Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]>CN1CCCC1=O>[CH3:4][C:5]1[CH:10]=[C:9]([NH:2][NH2:3])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: NN
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(NN)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h

Procedure:
5 g of hydrazine hydrate were slowly added dropwise to a solution of 15.9 g of 2-methyl-4-fluoronitrobenzene in 10 ml of N-methylpyrrolidone at room temperature, and the mixture was heated with stirring at 65° C. for 4 hours. The product was precipitated by adding 70 ml of water and was filtered off with suction and then recrystallized from isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[NH2:9])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26].[CH:28](OC(=O)C)=[O:29].C(OC(=O)C)(=O)C.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[NH:9][CH:28]=[O:29])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(=O)OC=O
Reactant: CC(C)Oc1cc(C(N)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)Oc1cc(C(NC=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine (2.8 g, 7.1 mmol) in CH2Cl2 (30 mL) at 0° C. was added acetic formic anhydride (2.8 mL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ISCO (120 g silica gel column, 0 to 60% EtOAc/hexane over 60 min gradient) to give N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (2.56 g, 85% yield) as a colorless oil. LCMS: RT=1.99 min [M+H] 422.0 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm). To a solution of N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (225 mg, 0.53 mmol) in THF (2 mL) at 0° C. was added Et3N (0.4 mL, 2.9 mmol) followed by phosphorous oxychloride (74 μL, 0.80 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was diluted with ice water (15 mL) and extracted with Et2O (3×15 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by ISCO (12 g silica gel column, 0-50% EtOAc/hexane over 30 min) to yield 1-fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene (143 mg, 67% yield) as a pale yellow oil. LCMS: RT=2.13 min [M-NC] 377 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0. % TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.07-7.13 (1H, m), 6.91-7.03 (4H, m), 6.84-6.86 (1H, m), 5.78-6.04 (1H, m), 5.82 (1H, s), 4.54 (1H, ddd, J=11.97, 6.15, 6.04 Hz), 1.35 (6H, t, J=5.05 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1)=[O:14].BrCCF.[F:32][CH:33]([F:36])[CH2:34]I>>[F:32][CH:33]([F:36])[CH2:34][N:25]1[CH2:24][CH2:23][CH:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:13]([NH:12][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[O:14])[N:21]=2)[CH2:27][CH2:26]1
Reactant: FC(F)CI
Reactant: O=C(Nc1cccc(C2CCNCC2)n1)Nc1ccnc2c(F)cccc12
Agent: FCCBr
Product: O=C(Nc1cccc(C2CCN(CC(F)F)CC2)n1)Nc1ccnc2c(F)cccc12

Procedure:
The title compound was prepared as described in example 32, substituting 1-(6-(piperidin-4-yl)quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea by 1-(8-fluoro-quinolin-4-yl)-3-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-urea (example 62) and 1-bromo-2-fluoroethane by 1,1-difluoro-2-iodoethane.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:41]([C:43]1[CH:44]=[CH:45][C:46]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[C:47]([CH:51]=1)[C:48](O)=[O:49])=[O:42]>CN(C)C=O.O.C(OCC)(=O)C>[CH:41]([C:43]1[CH:44]=[CH:45][C:46]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[C:47]([CH:51]=1)[C:48]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:49])=[O:42]
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 72 h
Yield: 33.1 %

Procedure:
Diisopropylethylamine (0.95 ml, 5.46 mmol), 3-aminopyridine (514 mg, 5.46 mmol) and HATU (1.56 g, 4.1 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 97; 770 mg, 2.73 mmol) in dimethylformamide (10 ml). The solution was stirred for 72 hours. Ethyl acetate (40 ml) and H2O (40 ml) were added and the organic layer was washed with H2O (3×20 ml), dried and the solvent removed in vacuo to give a solid. The solid was purified by column chromatography (ethyl acetate) to yield the title compound as a white solid (300 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[N:24][N:25]=1>C(O)CCC>[CH3:26][C:23]1[S:22][C:21]2=[N:20][C:3]([C:5]3[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:7][N:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=34)=[CH:2][N:25]2[N:24]=1
Reactant: Cc1nnc(N)s1
Reactant: O=C(CBr)c1c(-c2ccccc2)nn2ccccc12
Solvent: CCCCO
Product: Cc1nn2cc(-c3c(-c4ccccc4)nn4ccccc34)nc2s1
Yield: 54.2 %

Procedure:
A mixture of 3-(2-bromoacetyl)-2-phenylpyrazolo[1,5-a]pyridine (1.87 g), 2-amino-5-methyl-1,3,4-thiadiazole (0.68 g) and 1-butanol (19 ml) was refluxed for 5 hours and 20 minutes. The reaction mixture was evaporated in vacuo and the residue was taken up methylene chloride (40 ml). The methylene chloride solution was washed with an aqueous solution of potassium carbonate and dried over magnesium sulfate. The solvent was removed and the residue was subjected to chromatography on silica gel (25 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.06 g), which was recrystallized from acetone gave crystals (0.69 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(C)(C)C)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (71 mg, 81%), MS (ISP) m/z=351.5 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH2:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CC2CCCN2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of (2RS)-2-benzyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.21 g, 4.6 mmol) in ethyl acetate (20 ml) was added hydrogen chloride (4N) in ethyl acetate (20 ml) at room temperature. The mixture was stirred at room temperature for 2 hours and was concentrated. The residue was partitioned between aqueous sodium hydrogen carbonate and chloroform, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford (2RS)-2-benzyl-pyrrolidine (0.7 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(CCC2CCCN2)cc1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2CCc2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-phenethylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.99 minutes; C29H28Cl2N4O2 (535.47); mass spectrum: (M−H)−=535/537 (chlorine isotope).
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([S:17]([OH:20])(=[O:19])=[O:18])[CH:9]=[C:10]2[S:13]([O-:16])(=[O:15])=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24].Cl>O>[Na+:1].[Na+:1].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([S:17]([O-:20])(=[O:19])=[O:18])[CH:9]=[C:10]2[S:13]([O-:16])(=[O:15])=[O:14])=[CH:5][CH:4]=1)=[O:30])([O-:25])=[O:24]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(S(=O)(=O)[O-])c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c2c1)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A 52.2 g portion of 7-amino-1,3-naphthalenedisulfonic acid monosodium salt (technical) is suspended in 80 ml of water and 160 ml of 1N sodium hydroxide is added, then 60.0 g of m-nitrobenzoyl chloride is added all at once (a large lump of crystalline solid is separated on addition of the acid chloride). The mixture is diluted with an additional 80 ml of water and a second 160 ml portion of 1N sodium hydroxide is added after brief initial shaking. Shaking is continued and the latter addition of sodium hydroxide and shaking is repeated two more times with intermitent attempt at breaking up any crystalline lumps with a spatula. The resulting mixture is shaken at least one hour after the final base treatment. Since complete solution is not attained, eight 150 ml portions of water are added then two 500 ml portions still without complete solution. The material is allowed to stand overnight and a gel is formed which is further diluted with water and is broken up with a spatula. The mixture is then acidified with 17 ml of concentrated hydrochloric acid and is copiously extracted with ether. The ether is removed after each extraction by vacuum siphoning. The gel is filtered over a period of 2 days in two funnels. The residue is combined and dissolved in boiling water then is filtered. The filtrate (about 710 ml) is diluted with an equal amount of 3A alcohol and is allowed to stand at room temperature overnight. The resulting precipitate is filtered and is washed with several 100 ml portions of 50% ethyl alcohol then is slurried twice with 250 ml portions of absolute ethyl alcohol and finally with two 250 ml portions of ether to give 7-(m-nitrobenzamido)-1,3-naphthalenedisulfonic acid disodium salt which is oven dried at 120° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:22]2[CH2:23][CH2:24][C:19]([O:18][CH3:17])([CH3:25])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: COC1(C)CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1(C)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
A mixture of 4-bromobenzyl bromide (0.44 g, 1.74 mmol), triethylamine (0.37 mL, 2.61 mmol) and 4-methoxy-4-methylpiperidine (0.45 g, 3.49 mmol)in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as a yellow oil (0.50 g, 96%). 1H NMR (CDCl3, 300 MHz): 7.45-7.39 (m, 2H), 7.22-7.17 (m, 2H), 3.44 (s, 2H), 3.17 (s, 3H), 2.52-2.42 (m, 2H), 2.36-2.25 (m, 2H), 1.79-1.70 (m, 2H), 1.59-1.47 (m, 2H), 1.13 (s, 3H).
Reaction SMILES: [O:1]1[CH2:29][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][C@@H:12]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1.[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>N1CCCCC1.C(O)C>[C:33]1(=[O:35])[N:34]([CH2:29][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([C@@H:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[CH2:14][CH2:13][C@@H:12]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:9][CH:10]=2)[C:30](=[O:36])[CH2:31][CH2:32]1
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCC2CO2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCC(O)CN2C(=O)CCC2=O)cc1

Procedure:
A mixture of 3.0 g. of cis-1-[p-(2,3-epoxypropoxy)phenyl]-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene, 0.80 g. of succinimide and 4 drops of piperidine in 100 ml. of absolute ethanol is heated under reflux for 17 hours. The resulting mixture is concentrated to approximately one-third volume by distillation under reduced pressure and the residue is diluted with water. The mixture so obtained is extracted with methylene chloride and the methylene chloride extract is washed with water and saturated sodium chloride solution before being evaporated to dryness. The residue is recrystallized from aqueous alcohol to yield cis-1-[p-(3-succinimido-2-hydroxy-propoxy)phenyl]-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene. The latter compound is then heated under reflux for 20 hours with a solution of 16 g. of sodium hydroxide in 320 ml. of ethanol. The resulting product is concentrated by distillation under reduced pressure and the residue is extracted with a mixture of methylene chloride and water. The methylene chloride solution is separated, washed with water, and taken to dryness. Hydrogen chloride is bubbled through a solution of the residue in ether. The solid which separates is isolated by filtration, and dried. There is thus obtained cis-1-[p-(3-amino-2-hydroxy-propoxy)phenyl]-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride. The corresponding free base is obtained by dissolving the hydrochloride in methylene chloride, washing the resulting solution with an aqueous sodium bicarbonate solution, and evaporating the methylene chloride solution to dryness.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:4].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33]>CN(C)C=O>[OH:34][C@@H:32]([CH3:33])[CH2:31][C@@H:30]([CH3:29])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.68 g of 55% sodium hydride was mixed with 10 ml of dimethylformamide. A solution of 2.50 g of 4-(4'-cyanophenyl)phenol in 5 ml of dimethylforamide was added dropwise thereto under ice-cooling. Then the obtained mixture was stirred at room temperature for one hour. A solution of 3.7 g of monotosylate of (R,R)-2,4-pentanediol in 5 ml of dimethylforamide was added dropwise thereto and the obtained mixture was stirred at 80° C. for two hours. After cooling, the reaction mixture was poured into 100 ml of ice-water and extracted with diethyl ether. After washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (3:2) as a developing solvent. Thus 1.8 g of (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[C:9]([C:25]([NH2:27])=[O:26])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:12](Cl)[N:13]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>O.O1CCOCC1.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>[NH2:7][C:8]1[C:9]([C:25]([NH2:27])=[O:26])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:12]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)[N:13]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2cccs2)ccc1=O
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
Under nitrogen atmosphere, a solution of Na2CO3 (138 mg) in water (0.8 ml) was added to a suspension of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (100 mg), 2-thienylboronic acid (104 mg) and tetrakis(triphenylphosphine)palladium (11.3 mg) in dioxane (2 ml) and the mixture was stirred at 100-105° C. for 4 hours. After addition of water (10 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-(2-thienyl)-2-pyrazinecarboxamide as a solid (85 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([O:34][C:35]([NH:37][C:38]([CH3:43])([C:40](O)=[O:41])[CH3:39])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:40](=[O:41])[C:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:43])[CH3:39])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2noc(C3CNCC(c4ccc(OC(F)(F)F)cc4)C3)n2)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
150 mg (0.30 mmol) of the compound from Example 178A and 66 mg (0.32 mmol) of N-(tert-butoxycarbonyl)-2-methylalanine were reacted according to the General Method 7. Yield: 117 mg (64% of theory)
Reaction SMILES: [H][H].C([N:10]1[C:14]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][N:12]=[N:11]1)C1C=CC=CC=1>C(O)(C)C.O.[Pd](Cl)Cl>[NH:10]1[C:14]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][N:12]=[N:11]1
Reactant: [H][H]
Reactant: O=C(O)COCCc1cnnn1Cc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CC(C)O
Solvent: O
Product: O=C(O)COCCc1cnn[nH]1
Yield: 120.3 %

Procedure:
Pressurize 1 atmosphere of hydrogen (g) to a flask containing [2-(1-benzyl-1H-1,2,3-triazol-5-yl)ethoxy]acetic acid (10.1 g; 1.00 equiv; 38.66 mmoles) and palladium (II) chloride (3 g; 16.92 mmoles; 3.00 g) in isopropyl alcohol (300 mL) and water (60 mL). Maintain the flask under a hydrogen atmosphere for 3 h, then filter through Celite™ and concentrate. Add toluene (2×50 mL) and concentrate to afford the title compound (7.96 g, 100%). 1H NMR (d6-DMSO): 2.86 (t, J=7 Hz, 2H), 3.65 (t, J=7 Hz, 2H), 3.98 (s, 2H), 7.77 (s, 1H), 13.4-13.6 (br s, 2H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][CH:12](OS(C)(=O)=O)[CH2:11][N:10]1[C:19](=[O:21])[CH3:20])[CH3:6]>CN(C=O)C>[CH2:5]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][CH:12]([N:1]=[N+:2]=[N-:3])[CH2:11][N:10]1[C:19](=[O:21])[CH3:20])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(C)=O
Temperature: 0 °C
Yield: 99.1 %

Procedure:
243 g of sodium azide was added to a solution of 802 g of N-acetyl-4-mesyloxy-L-proline ethyl ester and 2.4 L of DMF, and the mixture was reacted at an inner temperature of 70° C. for 7 hours. The reaction solution was cooled, poured into ice water (4.8 L), and extracted with chloroform (3.2 L). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 644 g of N-acetyl-4-azido-L-proline ethyl ester as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[SH:13].[C:14]1(=[O:32])[N:18]([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH2:21]Cl)[C:17](=[O:27])[C:16]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:15]12>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[N:18]1[C:17](=[O:27])[C:16]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:15]2[C:14]1=[O:32]
Reactant: Sc1nccn1Cc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1c1ccccc1CCl
Product: O=C1c2ccccc2C(=O)N1c1ccccc1CSc1nccn1Cc1ccccn1

Procedure:
1-(2-pyridylmethyl)-2-mercaptoimidazole and 2-phthalimidobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(2-pyridylmethyl)-2-(2-phthalimidobenzylthio)imidazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:17]=3[N:18]=2)[C@H:10]([CH2:27][OH:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)[C@H:10]([CH2:27][O:28][CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(C(F)(F)F)cc3s2)[C@H](CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of (S)-3-hydroxymethyl-4-(6-trifluoromethyl benzothiazole-2-yl) piperazine-1-carboxylic acid t-butyl ester (209 mg) in dimethylformamide (2 mL) were sequentially added methyl iodide (0.5 mL) and sodium hydride (62.4 mg). The mixture was stirred at room temperature for 24 hours. To the reaction solution was added ice water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (167 mg).