Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.CO[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH:12]=[O:13])=[O:11].[CH3:14][C:15]([NH2:27])([CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1.[CH3:28]S(C)=O>>[CH3:26][C:15]([N:27]=[C:12]([O:13][CH3:28])[C:10]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:11])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1
Reactant: CC(C)(N)Cc1ccc2c(c1)OCO2
Reactant: CS(C)=O
Reactant: COc1ccccc1C(=O)C=O
Solvent: O
Product: COC(=NC(C)(C)Cc1ccc2c(c1)OCO2)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 590 mg of 2-methoxyphenylglyoxal hydrate, 500 mg of α,α-dimethyl-3,4-methylenedioxyphenethylamine and 1.5 ml of dimethylsulfoxide is stirred at room temperature for 45 minutes, whereby a solution of α-(α,α-dimethyl-3,4-methylenedioxyphenethylimino)-2-methoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([CH:36]=[C:37]([CH3:39])[CH:38]=2)[NH2:35])[CH2:27][CH2:26]1)(=[O:24])[CH3:23]>CO.C(Cl)Cl>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([NH:35][C:5]3[N:10]=[C:9]([N:11]4[CH:15]=[CH:14][N:13]=[C:12]4[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:8]=[CH:7][N:6]=3)[CH:36]=[C:37]([CH3:39])[CH:38]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CCN(Cc2cc(C)cc(N)c2)CC1
Reactant: CS(=O)(=O)c1nccc(-n2ccnc2-c2ccccc2)n1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2cc(C)cc(Nc3nccc(-n4ccnc4-c4ccccc4)n3)c2)CC1
Temperature: 130 °C

Procedure:
2-(Methylsulfonyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (1-3, 100 mg, 0.33 mmol) and 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylaniline (240 mg) were combined neat and heated to 130° C. After 2 hours the mixture was cooled to room temperature. Flash column chromatography (gradient, 2-5% MeOH/CH2Cl2) gave the title compound as an off-white foam. 1H-NMR (300 MHz, CDCl3) δ 8.26 (d, J=5.5 Hz, 1H), 7.68 (d, J=1.53 Hz, 1H), 7.50 (m, 2H), 7.40 (m, 4H), 7.30 (s, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 6.25 (d, J=5.49 Hz, 1H), 3.64 (t, J=5.19 Hz, 2H), 4H), 3.46 (m, 4H), 2.44 (m, 4H), 2.35 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:35])[C:19]2[CH:24]=[N:23][C:22](SC)=[N:21][C:20]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:16])[CH3:13].[O-:36][S:37]([O-:39])=O.[Na+].[Na+]>ClCCl>[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:35])[C:19]2[CH:24]=[N:23][C:22]([S:37]([CH3:1])(=[O:39])=[O:36])=[N:21][C:20]=2[N:27]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH:28]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(SC)ncc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reaction time: 2 h

Procedure:
m-CPBA (0.33 g, 1.5 mmol of a 70% w/w mixture) was added to a solution of 8-cyclohexyl-2-methylsulfanyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.206 g, 0.59 mmol) in dichloromethane (15 mL). After 2 hours, a 10% solution of Na2SO3 (1 mL) was added and the mixture was partitioned between sat. NaHCO3 and dichloromethane. The organic layer was dried (MgSO4) and concentrated to provide 0.22 g of the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C17H21N3O5S: 379.12. found: (M+H) 380.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:25]=[C:24]4[C:19]([N:20]=[CH:21][C:22](=O)[NH:23]4)=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.C[N:28]([CH:30]=[O:31])C>O=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(O)(C)C.[C-]#N.[C-]#N.[Zn+2].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>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:25]=[C:24]4[C:19]([N:20]=[CH:21][C:22]([C:30]([NH2:28])=[O:31])=[N:23]4)=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(=O)[nH]c4c2)CCC3)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(C(N)=O)nc4c2)CCC3)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
Reflux 7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one (Example 55b; 20 mg, 0.055 mmol,) in POCl3 overnight. After removing POCl3, treat the residue with Zn(CN)2 (11.6 mg, 0.11 mmol) and Pd(PPh3)4 (3 mg, 0.003 mmol) in DMF (1 mL) at 100° C. for 20 min in microwave. Cool the solution to room temperature, dilute with chloroform/isopropyl alcohol and wash with brine. Dry the solution over sodium sulfate, filter, and evaporate the solvents to give a viscous mixture. Purify the crude product by column chromatography eluting with a gradient from dichloromethane to 10% methanol in dichloromethane to give the desired compound 12 mg (59%). MS (electrospray, m/z) 371.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH:17]=[O:18])=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC([O-])=O.[Na+].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH2:7][CH:8]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=[CH:20]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][OH:18])=[CH:15][N:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ncc(CO)s1)C(CC1CCCCC1)n1cnc2ccc(F)cc2c1=O
Reaction time: 0.5 h

Procedure:
A mixture of Compound 150 (0.2 g, 0.4675 mmol) and NaOAc (46 mg, 0.561 mmol) was dissolved in DCM:MeOH (20:1, 1 mL) and stirred for 30 min. To this solution was added NaBH3CN (0.056 mg, 0.891 mmol) and the mixture was stirred at RT overnight. The reaction was quenched with aqueous NaHCO3 and extracted into DCM. The organic layer was washed with water and dried over MgSO4. The crude product was purified via preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88-1.31 (m, 6H) 1.73 (s, 5H) 1.99-2.10 (m, 1 H) 2.14-2.26 (m, 1H) 4.82 (s, 2H) 5.83 (dd, J=8.84, 7.07 Hz, 1H) 7.47 (s, 1H) 7.48-7.56 (m, 1H) 7.77 (dd, J=8.97, 4.67 Hz, 1H) 7.95 (dd, J=8.34, 2.78 Hz, 1H) 8.31 (s, 1H). [M+H] calc'd for C21H23FN4O3S, 431; found, 431.
Reaction SMILES: [CH2:1]=O.Cl.[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[SH:15]>O.C(OCC)C.C(N(CC)CC)C>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][C:6]2[S:15][CH2:1][NH:4][C:5]=2[CH:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: FC(F)(F)c1ccc2c(c1)NCS2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
37% formalin (0.22 mL) was diluted with water (6 mL), and diethylether (6 mL), triethylamine (0.37 mL) and 2-amino-4-trifluoromethylbenzenethiol hydrochloride (611 mg) were added to the solution, and then the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and the aqueous layer was extracted with diethylether. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (b).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)(=[O:4])=[O:3].[Br:12]CC1C=CC(S(C)=O)=NC=1.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][CH:7]=1
Reactant: CS(=O)c1ccc(CBr)cn1
Reactant: Cc1ccc(S(C)(=O)=O)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(CBr)cn1
Temperature: 25 °C

Procedure:
To a solution of 0.25 g of 2-methanesulfonyl-5-methyl-pyridine (from the preparation of 5-bromomethyl-2-methanesulfinyl-pyridine, step b)) in 20 mL carbon tetrachloride was added 0.27 g NBS and 4 mg benzoyl peroxide. This mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, and concentrated to dryness. Purification by flash chromatography (silica, heptane/ethyl acetate) provided 0.11 g of 5-bromomethyl-2-methanesulfonyl-pyridine.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1([CH3:23])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][C:15]1=[O:22].CI>COCCOC>[CH3:13][C:14]1([CH3:23])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH:16]([CH3:1])[C:15]1=[O:22]
Reactant: [Li]CCCC
Reactant: CC1(C)CCC(C)(C)C(=O)C1
Solvent: CI
Solvent: COCCOC
Solvent: CC(C)NC(C)C
Product: CC1C(=O)C(C)(C)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
106.9 ml of n-butyl lithium (2 molar in hexane) are added dropwise while cooling with ice to a solution of 21.6 g of diisopropylamine in 340 ml of ethylene glycol dimethyl ether. After stirring for 30 minutes at 0° C., a solution of 23.2 g of 2,2,5,5-tetramethylcyclohexanone in 100 ml of ethylene glycol dimethyl ether is added while cooling with ice. The mixture is stirred at room temperature for a further 45 minutes, again cooled to 0° C. and 213.9 g of methyl iodide are added thereto rapidly. The mixture is stirred at 50° C. for 45 minutes, cooled, poured on to ice and extracted with ether. After washing the organic phase with 5% hydrochloric acid and diluted sodium hydrogen carbonate solution, it is dried over sodium sulphate and evaporated. Distillation of the crude product on a spinning band column gives 13.7 g of 2,2,5,5,6-pentamethylcyclohexanone as a colourless liquid of boiling point 86°-94° C./16 mm Hg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(CCCCCl)c1cccc([N+](=O)[O-])c1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B using 5-chloro-1-(3-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 438.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9]CN)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[O:20]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)(Cl)Cl.[CH3:39][N:40](C)C=O>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:40]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:28]=2)[CH3:39])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Oc2ccccc2)c1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
Following the process to be described below, Compound 1 was prepared. Namely, 10.16 g of m-phenoxytoluene, 9.82 g of N-bromosuccinimide and 0.15 g of benzoyl peroxide were weighed and added to 90 ml of carbon tetrachloride as a solvent. The resulting mixture was heated under reflux for 3 hours to conduct a reaction. The reaction mixture was allowed to cool down, the insoluble matter was filtered off, and the filtrate was then concentrated. The concentrate was purified by chromatography on a silica gel column (eluent: chloroform), whereby 10.9 g of 3-phenoxybenzyl bromide were obtained. In 20 ml of N,N-dimethylformamide, 2.79 g of N-(4-tert-butylbenzyl)methylamine and 1.67 g of sodium carbonate were mixed, to which a solution of 3.77 g of 3-phenoxybenzyl bromide in 25 ml of N,N-dimethylformamide was added dropwise under ice cooling. The temperature of the reaction mixture was allowed to rise to room temperature, at which a reaction was allowed to proceed for 12 hours. Chloroform and water were added to the reaction mixture to conduct liquid-liquid extraction. An organic layer was collected and then washed with water and a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous sodium sulfate and was then concentrated. The concentrate was purified by chromatography on a silica gel column (eluent:hexane:chloroform:ethyl acetate=9:1:0→0:10:0→0:0:100). Relevant fractions were concentrated, whereby 4.49 g of N-(4-tertiary-butylbenzyl)-N-methyl-3-phenoxybenzylamine (Compound 1) were obtained (yield: 87.8%). The following is its NMR data (CDCl3 δ ppm): 1.28(9H,s), 2.18(3H,s), 3.476(2H,s), 3.483(2H,s), 6.86-7.35(13H,m).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[C:11]([F:29])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[C:24]([CH:26]([F:28])[F:27])[CH:25]=2)[C:21]#[N:22])[C:13]([Cl:16])=[CH:14][CH:15]=1.[Br:30][C:31]1[N:32]=[CH:33][NH:34][C:35]=1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:30][C:31]1[N:32]=[CH:33][NH:34][C:35]=1[C:36]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][C:18]2[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:20]([C:21]#[N:22])[CH:19]=2)[C:11]=1[F:29])=[O:37]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)F)c1
Reactant: O=C(O)c1[nH]cnc1Br
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Br)c2F)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(difluoromethyl)benzonitrile trifluoroacetate (90 mg, 0.204 mmol), 4-bromo-1H-imidazole-5-carboxylic acid (39.0 mg, 0.204 mmol) and HOBT (31.3 mg, 0.204 mmol) in DMF (3 ml) was added EDC (39.1 mg, 0.204 mmol) and the reaction mixture was stirred at RT for 30 minutes. The crude material was purified via reverse phase HPLC to give the title compound (56 mg, 55% yield). 1H NMR (DMSO-d6) δ ppm 8.42 (br. s., 1H) 7.85 (s, 1H) 7.79 (s, 1H) 7.72 (s, 1H) 7.47-7.58 (m, 2H) 7.38 (t, 1H) 7.07 (t, 1H) 4.51 (d, 2H). LC-MS (ES+) m/z 499.00 [M+H].
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:11][N:12]3CCC#N)=[CH:7][C:6]=2[F:25])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([OH:21])=[O:20])=[CH:11][NH:12]3)=[CH:7][C:6]=2[F:25])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c[nH]c2nc(N3CCC3)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 7D in THF (400 mL) and methanol (200 mL) at reflux was treated with 1M LiOH (200 mL), stirred for an 3 hours then cooled, concentrated to half volume, acidified with 10% citric acid, and filtered.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:22]([C:19]1[CH:18]=[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[NH:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2ccccc2F)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2F)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 92.9 %

Procedure:
DIPEA (92 mg, 0.12 mL, 0.71 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (59 mg, 0.28 mmol) in DMF (2 mL). HOBT (40 mg, 0.29 mmol) and EDCI (57 mg, 0.29 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (100 mg, 0.28 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 131 mg (91.6% yield) of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.28%. 1H NMR (DMSO-d6): δ 13.8 (d, 1H), 8.0 (m, 1H), 7.6 (m, 3H), 7.2 (m, 4H), 7.1 (m, 1H), 4.1 (d, 2H), 3.5 (m, 4H), 3.35 (m, 2H), 3.0 (m, 2H).
Reaction SMILES: [I:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18](O)=[O:19].[N:21]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]1>>[OH:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([CH:28]2[CH2:33][CH2:32][N:31]([C:18]([C:3]3[N:4]([CH3:17])[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:6][C:2]=3[I:1])=[O:19])[CH2:30][CH2:29]2)[CH2:22]1
Reactant: OC1CCCN(C2CCNCC2)C1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)O
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC(O)C2)CC1

Procedure:
In analogy to the procedure described for example 2, 5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazole-4-carboxylic acid (example 36) was coupled with (rac)-[1,4′]bipiperidinyl-3-ol to give the title compound as off-white solid. MS: 563.2 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.[CH2:11]([CH:13]([C:19](=O)[CH3:20])[C:14](OCC)=[O:15])[CH3:12].C[O-].[Na+]>C(O)C>[Cl:2][C:3]1[S:7][C:6]([C:8]2[NH:10][C:14](=[O:15])[C:13]([CH2:19][CH3:20])=[C:11]([CH3:12])[N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: N=C(N)c1ccc(Cl)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)[nH]c1=O
Temperature: 25 °C
Yield: 47 %

Procedure:
A 100-mL round bottomed flask was charged with 5-chlorothiophene-2-carboxamidine HCl salt (394 mg, 2 mmol, 1 eq.), ethyl 2-ethyl-3-oxo-butanoate (950 mg, 6 mmol, 3 eq.), and ethanol (10 ml). To the mixture was added sodium methoxide (25 w % in methanol, 1.73 g, 8 mmol, 3 eq.). The resulting mixture was stirred under reflux for 7 hr. After cooling to room temperature, the mixture was evaporated under reduced pressure to dryness and the residue was treated with 2N HCl (4.5 ml). Solid was collected by filtration and washed with water followed by hexane. The product thus obtained was forwarded to the next step without any further purification (240 mg, 47% yield).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:6]3[C:7]4[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=4[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[N:10][CH2:11][C:5]3=[N:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: OCCN1CCNCC1
Reactant: Brc1nnc2n1-c1ccccc1C(c1ccccn1)=NC2
Product: OCCN1CCN(c2nnc3n2-c2ccccc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]=[CH:7][N:8]([CH3:10])[CH3:9])[CH3:2].CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15].CC([O-])(C)C.[K+]>>[CH2:1]([O:3][C:4](=[O:11])/[C:5](/[N:6]=[CH:7][N:8]([CH3:10])[CH3:9])=[C:14](\[N:16]([CH3:18])[CH3:17])/[CH3:15])[CH3:2]
Reactant: CCOC(=O)CN=CN(C)C
Reactant: COC(C)(OC)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)/C(N=CN(C)C)=C(/C)N(C)C

Procedure:
A mixture of 4.7 g of N(dimethylaminomethylene)-glycine-ethyl ester (W. Kantlehner et al., Liebigs Ann. Chem. 1980, 344), 8 g of dimethylacetamide-dimethylacetal and 0.4 g of potassium tert-butylate, analogously to 1b), is heated for 8 hours with distilling off of the resulting alcohols. The residue is fractionated.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]([CH3:53])([CH2:51][CH3:52])[CH2:10][C:11]1[N:12]=[C:13]([CH2:35][CH:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][N:45]=3)=[CH:40][CH:39]=2)[NH2:37])[N:14]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1>ClCCl>[CH3:8][C:9]([CH3:53])([CH2:51][CH3:52])[CH2:10][C:11]1[N:12]=[C:13]([CH2:35][CH:36]([NH:37][C:5](=[O:7])[CH3:6])[C:38]2[CH:39]=[CH:40][C:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][N:45]=3)=[CH:42][CH:43]=2)[N:14]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(C)=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 2 h

Procedure:
Acetic anhydride (16 μL, 0.17 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (51 mg, 0.08 mmol) in dichloromethane (4 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture concentrated in vacuo to afford N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}acetamide which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].P(C)(C)C>C1COCC1.O.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@:10]2([NH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OCc3ccccc3)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: CP(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OCc3ccccc3)[C@@](N)(C(=O)OCc3ccccc3)[C@@H]21
Reaction time: 4 h
Yield: 51.3 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-benzyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-3) (120 mg, 0.276 mmol) in THF (4 mL) and H2O (0.4 mL) was added Me3P (0.30 mL, 0.30 mmol, 1 M sol. in THF) and stirring was continued at 23° C. for 4 h. The reaction mixture was diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over Na2SO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 1:1 (+small amount of Et3N) to give (1S,2R,3R,5R,6S)-2-amino-3-benzyloxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-3) (58 mg, 51%) as a yellow oil. 1H-NMR (250 MHz, CDCI3) □1.23 (3H, t, J=7.1 Hz), 1.72 (1H, t, J=3.5 Hz), 1.93 (2H, bs), 2.00 (1H, m), 2.10 (1H, dd, J=7, 3.5 Hz), 2.19 (1H, m), 2.27 (1H, dd,J=12,7 Hz), 3.46 (1H, dd,J=8, 7 Hz), 4.10 (2H, q,J=7.1 Hz), 4.47 (2H, s),5.20 (1H,d,J=12 Hz), 5.30 (1H, d,J=12 Hz), 7.18-7.42 (10H,m);MS[ISP] 410 [(M+H)+ ]; □D20 +3.54° (c=0.90, CHCl3).