Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([CH3:25])([O-])[CH3:23].[Li+]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][C:22]([CH3:25])([CH3:23])[CH3:21])=[O:11])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: CC(C)(C)[O-]
Reactant: C=CCCCc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=CCCCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(4-pentenyl)benzoic acid (42 g, 0.22 mol) in benzene (250 ml) was added dropwise to a solution of oxalyl chloride (60 ml) in benzene (200 ml) over 1 hour. The solution was stirred for 1 hour at room temperature and then heated under reflux for 2 hours. The solvent and excess oxalyl chloride was evaporated off under reduced pressure to give an oily residue which was dissolved in dry tetrahydrofuran (250 ml) and added dropwise over 1 hour to a stirred solution of lithium t-butoxide [prepared from t-butanol (21 g, 0.283 mol) in dry tetrahydrofuran (200 ml) at -20° C. and n-butyl lithium (114 ml of 2.5M solution in hexane, 0.285 mol)]. The resulting mixture was allowed to warm up to room temperture and stirred for an additional 12 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water (500 ml) and extracted with chloroform (3×500 ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield crude 1,1-dimethylethyl 4-(4-pentenyl)benzoate as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:20])([F:19])[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:15][C:16]([F:20])([F:19])[CH2:17][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: OCC(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (30.0 g), 2,2,2-trifluoroethanol (149 g) and triphenylphosphine (58.6 g) in tetrahydrofuran (450 ml) was slowly added diethyl azodicarboxylate (38.9 g) at 8° C. The mixture was stirred at room temperature for 2 hours, and at 60° C. for 8 hours. The reaction mixture was concentrated in vacuo to give the crude product of the title compound. The crude product was purified by chromatography on silica gel.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=3)[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:29]([C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[NH:46][C:47](=[O:49])[CH3:48])#[N:30]>>[C:47]([NH:46][C:32]1[CH:33]=[CH:34][C:35]([C:14]2[C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:11]([C:8]3[CH:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][NH:1]4)=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:36][C:31]=1[C:29]#[N:30])(=[O:49])[CH3:48]
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OS(=O)(=O)C(F)(F)F
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1-c1ccc(NC(C)=O)c(C#N)c1

Procedure:
Methyl 3-(4-acetamido-3-cyanophenyl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (37C) was prepared following a similar procedure as that described in example 29, except methyl 6-(1,2,3,4-tetrahydroquinolin-7-yl)-3-(trifluoromethylsulfonyloxy)picolinate (29F) was used instead of tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29E), and N-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (37B) was used instead of phenylboronic acid in step 7 of example 29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: C[C@H](NC(=O)c1ccccc1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and benzoyl chloride (21 mg, 150 μmol). Yield 19 mg (82%).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].Cl[C:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:9]=[C:8]([C:21]2[CH:30]=[CH:29][C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[N:22]=2)[N:7]=1>C(O)C>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][C:10]1[N:9]=[C:8]([C:21]2[CH:30]=[CH:29][C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[N:22]=2)[N:7]=[C:6]([O:3][CH2:2][CH3:1])[CH:11]=1
Reactant: CC[O-]
Reactant: Clc1ccc(Cc2cc(Cl)nc(-c3ccc4c(n3)CCCC4)n2)c(Cl)c1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(Cc2ccc(Cl)cc2Cl)nc(-c2ccc3c(n2)CCCC3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
1.95 g (0.006 mol) of a 21% strength solution of sodium ethylate in ethanol were added dropwise to the solution of 2.0 g (0.005 mol) of 4-chloro-6-(2,4-dichlorobenzyl)-2-(5,6,7,8-tetrahydroquinolin-2-yl)-pyrimidine in 50 ml of absolute ethanol. The mixture was stirred for 16 hours at 25° C., and the solvent was distilled off in vacuo. The residue was dissolved in water, the solution was extracted three times using dichloromethane, and the organic phase was dried (MgSO4) and concentrated. Drying in vacuo gave 1.7 g (85%) of a white solid of melting point 98° C. to 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[CH:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH:14]=[O:15])=[CH:17]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (10 ml) was added 3-formylindole (623 mg) and potassium carbonate (593 mg), the mixture was heated at 90° C. for 1.5 hrs. The reaction was cooled to room temperature and diluted with water (200 ml) and extracted with ether (200 ml). The organic fraction was separated and evaporated to dryness to give the title compound as a pale yellow crystaline material, m.p. 167-169° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:18](=O)[CH3:19])[C:3]=1[O:21][CH:22]([CH3:24])[CH3:23].[CH3:25][CH2:26][O:27][C:28]([CH:30](P(OCC)(OCC)=O)[F:31])=[O:29].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:19])=[C:30](/[F:31])\[C:28]([O:27][CH2:26][CH3:25])=[O:29])[C:3]=1[O:21][CH:22]([CH3:23])[CH3:24]
Reactant: CC(=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-8-tert-butyl-3-isopropoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-115, 143 mg, 0.36 mmol) and triethyl 2-fluoro-2-phosphonoacetate (352 mg, 1.46 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 0.91 mL, 1.46 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32]OS(C)(=O)=O)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 90 °C
Yield: 76.6 %

Procedure:
2-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (10 g) was dissolved in 180 ml of dimethylformamide, to which 5.7 g of 1H-1,2,4-triazole and 23.2 g of potassium carbonate were added. The mixture was heated at 90° C. for 5 hours. The reaction solution was concentrated under reduced pressure to ca. 100 ml and diluted with a mixture of 400 ml of ethyl acetate and 200 ml of diisopropyl ether. The mixture was washed with 100 ml of water, 1N-hydrochloric acid (100 ml×2) and 100 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 70 g, eluent; hexane:ethyl acetate=3:4 to ethyl acetate). The desired fraction was concentrated and the residue was recrystallized from a mixture of 10 ml of ethyl acetate and 80 ml of diisopropyl ether to give 7.3 g of 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (yield: 80%) as a colorless powdery crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:8]2[C:7]([CH3:11])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=2)=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(C=O)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)c(F)cc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 48.8 %

Procedure:
To a solution of 2,4-difluoro-5-methylbenzaldehyde (100 mg, 0.64 mmol) and 4-chloro-3-trifluoromethylphenol (126 mg, 0.64 mmol) in DMSO was added potassium carbonate. The reaction was stirred at room temperature for 36 hours. The reaction was diluted with ethyl acetate (30 mL) and washed with water (2×50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with acetonitrile:water (plus 0.1% aqueous formic acid) 5:95 to 100:0 to furnish the title compound as a white solid 104 mg, 49%.
Reaction SMILES: [CH:1](OCC)=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.C[O-].[Na+].Cl>CCOCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][CH:1]=[O:2])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Ethyl formate (8.15 g, 0.11 mol) and 4'-chloroacetophenone (15.4 g, 0.1 mol) were stirred in ether (150 mL) at room temperature. Sodium methoxide (25%) (23.77 g, 0.11 mol) was added dropwise. The mixture was stirred at room temperature for 16 hours and was then treated with 150 mL of 1N hydrochloric acid. The phases were separated and the ethereal solution washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 18.3 g of a yellow oil. The resulting crude mixture was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) in 1,2-dichloroethane (5 mL) was added acetic acid (0.2 mmol), formaldehyde (37% water solution, 0.037 mL), and NaBH(OAc)3 (0.2 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (2 M NH3 in MeOH/CH2Cl2) afforded 0.015 g of the title compound. MS (ESI): exact mass calculated for C21H22ClN3, 351.15. found, m/z 352.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.45-7.42 (m, 2H), 7.32-7.29 (m, 2H), 7.26-7.19 (m, 3H), 7.03-7.01 (br m, 2H), 5.27 (s, 2H), 2.75-2.68 (m, 4H), 2.64-2.58 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (56.4 mg, 48%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45](O)[CH3:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.C(N(S(F)(F)[F:54])CC)C.C([O-])(O)=O.[Na+].Br.CC(O)=O>C(Cl)Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH:45]([F:54])[CH3:46])[CH:27]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(F)c1ccc2cc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)nc2c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Benzyl [2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-hydroxyethyl)quinolin-3-yl]carbamate (8.0 mg, 0.012 mmol) (from Example 15, step 6) was dissolved in DCM (0.3 mL), cooled to −78° C., and then treated with diethylaminosulfur trifluoride (50 mg, 0.3 mmol). The resulting reaction mixture allowed to warm to room temperature and stirred at room temperature for 2 h. The reaction mixture was poured into ice-water containing NaHCO3, extracted three times with DCM, dried over Na2SO4, filtered and concentrated under reduced pressure. HBr in AcOH (8.0 M; 0.20 mL, 1.6 mmol) was added to the residue. The reaction mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The residue was diluted with MeOH and neutralized with small amounts of NH4OH. The mixture was filtered and purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C22H26FN6O (M+H)+: m/z=409.1. Found: 409.0.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH2:20]([O:18][C:15]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Yield: 69 %

Procedure:
To a refluxed suspension of K2CO3 (32.8 g, 238 mmol) in methanol (180 mL) and CHCl3 (350 mL) was then added a mixture of methyl 2,5-dihydroxybenzoate (10.0 g, 59.5 mmol) and bromomethylbenzene (7.10 mL, 59.5 mmol) in methanol/CHCl3 (50 mL/25 mL) drop wise over 30 minutes. The resulting mixture was stirred at reflux for another 4 hours. After cooling down and filtration, the filter cake was washed with CHCl3 (20 mL). The combined filtrate was concentrated under reduced pressure. The residue was redissolved in CHCl3 (200 mL), washed with HCl (1N) (100 mL×2). The organic was then washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (8:1) to give methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 69.0%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH2:13]>C(#N)C.[Cl-].[Na+].O>[CH3:12][NH:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in acetonitrile (60 ml) is added dropwise to a stirred solution of aqueous methylamine (65 mL, 40 wt. %, 0.75 mol) in acetonitrile (50 mL) at 0° C. After stirring an additional 15 minutes, the solution is poured into brine and extracted 2× with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(methylaminomethyl)nitrobenzene (4.04 g).
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:28])[CH:22]=[CH:21][C:20]([S:23]([NH:26][NH2:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1>S(=O)(=O)(O)O.C(O)C>[C:17]1([CH3:28])[CH:18]=[CH:19][C:20]([S:23]([NH:26][N:27]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C(C(=O)N1CCCCC1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN=C(C(=O)N2CCCCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of 98% sulfuric acid (121.7 g, 1.22 mol, 0.02 eq) in abs ethanol (1.0 L) was added dropwise to a stirred mixture of 1-(phenylglyoxylyl)piperidine (17.58 Kg, 80.9 mol, 1 eq), p-toluenesulfonhydrazide (16.20 Kg, 87.0 mol, 1.08 eq) and abs ethanol (50 L) at 20-30° C. The obtained mixture was stirred under reflux conditions until 1-(phenylglyoxylyl)piperidine disappeared (˜7 hours, TLC control). The mixture was stirred for 1 hour at 20-30° C. and kept overnight at 4-6° C. The precipitated solid was filtered off, washed on the filter with cold methanol and cold hexane and dried under reduced pressure to a constant weight to yield 28.25 Kg (90.6%) of 1-(phenylglyoxylyl)piperidine p-toluenesulfonylhydrazone with 99.9% purity by HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](N)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1.ClC(Cl)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)CNc2cccc(Cl)c2C)cc1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
200 mg of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)glycinamide was dissolved in 2.0 mL of pyridine, and a solution (2.0 mL) of 200 mg of 4-hydroxybenzenesulfonamide in dichloroethane was added thereto, followed by stirring at 80° C. overnight. The reaction liquid was concentrated under reduced pressure, to the residue was added water, followed by extraction with ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70), and further purified by silica gel column chromatography (chloroform:methanol=100:0 to 97:3), and the obtained residue was crystallized from diisopropyl ether to obtain 68 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-hydroxyphenyl)sulfonyl]-N-(4-methoxybenzyl)glycinamide.