Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17](F)[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>>[CH:22]1([NH:27][C:17]2[CH:16]=[C:15]([C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=3[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=3)[CH:20]=[CH:19][N:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(F)c2)s1
Reactant: NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC3CCCC3)c2)s1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 2-ethyl-5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazole (0.48 g, 1.6 mmol) and cyclopentylamine (1.6 mL, 16 mmol) was heated under reflux for 14 hrs. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (0.19 g, yield 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C.CCOC(C)=O>[N:31]([CH2:24][CH2:23][O:22][C@@H:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:30])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(Cl)cc1[C@H](OCCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1[C@H](OCCN=[N+]=[N-])[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 93.5 %

Procedure:
(R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (8.4 g, 18.3 mmol) was dissolved in anhydrous DMF (150 mL), solid NaN3 (3.56 g, 54.8 mmol.) was added and the reaction mixture was heated to 60° C. for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (500 mL), the organic phase was washed with water (5×50 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-((R)-(2-azidoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (7 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[S:34][C:33]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:32]=2[CH:31]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH:17]([CH3:19])[N:16]([CH2:29][C:30]4[S:34][C:33]5[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:32]=5[CH:31]=4)[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ccc2cc(CBr)sc2c1
Reactant: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1Cc1cc2ccc(Cl)cc2s1
Reaction time: 8 h
Yield: 10.3 %

Procedure:
(3 S,5RS)-1-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (260 mg, 0.56 mmol), EXAMPLE 88, is dissolved in 5 mL of DMF. Potassium carbonate (193.4 mg, 1.4 mmol) is added followed by the addition of 2-bromomethyl-6-chloro-benzo[b]thiophene (218 mg, 0.84 mmol), EXAMPLE 5. Reaction is left to stir overnight. The crude mixture is purified by reverse phase HPLC (10-70% ACN/H2O) to afford the product (27 mg, 6%) as a clear wax with a melting point of 130-131° C. C24H24ClN5OS MS m/z: 466, 468.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([C:12]1([CH:29]=O)[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].O>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([C:12]1([CH:29]=[CH2:1])[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCC1CCC(C2CCC(C=O)(CCCCC)CC2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17.84 g of KOtBu in 100 ml of THF is added dropwise at 0° C. to a suspension of 53.20 g of 4,4′-dipentylbicyclohexyl-4-carbaldehyde and 56.80 g of methyltriphenylphosphonium bromide in 300 ml of THF. The mixture is stirred at RT overnight, water is added, and the mixture is extracted with MTB ether. The combined organic phases are subjected to conventional work-up, giving 4,4′-dipentyl-4-vinylbicyclohexyl.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:5][CH:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC1=CC=C(c2ccccc2)C(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(CC(=O)O)=CC=C1c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 2,2-dimethyl-(4-biphenyl)acetic acid, methyl ester (4.18 g, 16.5 mmol) and sodium hydroxide (3.29 g) in ethanol (57 mL) and water (25 mL) was heated under reflux for 18 hours. The mixture was cooled to rt and acidified to pH 2 with 6N HCl. The precipitate was collected by filtration and recrystallized from ether to give 2,2-dimethyl-(4-biphenyl)acetic acid (1.37 g 5.7 mmol, 35%).
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)=[O:6].[NH2:13][C:14]([NH2:16])=[O:15].CC#N>CN(C=O)C>[CH3:3][O:4][C:5]([N:7]1[CH2:8][CH:9]=[CH:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][C@@H:12]12)=[O:6]
Reactant: NC(N)=O
Reactant: COC(=O)N1C=CC=CC1
Agent: BrBr
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)N1CC=C[C@H]2OC(N)=N[C@H]21
Yield: 49.9 %

Procedure:
A solution of Br2 (1 ml, 19.3 mmol, 1 equiv.) in DMF (5 ml) is added over 20 min to a solution of N-methoxycarbonyl-1,2-dihydropyridine 1 (2.68 g, 19.3 mmol, 1 equiv.) and of urea (2.3 g, 38.6 mmol, 3 equiv.) in a mixture of DMF (19 ml) and of CH3CN (6 ml) at ambient temperature and under argon. The reaction being complete from the end of the addition of the bromine, the reaction mixture is concentrated to dryness. The residue is dissolved in methanol (30 ml), poured onto ice-cold water (150 ml) and then filtered through a Buchner funnel. The filtrate is basified (5% Na2CO3) until a pH of greater than 10 is obtained. After extracting with dichloromethane (4×100 ml), the aqueous phase is saturated with NaCl and then reextracted with dichloromethane (4×100 ml). After drying over MgSO4 and evaporating the solvent, the solid obtained (5.94 g) is chromatographed on silica gel using dichloromethane (DCM) saturated with ammonia and then DCM saturated with NH3:MeOH, 98:2. The product is obtained in the form of a beige solid (1.9 g, 50%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[N:29]=[C:30]([C:33]([OH:35])=O)[S:31][CH:32]=1)([CH3:27])[CH3:26].[O:36]1[C:41]2([CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)[CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CN(C=O)C>[CH:25]([C:28]1[N:29]=[C:30]([C:33]([N:39]2[CH2:40][C:41]3([CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]3)[O:36][CH2:37][CH2:38]2)=[O:35])[S:31][CH:32]=1)([CH3:26])[CH3:27]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.924 g) was added in one portion to a stirred solution at 0° C. of 4-isopropylthiazole-2-carboxylic acid (0.32 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 12, step b) (0.547 g) and triethylamine (0.781 mL) in DMF (12 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.54 g.
Reaction SMILES: [NH:1]([C:8]1[CH:12]([N:13]2[CH:17]=[C:16]([NH2:18])[C:15]([CH3:19])=[N:14]2)[C:11](=[O:20])[N:10]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=2[Cl:29])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(OCC)(=O)C>C(#N)C>[NH:1]([C:8]1[CH:12]([N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:15]([CH3:19])=[N:14]2)[C:11](=[O:20])[N:10]([C:21]2[C:22]([Cl:29])=[CH:23][C:24]([Cl:28])=[CH:25][C:26]=2[Cl:27])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1nn(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCCCCCCC(=O)Nc1cn(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2Nc2ccccc2)nc1C

Procedure:
The 4-(4-amino-3-methyl-1-pyrazolyl)-3-anilino-1-(2,4,6-trichlorophenyl)-5-oxo-2-pyrazoline obtained in Step 2 was suspended in 100 ml of acetonitrile and stirred with heating. To the solution, 9 g of tetradecanoylchloride was added and the mixture was refluxed for 2 hours. To the reaction mixture, 500 ml of ethyl acetate was added and the mixture was washed several times with water. The oil layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and benzene, 8 g of Coupler (23) was obtained. The melting point of the coupler was 123° to 131° C.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:2]([C:10]([NH:12][CH2:13][C:14](O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[C:60]([NH:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][NH2:74])([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>C1COCC1>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][NH:67][C:60]([O:62][C:63]([CH3:64])([CH3:65])[CH3:66])=[O:61])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a solution of Fmoc-Phe-Gly-OH (0.66 g) in anhydrous THF (20 mL) at 0° C. under N2 was added N,N′-dicyclohexylcarbodiimide (0.307 g) and 1-hydroxybenzotriazole hydrate (0.201 g). After stirring for 15 min, N-Boc-1,6-diaminohexane (0.322 g) was added. The reaction mixture was allowed to warm to RT and stirred overnight. Solids were filtered off and they were washed with EtOAc. The filtrate and washings were then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0 to 10% MeOH in CH2Cl2) to afford Fmoc-Phe-Gly-NH—(CH2)6NH-Boc as a white solid (0.9 g).
Reaction SMILES: Cl[C:2]([F:28])([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:4]=1[C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH2:21]([N:18]([CH2:19][CH3:20])[C:5]1[C:4]([C:23]([O:25][CH3:26])=[O:24])=[C:3]([CH:2]([F:27])[F:28])[N:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:22]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(CC)CC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N(CC)CC
Yield: 68.2 %

Procedure:
A mixture of 2.5 g (0.006 mol) of product of Example 53, 0.61 g (0.006 mol) of triethylamine and 0.12 g of Pd/C (10%) in 35 ml of ethanol was hydrogenated at 50° C. under 480 kPa of hydrogen pressure for 45 minutes. Reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in ether, washed with 10% HCl and the aqueous 10% HCl layer was extracted with chloroform. The combined organic layers were dried (MgSO4) and concentrated in vacuo to 1.91 g. Crude was kugelrohr distilled at 109 Pa, pot temperature 99° C., affording 1.63 g (68.2%) of this product as a yellow oil, nD25 1.4682.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH:23]([C:28](=O)[CH2:29][CH2:30][CH3:31])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1)#[N:9].C([O-])(=O)C.[NH4+:37].C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:37]/[C:28](/[CH2:29][CH2:30][CH3:31])=[C:23](/[CH2:22][C:19]1[CH:20]=[N:21][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]#[N:9])=[CH:17][CH:18]=1)\[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC/C(N)=C(\Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Process 2: A toluene (45 mL)-acetic acid (5 mL) mixture containing methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxohexanoate (1.2 g, 3.6 mmol) and ammonium acetate (8.3 g, 108 mmol) was refluxed under heating for 1 hour. After cooling to room temperature, saturated aqueous solution of sodium hydrogen carbonate was added and extraction was carried out with toluene. After washing with brine, it was dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl (Z)-3-amino-2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-2-hexenoate (1.15 g) as brown oil crude product. It was used for the next process without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (560 mg, 1.42 mmol) in methanol (30 ml) was added sodium hydroxide (227.9 mg, 5.69 mmol) and water (2 ml) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo and dissolved in water (30 ml), adjusted to pH 5 with HCl (3N). The product was precipitated from water and collected by filtration to afford 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (486 mg, 90%).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[C:14]([OH:16])[CH:15]=[C:11]3[CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:27][C:28]([F:43])([S:39](F)(=[O:41])=[O:40])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]>C1COCC1.CCOC(C)=O>[F:43][C:28]([F:27])([S:39]([O:16][C:14]1[CH:15]=[C:11]2[CH2:10][CH2:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]2[N:13]=1)(=[O:41])=[O:40])[C:29]([F:37])([F:38])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]
Reactant: Oc1cc2n(n1)C(c1ccccc1)=CCC2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1cc2n(n1)C(c1ccccc1)=CCC2)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Step AAH (7): To a soln of 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-ol (500 mg, 2.356 mmol) in THF (15 mL) was added NaHMDS (1.0 M in THF, 2.94 mL, 2.94 mmol) at −78° C. under nitrogen. After stirring for 10 min, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1281 mg, 4.24 mmol) was added. The mixture was allowed to warm from −78° C. to rt over 3 h. The reaction was diluted with EtOAc (200 mL) and washed sequentially with 0.1 N aqueous sodium hydroxide, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (30% EtOAc/hexanes) to afford 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.0 g, 86% yield). LC-MS (M+H)+ 495.12.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:18]1[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:25][C:24]([F:27])([F:26])[C:21]1[N:22]=[CH:23][C:18]([NH:1][CH2:2][C@@H:3]2[CH2:9][C@H:8]3[C@H:6]([CH2:7]3)[CH2:5][N:4]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:19][CH:20]=1
Reactant: FC(F)(F)c1cnc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CNc1cnc(C(F)(F)F)cn1
Temperature: 50 °C

Procedure:
1,1-dimethylethyl (1S,4S,6S)-4-(aminomethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D29 (400 mg) and 2-bromo-5-(trifluoromethyl)pyrazine (401 mg, 1.767 mmol) were dissolved in DMF (2 ml) then sodium carbonate (375 mg, 3.53 mmol) was added and the mixture was heated to 50° C. for 2 hours. DMF was concentrated under vacuum and the residue was taken up with DCM (3 ml) and washed with NaHCO3 saturated solution (4 ml). The organic phase was filtered through a phase separator tube, concentrated under vacuum and purified by silica gel chromatography (Biotage SP—column size 25 g SNAP using Cy:EtOAc=8:2 to 2:8 as eluent). It was recovered the title compound D30 (300 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH:19]([C@@H:21]1[CH2:26][C@H:25]([N:27]([C:32]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]3[CH:45]=[CH:46][CH:47]=[CH:48][C:36]=3[N:35]=2)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:24][N:23]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:22]1)=[O:20].[Cl-].[NH4+]>C1COCC1>[OH:20][CH:19]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C@@H:21]1[CH2:26][C@H:25]([N:27]([C:32]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]3[CH:45]=[CH:46][CH:47]=[CH:48][C:36]=3[N:35]=2)=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:24][N:23]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:22]1
Reactant: Brc1ccccn1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(O)c3ccccn3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of bromopyridine (0.058 ml) cooled to −78° C. in THF (5 ml) was added 1.6M-butyllithium hexane solution (0.33 ml) and the mixture was stirred for 30 min. A solution of tert-butyl (3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (257 mg) in THF (5 ml) was added and the mixture was stirred at −20° C. for 2 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:37](I)[CH3:38]>C(OCC)(=O)C>[CH2:37]([N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[C:12]([CH3:25])[C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH3:38]
Reactant: CCOC(=O)c1cc2c(C)c(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)c(C)cc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a mixture of ethyl 7-[(2-thienylsulfonyl)amino]-4,5-dimethyl-1H-indole-2-carboxylate (0.35 g), potassium carbonate (0.13 g) and N,N-dimethylformamide (8 mL) was added dropwise ethyl iodide (0.074 mL) under ice-cooling. The mixture was stirred at from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8), and the obtained colorless crystals were recrystallized from ethyl acetate-hexane to give the title compound (253 mg, yield 67%) as colorless prism crystals. melting point 134-135° C.
Reaction SMILES: [N:1]1([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:8][C:7](=[O:9])[CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CCCCC(C(C)=O)n1ccnc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCC(C(=O)C=Cc1ccc(Cl)c(Cl)c1)n1ccnc1

Procedure:
2.7 g of 3-(imidazole-1-yl)-2-heptanone and 3.0 g of 3,4-dichlorobenzaldehyde were dissolved in 50 ml of methanol. While stirring this solution under cooling with ice (0°-5° C.), 2.1 g of potassium carbonate was added. Then, the mixture was stirred at the same temperature for 7 hours. The reaction mixture was poured into water and extracted with chloroform. The extraction solution was treated by a usual method, and the obtained oily product was purified by chromatography, whereby 1-(3',4'-dichlorophenyl)-4-(imidazole-1-yl)-1-octene-3-one was obtained as an oily product.