=4)[CH:23]=3)[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:49](OC(=O)C)(=[O:51])[CH3:50].ClCCl>O>[C:49]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:20]3[C:21]4[N:22]([CH:24]=[CH:25][N:26]=4)[CH:23]=[C:18]([C:14]4[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]5[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:41][CH:40]=5)[CH:17]=[CH:16][CH:15]=4)[N:19]=3)=[CH:29][CH:30]=2)[CH2:39][CH2:38]1)(=[O:51])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc(N5CCNCC5)cc4)n3)c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(NC(=O)c5ccc(C(C)(C)C)cc5)c4)cn4ccnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide (16) (0.55 mmol), triethylamine (1.1 mmol), acetic anhydride (0.60 mmol), and dichloromethane (10 mL) is stirred at room temperature for 1 hr. Water (30 mL) is added, the mixture extracted with dichloromethane (2×50 mL), the extracts washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is triturated with diethyl ether and ethyl acetate to give N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide (17) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>ClCCl.O1CCOCC1.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 200.3 %

Procedure:
To a solution of tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]piperidine-1-carboxylate (1 g) in dichloromethane (40 mL) was added 4M HCl in dioxane (6 mL) and methanol (5 mL). The mixture was stirred at room temperature for 2 hours and then evaporated to give the title compound as a white foam (0.87 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:43]=[C:39]1[CH2:40][CH2:41][CH2:42][N:38]1[C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:33][CH:34]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCc1ccc(N2CCCC2=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCc2ccc(N3CCCC3=O)cc2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl phenyl pyrrolidin-2-one (42.94 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-(2-oxo-pyrrolidin-1-yl)-benzylamide (48.9 mg, 40.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H36Cl2N4O2S+H [(M+H)+]: 603.2288. found: 603.2289.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CCOCC>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a solution of phenol (1.88 g, 20.0 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate (2.34 mL, 21.0 mmol), and the mixture is stirred at 70° C. for 18 h. The mixture is cooled to RT, Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled to give 3.39 g of the product 430.
Reaction SMILES: [C:1](C1C=CC(C2C=CC(F)=CC=2F)=C(F)C=1)(=O)[CH3:2].[S].N1CCOCC1.S(=O)(=O)(O)O.[F:31][C:32]1[CH:37]=[C:36]([CH2:38][C:39]([OH:41])=[O:40])[CH:35]=[CH:34][C:33]=1[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49]>O.C(O)(=O)C>[F:31][C:32]1[CH:37]=[C:36]([CH2:38][C:39]([O:41][CH2:1][CH3:2])=[O:40])[CH:35]=[CH:34][C:33]=1[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Agent: O=S(=O)(O)O
Agent: [S]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCN1
Product: CCOC(=O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Temperature: 0 °C

Procedure:
A mixture of 4-acetyl-2,2',4'-trifluorobiphenyl (4.4 g., 17.6 m.moles), sulphur (1 g.) and morpholine (5 ml.) was stirred under reflux for 16 hours to give the thiomorpholide. After cooling, and the addition of acetic acid (glacial, 25 ml.), concentrated sulphuric acid (4 ml.) and water (10 ml.) the mixture was stirred and refluxed for 24 hours. Ice-water was added to precipitate a crude solid. This was taken up in ether and back-extracted with aqueous potassium carbonate. The extracts were washed with ether, acidified, and re-extracted with ether. Evaporation gave 4.2 g. of crude 2,2',4'-trifluoro-4-biphenylylacetic acid. This was then mixed with absolute alcohol (65 ml.) and concentrated sulphuric acid (3 ml.) and the mixture refluxed overnight. Excess alcohol was distilled off and the residue diluted with water (100 ml.). The product was isolated with ether, washed with aqueous sodium bicarbonate, dried, evaporated and distilled (b.p. 130°-136°/0.4 mm.) to give 3.2 g. of pale yellow oil which solidified on standing. This was recrystallised from 40-60 petroleum ether to give ethyl 2,2',4'-trifluoro-4-biphenylylacetate having a m.p. of 50°-52° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:49])[NH:34][CH2:35][CH2:36][CH2:37][C@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][NH2:40])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH2:13][C:14]([NH:40][CH2:39][C@@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:49])=[O:16])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NC[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.1 g (0.26 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid (J. Med. Chem. (2002) 45:4246-4253) and 0.11 g (0.34 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.065 g (0.34 mmol) of EDC and 0.011 g (0.079 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18](O)=[O:19])[CH2:6][C:5]2=1.C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15]([NH2:16])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:19])[CH2:6][C:5]2=1
Reactant: NC(=O)c1cc(Br)cc2c3c([nH]c12)CCC(C(=O)O)C3
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2c3c([nH]c12)CCC(C(=O)N1CCOCC1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
To a solution of 6-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (0.8 g, 2.135 mmol), EDC (0.491 g, 2.56 mmol), and 1-hydroxybenzotriazole hydrate (0.392 g, 2.56 mmol) in THF/CH2Cl2 (5/1) (30 mL) was added morpholine (0.4 mL, 4.27 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the solid was washed with ethyl acetate, and water. The organic layer was dried over Na2SO4 and concentrated to afford the crude product as a pale solid. The solid was washed with hexane-ethyl acetate to give 800 mg of pure 6-bromo-3-(morpholine-4-carbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide. MS (ESI) m/z 406 (M+H). 1H NMR (DMSO-d6) δ ppm 10.9 (s, 1H), 8.2 (bs, 1H), 7.81 (d, 1H), 7.75 (s, 1H), 3.92 (m, 4H), 3.77 (q, 2H, J=7.8 Hz), 2.52-2.81 (m, 7H).
Reaction SMILES: [Li]CCCC.CCCCCC.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[C:21]3[CH:27]=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1.CN(C1C=CN=CC=1)C>[C:29]([Si:32]([CH3:34])([CH3:33])[N:25]1[C:22]2=[N:23][CH:24]=[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)[CH:20]=[C:21]2[CH:27]=[CH:26]1)([CH3:31])([CH3:30])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1cccc(-c2cnc3[nH]ccc3c2)c1
Agent: CN(C)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccc(F)c3)cnc21
Yield: 80.6 %

Procedure:
2.5 M solution of n-BuLi in hexane (13.7 mL, 34.3 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of azaindole 7 (6.04 g, 28.5 mmol) in THF (30 mL). After the mixture was stirred for 10 min at −78° C., DMAP (66 mg, 0.54 mmol) was added, followed by a solution of TBSCl (5.14 g, 34.1 mmol) in THF (2.5 mL). The mixture was stirred at −78° C. for 1 h. Cooling bath was removed, the mixture was stirred at r.t. for 3 days, and separated between AcOEt:saturated aqueous NaHCO3 solution. The aqueous layer was extracted with AcOEt (3×). Combined organic solutions were dried (MgSO4), concentrated, and separated by means of SGC with hexane:benzene as eluent in gradient (up to 15% benzene) to afford 8 (7.50 g, 81%) as white solid. 1H NMR (400 MHz, CDCl3) δ 0.67 (s, 6H), 0.96 (s, 9H), 6.59 (d, J=3.5 Hz, 1H), 6.99-7.07 (m, 1H), 7.29 (d, J=3.5 Hz, 1H), 7.33 (ddd, J=10.9, 3.0, 1.7 Hz, 1H), 7.38-7.44 (m, 2H), 8.04 (d, J=2.3 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][C:43]([CH3:45])=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH:43]([CH3:45])[CH3:42])[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: CC(C)=O
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
(4Z)-6-iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (23.7 mg, 0.05 mmol) is dissolved in N-methylpyrrolidinone (0.5 mL) and methylene chloride (0.15 mL), followed by addition of sodium triacetoxyborohydride (122 mg, 0.575 mmol), acetone (0.095 mL, 1.29 mmol) and acetic acid (0.075 mL, 1.31 mmol). After stirring at room temperature for 1 h, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 18.8 mg (73%) of the title compound as a yellow solid. MS (ESI) m/z 517.0 (M+H)+1
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#N)=[CH:18][CH:17]=1)([F:14])[F:13].[O:24]1CCOCC1.Cl>C(OCC)C.O>[F:11][C:12]([F:14])([F:13])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:24])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Reactant: C1COCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 3 h

Procedure:
Diisobutylaluminium hydride (11.8 ml. 1M solution in toluene) was added to a stirred solution of 4-cyanophenyl trifluoromethyl ether (2.0 g., Fairfield) in dry diethyl ether (100 ml.). The mixture was refluxed with stirring for 3 hours. The mixture was cooled and dioxane (5 ml.) containing water 1.0 ml.) was added. Dilute hydrochloric acid was added (60 ml. of 10% solution). The mixture was stirred for 30 minutes and extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography on silica, eluting with 9:1 hexane:diethyl ether. 4-Trifluoromethoxybenzaldehyde was obtained as a colourless liquid (1.65 g.).