Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36]([Cl:39])(=[O:38])[CH3:37]>C(Cl)Cl>[ClH:39].[C:36]([N:6]1[CH2:7][CH2:8][N:3]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])=[CH:27][CH:28]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5]1)(=[O:38])[CH3:37]
Reactant: CCN(CC)C(=O)c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C(c2ccccc2)N2CCN(C(C)=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
The free amine of compound 64 (100 mg, 0.28 mmol) was dissolved in methylene chloride (5 ml), cooled to 0° C. Triethyl amine (43 μl, 0.31 mmol) was added and then acetyl chloride (22 μl, 0.31 mmol) was added dropwise. After 10 min, the solution was washed with potassium carbonate (10%), dried (K2CO3) and evaporated in vacuo. The residue was purified by chromatography on silica (CH2Cl2 /MeOH/NH3, 95:5:0.5) to give 116 mg of compound 77 (~100 %).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:18]2[C:19]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]3[OH:28])[C:17]=2[CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[C:18]2[C:19]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])[C:17]=2[CH:16]=[CH:15][N:14]=1
Reactant: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2C1CCCCC1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2C1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of oxalyl chloride (910 mg) in dichloromethane (3 mL) was added DMSO (670 mg) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 30 min, and a solution of 2-(4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexanol (350 mg) in dichloromethane (2 mL) was added thereto. The reaction mixture was stirred at −78° C. for 1 hr, and triethylamine (1.2 g) was added thereto. The reaction mixture was stirred at −78° C. for 1.5 hr, and added to ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (190 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([CH:9]1[CH2:27][CH2:26][N:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:11]2[CH2:10]1)#[N:8].O>CCOCC.C1COCC1>[NH2:8][CH2:7][CH:9]1[CH2:27][CH2:26][N:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:11]2[CH2:10]1
Reactant: N#CC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
To a suspension of 10 g LiAlH4 in 400 ml of dry ether a solution of 8 g of 2-cyano-1,2,3,4,10,14b-hexahydro-pyridino[ 1,2-a]-dibenzo[c,f]-azepine (axial) in 300 ml of THF is added. Then the mixture is refluxed for 30 minutes, whereupon it is cooled by means of ice. After that 40 ml of water are added to the mixture carefully so as to hydrolyse the excess of LiAlH4. The resulting precipitate is filtered off after which the filtrate is evaporated.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH3:23])([O-:13])=[O:12].N1CCCCC1>C1(C)C(C)=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[CH:23][C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a 2 liter 3-necked round-bottomed flask equipped with a condenser, a Dean-Stark trap, a mechanical stirrer, nitrogen inlet, heating mantle, thermometer, and a Therm-o-watch® temperature controller, was added p-anisaldehyde (149.8 grams, 1.1 moles), 2,4-dinitrotoluene (182 grams, 1.0 mole), xylene (500 milliliters), and piperidine (50 milliliters, 0.5 mole). The resulting mixture was heated with the temperature on the Therm-o-watch® temperature controller set at 145° C. After stirring and heating for about 2 hours, approximately 20 milliliters of water had collected in the Dean-Stark trap. The reaction solution was allowed to cool to room temperature, and then further cooled with an ice water bath for an additional hour during which time the desired product crystallized from the solution. The solid material was filtered, rinsed with pentane, and dried in a vacuum oven at 100° C. for 12 hours to give 257.1 grams (85.6 percent of theory) of the desired product as a dark red crystalline solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@H:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:28]([CH2:6][CH2:7][C@@H:8]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[N+:29]=[N-:30]
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCN=[N+]=[N-])Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-4-(4-(trifluoromethyl)phenyl)butyl methanesulfonate from the previous reaction was dissolved in 25 mL DMF and NaN3 (1.3 g, 20 mmol) was added. The mixture was heated to 70° C. for 4 hours and cooled back to room temperature. Water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over MgSO4 and evaporated. Glass column chromatography (10% EtOAc in hexanes) provided the title compound as white solid. LCMS (API-ES) m/z (%): 259.0 (100%, M++H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11](O)(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[CH3:13][CH:12]1[CH2:14][C:3]2[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=2[NH:1][C:11]1=[O:15]
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: C=C(C)C(=O)O
Product: CC1CC2=C(CC(C)(C)CC2=O)NC1=O

Procedure:
Prepared analogously to Example G from 1-amino- 5,5-dimethylcyclohexen-3-one and methacrylic acid in an autoclave at 180° C. over a period of one hour.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:31][CH2:32][CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O>[CH2:34]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH2:27])[CH2:33][CH:32]=[CH2:31]
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0.3M solution of methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate in dry DMF, 60% NaH (1.5 eq) in mineral oil was added at 0° C.; after stirring for 45 min at RT, 4-bromobut-1-ene (1.5 eq) was added and the suspension was stirred for 5 h at 40° C. and then 1 day at RT (NaH and 4-bromobut-1-ene were added several times). The mixture was diluted with EtOAc, washed with 1N HCl, water and brine, dried (Na2SO4) and concentrated in vacuo to give, after chromatography (PE/EtOAc 95:5), the title compound (60%) along with recovered starting material (40%); MS (ES+) m/z 414 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: CN1CCNCC1
Solvent: CO
Product: COC(=O)c1nc(CN2CCN(C)CC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reaction time: 16 h

Procedure:
A mixture of 8.0 g (0.015 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 13(b)] and 3.3 ml of 1-methyl-piperazine in 160 ml of methanol is stirred for 16 hours at 40°. The reaction solution is then concentrated in vacuo; water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice water, and extraction is then performed twice with 2 N hydrochloric acid solution. To the aqueous acidified extracts there are added ice and sufficient 5 N sodium hydroxide solution to bring the pH-value to 10. The base that has precipitated is taken up in ether. The organic phase is washed twice with saturated sodium chloride solution; it is afterwards dried over sodium sulphate and concentrated in vacuo to dryness. There is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(4-methyl-1-piperazinyl)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester as solidified foam.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]3=[O:23])[CH:13]=2)[C:8]([CH3:25])([CH3:24])[CH2:7]1)(=[O:5])[CH3:4].[Cl:26][C:27]1[CH:32]=[C:31]([CH2:33]Cl)[CH:30]=[CH:29][N:28]=1>CN(C)C=O.O>[C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[N:17]([CH2:33][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=4)[C:16]3=[O:23])[CH:13]=2)[C:8]([CH3:25])([CH3:24])[CH2:7]1)(=[O:5])[CH3:4]
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)NC(C)(C)C3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To 949 mg of sodium hydride are added dropwise, under argon, 5 mL of dimethylformamide, followed by addition of a solution of 6.8 g of 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage g) below in 40 mL of dimethylformamide. The solution obtained is stirred for 1.5 hours at 25° C., followed by addition of 5.24 g of 2-chloro-4-chloromethylpyridine obtained in stage b) below. The reaction mixture is stirred at room temperature for 15 hours and diluted with 300 mL of water, and the solid formed is filtered off, washed with three times 20 mL of water and with twice 20 mL of diethyl ether and dried to give 8.8 g of 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[H-].[Na+].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH2:24]Br)=[CH:18][C:17]=2[CH:26]=1)([O-:12])=[O:11].O>CN(C)C=O.C(OCC)(=O)C>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH2:24][NH:5][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])=[CH:18][C:17]=2[CH:26]=1)([O-:12])=[O:11]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CBr
Reactant: NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CNC(=O)C(F)(F)F
Temperature: 70 °C
Yield: 32.9 %

Procedure:
2,2,2-trifluoroacetamide (0.53 g, 4.7 mmol) in dimethylformamide (2 ml) was added dropwise to a suspension of sodium hydride (80%, 1.4 g, 4.7 mmol) in dimethylformamide (2 ml). After one hour at room temperature 6-nitro-2,2-dimethyl-3-bromomethyl-2H-1-benzopyran (1.4 g, 4.7 mmol) was added and the mixture heated at 70° C. for eighteen hours. Water and ethyl acetate were added to the cooled solution and the organic phase separated and evaporated to give 0.51 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-2H-1-benzopyran, 1NMR (CDCl3): δ1.5 (s, 6H), 4.15 (d, 2H), 6.25 (s, 1H), 6.85 (d, 1H), 6.9 (br.s), 1H), 7.85 (s, 1H), 8.05 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26][C:25](=O)[CH:24]=1.Cl>C1COCC1.O>[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26]/[C:25](=[C:5]2/[C:6](=[O:11])[NH:7][C:8]3[C:4]/2=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)/[CH:24]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC1(C)OC(=O)C=C1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
To a solution of 5-fluorooxindole (7.5 g, 49 mmol) in THF (80 mL) at 0° C., was added 1 M LHMDS in THF (100 mL, 100 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one(6.4 g, 33 mmol) in THF (20 mL) was added to the reaction mixture. The reaction was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature over 5 hours. To the reaction mixture was added aqueous 2 M HCl (100 mL). The resulting mixture was stirred at 60-65° C. for 1 hour, cooled to room temperature, poured into water (3000 mL) and stirred at room temperature for 2 hours. The precipitates separated and were collected, washed with water, and dried in vacuo to provide 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (8.7 g, yield 80%), which was used for the next reaction without further purification.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CO.CS(C)=O.O>[CH2:10]([O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
3.3 g of sodium were dissolved in 60 ml of methanol and stirred with 15 g of 5-hydroxy-2-methylpyridine in 230 ml of DMSO for 1 hour at a temperature of 80° to 90° C. The methanol was spun or rotated out after cooling the mixture. 23.5 g of benzylbromide were then added, followed by stirring for 20 hours at room temperature. The reaction mixture was then acidified with 2N HCl and mixed with 1500 ml of water. The mixture was then extracted with diethyl ether and the ether phase was discarded. The pH-value of the aqueous phase was then adjusted to approximately 8 and the solution was extracted with ether. The organic phase was evaporated. 24.1 g of 5-benzyloxy-2-methylpyridine were obtained. The latter was dissolved in 200 ml of glacial acetic acid, mixed with 12 ml of hydrogen peroxide (30%) and refluxed for 2 hours. The mixture was then neutralized with 40% caustic soda solution and 1000 ml of water were added. The solution was extracted with dichloromethane and the organic phase evaporated. 25 g of 5-benzyloxy-2-methylpyridine-N-oxide were obtained.
Reaction SMILES: [C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][CH:11]([C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[CH:40][CH:41]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(N)c1cccc2ccccc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(C)c3cccc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 1-(naphthalen-1-yl)ethanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 553 (M+H).
Reaction SMILES: Cl.Cl.C([O:5][C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+].O.CO>[C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[O:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCC1CCNCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A solution of 3(S)-[1(S)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.35 g) in 1N sodium hydroxide solution (8 ml) is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (1.5 ml), the mixture is subjected to column chromatography on MCI gel (CHP 20P, 150-300μ, Mitsubishi Chemical) using water-methanol (2:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to yield 3(S)-[1(S)-carboxy-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.2 g) as colorless powder.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)[CH:18]=1
Reactant: Cc1ccnc(OCc2ccc(Br)cc2)c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(OCc2ccc(C=O)cc2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)-4-methyl-pyridine (5.70 g, 20.5 mmol) described in Manufacturing Example 43-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 9.21 mL, 24.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 20 minutes at −78° C. N,N-dimethylformamide (3.16 mL, 41.0 mmol) was then added dropwise thereto and stirred for 10 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.58 g, 55.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccc(F)cc1F
Product: COc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C2CCOCC2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5].ClCCCCN1C(OC)=NC2C1=NC(O[C@@H](C)CCC)=NC=2N.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59]N)[CH2:55][CH2:54]1>>[CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:59][CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: NCC1CCOCC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Agent: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 36 from 9-(4-chlorobutyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and (tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH2:28].[CH3:36]CN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][N:27]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (800 mg, 1.63 mmol) in DCE (15 mL) was added tert-butyl hydrazinecarboxylate (290 mg, 1.96 mmol), DMAP (218 mg, 1.86 mmol), EDC.HCl (279 mg, 1.86 mmol) and DIPEA (0.8 mL, 4.89 mmol). The reaction mixture was stirred at 25° C. for 12 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% hexane:EtOAc) afforded the title compound as a brown gum (800 mg, 72%): 1H NMR (300 MHz, DMSO-d6) δ 10.5 (bs, 1H), 7.96 (s, 1H), 7.91 (s, 2H), 7.66 (d, J=7.8 Hz, 1H), 7.37 (s, 1H), 7.03 (dd, J=15.3, 8.7 Hz, 1H), 6.78 (d, J=15.9 Hz, 1H), 4.87-4.81 (m, 1H), 3.08 (s, 3H), 1.43 (s, 9H).