Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[Na+].CC(O)C.F[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:14]([NH2:27])[N:13]=1>C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:14]([NH2:27])[N:13]=1)[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
Sodium t-butoxide (1.30 g, 13.53 mmol) was added to 2-propanol (16.95 ml, 220 mmol) portionwise with stirring over 5 minutes. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added and the reaction mixture heated and stirred at 50° C. for 4 hours and then allowed to cool to room temperature. The reaction mixture was then diluted with ethyl acetate (75 ml), washed with water (3×25 ml) and the combined aqueous layers extracted again with ethyl acetate (2×25 ml). The combined organic layers were dried by passage through a hydrophobic frit, filtered and evaporated to give an off-white solid (2.30 g). This material was dissolved in dichloromethane and purified using an aminopropyl SPE cartridge (70 g) eluted with a 0-100% ethyl acetate in cyclohexane gradient. The appropriate fractions were combined and evaporated to give a white solid (1.6 g) which was further purified by column chromatography using a reverse-phase (C18) Flashmaster II system loading in 1:1 MeOH/DMSO and eluting with 0-50% acetonitrile (+0.1% TFA) in water (+0.1% TFA) gradient over 40 minutes collecting fractions in vials containing ca. 2 mL of saturated aqueous sodium bicarbonate solution. The appropriate fractions were combined, and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried by passage through a hydrophobic frit and evaporated to give the title compound as a white solid (888 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10]([C:12]1[CH:21]=[C:20]([OH:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:23][CH3:24])[C:13]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])[CH3:8].Cl[C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:33]=[N:32][N:31]=1>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1[CH:21]=[C:20]([O:22][C:30]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=[N:32][N:31]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:23][CH3:24])[C:13]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])[CH3:8]
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2c(OC)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)OCC)cc(Oc2nnnn2-c2ccccc2)c2c(OC)cccc12
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 60.7 %

Procedure:
Potassium t-butoxide (1.03 g) was added to a solution of 1-butyl-4-hydroxy-5-methoxy-2-naphthalenecarboxylic acid ethyl ester (2.4 g) and 5-chloro-1-phenyl-1H-tetrazole (1.55 g) in dimethylformamide (20 mL) and the reaction was stirred at room temperature for 1.25 hours. After the solvent was removed in vacuo, the residual material was partitioned between dichloromethane (150 mL) and water (75 mL). The separated aqueous layer was re-extracted with dichloromethane, and after each organic extract was washed with water, they were combined, dried (Na2SO4) and evaporated. Crystallization of the crude product from diethyl ether-hexane gave 2.15 g of 1-butyl-5-methoxy-4-[(1-phenyl-1H-tetrazole-5-yl)oxy]-2-naphthalenecarboxylic acid ethyl ester, mp 144°-146° C. A portion was recrystallized from the same solvents to provide the analytical sample, mp 145°-146° C. Anal. Calcd for C25H26N4O4 : C, 67.25; H, 5.87; N, 12.55 Found: C, 67.07; H, 5.99; N, 12.51
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)CCc1sc(Sc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1sc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-thiazolyl]propionate (350 mg), 4-chloromethyl-5-methyl-2-phenyloxazole (196 mg), potassium carbonate (260 mg) and N,N-dimethylformamide (4 ml) was stirred at 50° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionate (400 mg, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:14]([NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19])[CH3:15].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([N:16]([CH2:14][CH3:15])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCNCC(=O)c1ccc(F)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC(=O)c1ccc(F)c(C)c1)C(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
2.9 g benzyloxy-acetyl chloride was added to 3.7 g 2-ethylamino-1-(4-fluoro-3-methyl-phenyl)-ethanone hydrochloride and 5 mL triethylamine in 40 mL dichlormethane. The reaction was stirred 3 h at RT. The reaction was diluted with dichlormethane, washed with water, 1 mol/L aqueous hydrochloride acid and with 5% aqueous potassium carbonate solution. The organic layer was dried and evaporated to yield 5.2 g of the desired product. Rt: 0.91 min (method J), (M+H)+: 344
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2[NH:12][N:13]=[C:14]([NH:15][CH3:16])[C:10]=2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([N:13]1[C:14]([NH:15][CH3:16])=[C:10]2[C:11]([N:6]([CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:21])[N:8]([CH2:18][CH2:19][CH3:20])[C:9]2=[O:17])=[N:12]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O
Solvent: c1ccncc1
Product: CCCn1c(=O)c2c(NC)n(C(C)=O)nc2n(Cc2cccc(Cl)c2)c1=O
Yield: 85 %

Procedure:
A solution of 7-(3-chlorobenzyl)-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.0 g, 2.9 mM) and acetic anhydride (1.0 ml, 9.8 mM) in pyridine (15 ml) was stirred at 80° C. for 5 hours. The solution was concentrated to dryness and the residue was triturated with water (10 ml). Recrystallization from chloroform/ether gave colorless needles (0.95 g, 85%), m.p. 169°-171° C.
Reaction SMILES: [CH:1]([C:14]([O:16][CH3:17])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:28])(=O)=O)=CC=1>O1CCCC1>[C:1]([C:14]([O:16][CH3:17])=[O:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[F:28]
Reactant: COC(=O)C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
4.8 milliliters KN(SiCH3)2 were dropped into 5 milliliters (C6H5)2CHCOOCH3 in tetrahydrofuran at -78° C. and the resulting yellow suspension was stirred for 45 minutes. 1.2 molar equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 4 milliliters tetrahydrofuran were dropped into the mixture and stirring continued at -78° C. for 1 hour. The mixture was allowed to warm up to room temperature, quenched with ammonium chloride, and acidified with 0.1N hydrogen chloride. Extraction with dichloromethane, drying, and evaporation were followed by purification on a silica gel column. White crystalline (C6H5)2CFCOOCH3 was obtained in 82% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=3)=[CH:21][CH:22]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)n2ccnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)n2ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A mixture of methyl [5-(4-aminobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (17 mg, 0.06 mmol), p-trifluoromethylbenzoyl chloride (0.01 mL, 0.07 mmol) and triethylamine (0.016 mL, 0.11 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water, and extracted with chloroform. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica gel, chloroform:methanol, 95/5) to give methyl [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (21.5 mg, 80%) as slightly yellow solid.
Reaction SMILES: C(OC([C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1)=O)C.BrC1SC2C=[C:42]([O:44]C)C=CC=2N=1>>[CH3:42][O:44][C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:15][CH:14]=3)[S:12][C:8]=2[CH:7]=1
Reactant: COc1ccc2nc(Br)sc2c1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1
Product: COc1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1

Procedure:
Tert-butyl 4-[5-(6-Methoxy-1,3-benzothiazol-2-yl)pyridin-2-yl]piperazine-1-carboxylate was prepared according to the method used for the preparation of 2-[6-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]-3-pyridinyl]-6-benzothiazolecarboxylic acid ethyl ester, from 2-bromo-6-methoxybenzothiazole (Yang et al. J. Biological Chem. 1989, 2, 891-898) (0.20 g), and obtained as a solid (0.23 g). 1H NMR δ 8.74 (s, 1 H) 8.12 (d, 1 H) 7.87 (d, 1 H) 7.67 (s, 1 H) 7.09 (dd, 1 H) 6.98 (d, 1 H) 3.84 (s, 3 H) 3.64 (br. s., 4 H) 3.45 (br. s., 4 H) 1.43 (s, 9 H); MS m/z M-1-H 427.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH:18]([CH3:20])[CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(Cc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)N(Cc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of isopropyl-(2-nitro-benzyl)-carbamic acid tert-butyl ester (730 mg, 2.48 mmol) in ethyl acetate (10 ml) was added acetic acid (0.156 ml, 2,73 mmol) and catalytic amount of palladium 10 wt. % on activated carbon. The mixture was stirred overnight under hydrogen atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (15% ethyl acetate-hexane) to afford (2-amino-benzyl)-isopropyl-carbamic acid tert-butyl ester (f) (568 mg, 2.15 mmol, 87%) as reddish oil.
Reaction SMILES: ClN1[C:6](=[O:7])CCC1=O.[CH2:9]1[CH:18]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH:10]1[CH2:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:22].CO>C(Cl)(Cl)Cl>[CH2:9]1[CH:18]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH:10]1[CH2:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[O:7][CH3:6])=[O:22]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1[nH]c2ccccc2c1C(=O)OCC1CCN2CCCCC2C1
Reaction time: 2 h

Procedure:
A stirred solution of N-chlorosuccinimide (220 mg, 0.0016 mole) in chloroform (6 ml) at room temperature under nitrogen was treated with a solution of eq-quinolizidin-2-ylmethylindole-3-carboxylate (E9b) (330 mg, 0.0011 mole) in chloroform (6 ml) and stirred for 2 h. The solution was then treated with methanol (0.71 ml, 0.022 mole) and stirring continued. After 3 h a beige precipitate began to form and afar a further 1 h this was filtered off, washed with chloroform,and dried to afford the title compound (E26) as its hydrochloride salt mp 212°-213° C.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH:17]1[C:28](=[O:29])[N:19]2[CH:20]([C:25]([OH:27])=[O:26])[CH:21]([OH:24])[CH2:22][S:23][C@H:18]12>C(OCC)(=O)C.CS(C)=O>[NH2:16][CH:17]1[C:28](=[O:29])[N:19]2[CH:20]([C:25]([O:27][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:26])[CH:21]([OH:24])[CH2:22][S:23][C@H:18]12
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 32 h
Yield: 68.1 %

Procedure:
A solution of dipheyldiazomethane (1.7 mol) in ethyl acetate (2.13 l) was added to a mixture of 7-amino-3-hydroxycepham-4-carboxylic acid (186 g) in dimethyl sulfoxide (1.5 l). The mixture was stirred at room temperature for 32 hours and filtered. To the filtrate was added water and the mixture was extracted with ethyl acetate. The extract was washed three times with water, dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was tritulated with diisopropyl ether to give benzhydryl 7-amino-3-hydroxycepham-4-carboxylate (223 g) as powder.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[C:14](O)(=[O:18])[CH2:15][CH:16]=[CH2:17]>ClCCl>[N:5]1([C:14](=[O:18])[CH2:15][CH:16]=[CH2:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=CCC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=CCC(=O)n1nnc2ccccc21
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Sulfurous dichloride (6.91 g, 58.1 mmol) was added to a stirred solution of 1H-benzo[d][1,2,3]triazole (27.7 g, 232 mmol) in anhydrous dichloromethane (100 mL) at room temperature under argon atmosphere. The mixture was stirred for 30 min and but-3-enoic acid (5.0 g, 58.1 mmol) was added in one portion and stirring was continued for 2 h. The resulting suspension was filtered off and washed with 2.0 M NaOH (3×50 mL), dried over MgSO4, and purified by column chromatography to give the title compound as white solid (5.12 g). LCMS m/z=188.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.24 (d, J=6.57 Hz, 2H), 5.28-5.42 (m, 2H), 6.04-6.19 (m, 1H), 7.61 (t, J=7.71 Hz, 1H), 7.78 (t, J=7.71 Hz, 1H), 8.24 (dd, J=10.61, 8.34 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][CH:47]1[CH2:52][C:51]([CH3:54])([CH3:53])[N:50]([CH3:55])[C:49]([CH3:57])([CH3:56])[CH2:48]1>CC(N(C)C)=O>[C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:46][CH:47]2[CH2:48][C:49]([CH3:56])([CH3:57])[N:50]([CH3:55])[C:51]([CH3:54])([CH3:53])[CH2:52]2)=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(=O)O)cc1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: CN1C(C)(C)CC(NC(=O)c2ccc(NNC(=O)OC(C)(C)C)cc2)CC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(N′-tert-Butoxycarbonyl-hydrazino)-benzoic acid (4.452 g) in DMA (30 ml) was added disopropyl ethyl amine (6.16 ml) and HBTU (6.69 g) with stirring at room temp. 4-Amino-1,2,2,6,6-pentamethylpiperidine (3 g) was then added to the stirred solution. Stirring continued at room temp for 4 hrs.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][O:30]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:33]2[CH2:34][C:29]([CH3:28])([CH3:38])[O:30][CH2:31][C@H:32]2[C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC1(C)CN[C@H](C(=O)O)CO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 58.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.26 g, 0.51 mmol) was reacted with (S)-6,6-dimethylmorpholine-3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure described in Example 1, Step C to give the title compound as a yellow solid (0.16 g, 59%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:16]([NH2:18])=[O:17])=[C:2]([N:1]=[CH:24][C:23]3[CH:26]=[CH:27][C:20]([OH:19])=[CH:21][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(F)c(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(F)c(Cl)c2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 53 %

Procedure:
5-amino-3-((3-chloro-4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (45 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chloro-4-fluorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (147 mg, 53% yield).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=O)C.[CH3:27][NH2:28]>C(O)CCC>[CH3:27][NH:28][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:3]
Reactant: CCOC(=O)CCCCCc1c(-c2cccnc2)n(C)c2ccccc12
Reactant: CN
Solvent: CCCCO
Product: CNC(=O)CCCCCc1c(-c2cccnc2)n(C)c2ccccc12

Procedure:
A solution of 4 g of 3-(5-ethoxycarbonylpentyl)-1-methyl-2-(3-pyridyl)indole in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness and the product is crystallized from ethyl-ether to yield the 3-[5-(N-methylcarbamoyl)pentyl]-1-methyl-2-(3-pyridyl)indole.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH:31]2[CH2:33][CH2:32]2)[C:13]([C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:19][CH:20]=2)=[O:14])[CH2:8][CH2:7]1)#[N:5].C(N(C(C)C)C(C)C)C>C(O)C>[CH:31]1([N:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[NH:5])[NH:2][OH:3])[CH2:7][CH2:8]2)[C:13]([C:15]2[CH:20]=[N:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:17][CH:16]=2)=[O:14])[CH2:33][CH2:32]1
Reactant: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C(=N)NO)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydroxylamine hydrochloride (21 mg) is added to 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide (130 mg, Intermediate 22) and ethyldiisopropylamine (634) in ethanol (30 mL) and the mixture is refluxed for 4 h. Another 10 mg hydroxylamine hydrochloride is added and the mixture is refluxed for 1 h and stirred at room temperature for 12 h. The solvent is removed in vacuo and the residue is purified by preparative HPLC (MeOH/H2O/TFA) to yield 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid cyclopropyl-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-amide as an intermediate. Subsequently 50 mg of the aforementioned intermediate are added to tetrahydrofuran (10 mL) followed by ethyldiisopropylamine (28 μL) and cyclopropanecarbonyl chloride (10 μL). The mixture is stirred at room temperature for 3 h. Acetonitrile is added and the mixture is refluxed for 12 h. After removal of the solvents the residue is purified by HPLC (MeOH/H2O/ammonia) to yield the desired product. LC (method 16): tR=1.17 min; Mass spectrum (ESI+): m/z=509 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:24][C:23]([F:26])([F:25])[CH2:22]3)=[C:17]([O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[N:16]=2)=[O:14])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.[CH3:32]I.[H-].[Na+]>>[CH:1]1([CH2:4][C@H:5]([N:12]([CH3:32])[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][C:23]([F:25])([F:26])[CH2:24]3)=[C:17]([O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[N:16]=2)=[O:14])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cc1nc([C@H](CC2CC2)N(C)C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
In analogy to the procure described in Example 16 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide was reacted with methyl iodide (CAN 74-88-4) in the presence of sodium hydride to give the title compound as colorless oil; MS (EI): m/e=448.2 [MH]+.