Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=[O:14])([O-:3])=[O:2].[CH3:16][C:17]1C([N+]([O-])=O)=CC=CC=1C(O)=O.N1C2C(=CC=CC=2)C(C(OCC)=O)=N1.[N+]([O-])(O)=O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CCOC(=O)c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
The conversion of ethyl indazole-3-acid to 5-nitroindazole-3-carboxylic acid is essentially the same method as described for methyl 3-nitrobenzoic acid: Kamm, O.; Segur, J. B. Org. Syn. Coll. Vol 1. 1941, 372. Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL concentrated sulfuric acid and the reaction mixture was cooled to 0° C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over the course of 1 h. The mixture was stirred for an additional 1 h at 0° C. and was poured onto of crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 mL acetonitrile and the mixture was heated at reflux for 2 h. The mixture was allowed to cool to room temperature and the solid was collected and dried in vacuo to provide ethyl 5-nitroindazole-3-carboxylate (53%) as a colorless solid. The ester was added to a solution of 10 N sodium hydroxide and the suspension was warmed to 60° C. After 2 h the solution was allowed to cool to room temperature and was acidified to pH ˜2. The precipitated solids were collected by filtration, washed with water, and dried to provide the acid as a light yellow solid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]#[C:13][CH2:14][O:15][CH3:16])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+:18].[ClH:19].C1(C)C=CC=CC=1>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([C:12]#[C:13][CH2:14][O:15][CH3:16])[CH:9]=1.[Cl-:19].[Li+:18]
Reactant: Cl
Reactant: COCC#Cc1cnc(C(=O)OC)c(N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCC#Cc1cnc(C(=O)O)c(N)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-5-(3-methoxy-prop-1-ynyl)-pyridine-2-carboxylic acid methyl ester (263 mg, 1.2 mmol) in THF (6 ml) was added 1N lithium hydroxide (1.32 ml, 1.32 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. To the mixture was added 1N HCl (1.2 ml, 1.2 mmol) at 0° C., after stirring for 5 min toluene was added and the solvents were evaporated to provide the title compound together with lithium chloride as an off-white solid. The mixture was used for coupling reactions without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.BrC1C=CC(C2N(C3C=CC(Cl)=CC=3)C(=O)C3C=NN(C4C=CC=C(SC)C=4)C=3N=2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([Cl:20])=[N:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: CSc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Solvent: Cc1ccccc1
Product: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 170 °C

Procedure:
4-Bromo-N-(4-chloro-phenyl)-benzimidoyl chloride is prepared by heating 4-bromo-N-(4-chloro-phenyl)-benzamide (17.6 g, 56.8 mmol) and thionyl chloride (125 mL) for 1 h. The clear solution is concentrated and the residue obtained is coevaporated with toluene (100 mL). Then 5-amino-1-(3-cyano-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (1, 9.70 g, 37.8 mmol) is added and the resulting mixture is heated to 170° C. without solvent for 6 h. The crude product obtained is purified by column chromatography.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:35][CH:34]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: CC1(C)OB(c2ccc(OCCCN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(OCCCN3CCOCC3)cc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)morpholine (65 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(4-(3-morpholinopropoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=465).
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[C:11]([O:16]C)[C:10]=3[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:7]2[C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=3[C:9]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
To a solution of 4-(1-cyclohexyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (53 mg) in acetonitrile (10 mL) were added sodium iodide (41 mg) and chloro(trimethyl)silane (119 mg), and the mixture was stirred at 60° C. for 20 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)[CH:12]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:42]C(C)([O-])C.[K+].CI.O1CCOCC1>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([C:37]([F:38])([F:39])[F:40])[CH:31]=2)[CH:12]=[C:13]([N:15]([C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)[CH3:42])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(F)cc(C(F)(F)F)c2)cc(N(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
A mixture of 2-[5′-fluoro-5-(3,5-bis-trifluoromethyl-phenylamino)-3′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester (57 mg, 0.096 mmol), potassium tert-butoxide (58 mg, 0.52 mmol), methyl iodide (60 μL, 0.11 mmol), dioxane (2 mL) and N-methylpyrrolidinone (0.2 mL) was stirred with microwave irradiation for 15 min at 130° C. The mixture was concentrated in vacuo, suspended in 1M HCl (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic layer was washed with brine, dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (silica, 0-5% diethyl ether in petroleum ether) to afford the title product as a colourless solid (33 mg, 56%). RT=5.24 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]=[C:6]2[CH3:16].[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[N:8]([CH3:20])[CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C)cn(C)c2cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
A solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (900 mg, 4 mmol) in 7 ml DMF was cooled to zero degrees C., and sodium hydride (104 mg, 4 mmol, 95% powder) was added. The reaction mixture was stirred 15 minutes at zero degrees C., and then iodomethane (270 ul, 4 mmol) was added. The reaction mixture was stirred for 1 hour and allowed to warm to room temperature. The reaction mixture was then cooled to 0° C., quenched by addition of 1 N NH4Cl, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-Methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg, 75%) as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4].Br[CH2:29][C:30]#[N:31].CCN(C(C)C)C(C)C>C(#N)C>[C:30]([CH2:29][NH:1][C@@H:2]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4])#[N:31]
Reactant: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Reactant: N#CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCC#N)n(C)n2)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a rt solution of 23.D (750 mg, 2036 μmol) and bromoacetonitrile (244 mg, 2036 μmol) in acetonitrile was added n,n-diisopropylethylamine (426 μl, 2443 μmol). After stirring at 60° C. for 2 hr, organic solvents were removed under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-12% MeOH/CH2Cl2 for elution gave the title product 23.E as yellow syrup (706 mg, 85%).
Reaction SMILES: C(O[C:4](=[O:23])[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22])C.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.[C-]#N.[Na+]>ClCCl>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:4](=[O:23])[CH2:5][N:6]2[CH2:10][CH2:9][N:8]([C:11]3[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=3)[C:7]2=[O:22])=[CH:27][CH:26]=1
Reactant: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Reactant: NCc1ccc(F)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)nc1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A mixture of ethyl 2-(3-(2-ethoxy-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.43 g, 1.25 mmol), 4-fluorobenzylamine (3 mL) and catalytic amount of sodium cyanide was stirred at 80° C. for 16 h. The reaction mixture was allowed to cool to ambient temperature, diluted with dichloromethane (25 mL) and filtered. The solid was washed with dichloromethane and hexanes on the filter. The filtrate was filtered again, and the solid was washed with hexanes. The combined material was dried to afford the title compound as a colorless solid (0.45 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.28-7.20 (m, 2H), 7.05-6.97 (m, 2H), 6.42 (br s, 1H), 4.42 (d, J=5.7 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.19-4.10 (m, 2H), 3.99 (s, 2H), 3.77-3.70 (m, 2H), 2.62 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoroaniline (50.0 g) and triethylamine (157 ml) in CH2Cl2 (700 ml) were added 2,2-dimethyl-propionyl chloride (58.0 ml) over a 30 minutes period. The resulting solution was stirred at r.t. for 2 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 86.0 g of the title compound. M.p. 124-125° C.; Retention Time HPLC 2.57 min; MS (ES+) 196 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1)(=[O:14])=[O:13])#[N:2]>CO.CS(C)=O.[Ni]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([S:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:23][O:22][B:21]([OH:24])[C:20]=3[CH:25]=2)(=[O:13])=[O:14])=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Ni]
Solvent: CS(C)=O
Solvent: CO
Product: N#Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a solution of 2-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide (400 mg, 1.1 mmol) in MeOH/DMSO (40 ml/1 ml) was added Raney Ni (100 mg) under nitrogen, then the solution was stirred under hydrogen atmosphere at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep. HPLC (column: YMC AQ 150×30.0 mm, 5 u; liquid phase: [A-H2O+0.075% TFA; B-MeCN+0.075% TFA] B %: 18%-48%, 10 min) to give the title compound (100 mg, 27.62%) as a yellow solid. 1H NMR: DMSO 400 MHz δ10.25 (s, 1H), 9.21 (s, 1H), 7.60 (d, J=9.6 Hz, 1H), 7.43 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.92 (s, 1H), 6.77 (d, J=10.4 Hz, 1H), 6.44 (brs, 2H), 4.89 (s, 2H). ESI-MS m/z 330 (M+H, positive); HPLC purity: 97.31% (MaxPlot 190-370 nm), 99.89% (220 nm).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([S:22][CH3:23])[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9]2.[OH-].[Na+].Cl>C(O)C.O>[C:16]([C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH:4]([S:22][CH3:23])[C:3]([OH:24])=[O:2])=[CH:15][CH:14]=2)#[CH:17]
Reactant: COC(=O)C(Oc1ccc2ncc(C#C[Si](C)(C)C)cc2c1)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of Methylsulfanyl-(3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetic acid methyl ester (5 g) in ethanol (50 ml), a 2 M solution of sodium hydroxide in water (9.74 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-could water (200 ml) and acidified with a 2 M solution of hydrochloric acid in water (9.74 ml). The precipitate was filtered off and washed with water to give (3-Ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid as yellowish solid (3.53 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[CH:12]([OH:14])[CH3:13].[OH2:15].[C:16]1(C)C=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:15][CH2:20][C@@H:19]1[CH2:18][CH2:17][CH2:16][C@@H:13]1[CH2:12][OH:14]
Reactant: O
Reactant: Cc1ccccc1
Reactant: CC(C)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OC[C@@H]1CCC[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
46 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 2.8 g of 2-hydroxymethyl-cyclobutanecarboxylic acid lactone (C. C. Schroff et al., J. Org. Chem. 36, 3356 (1971)) in 70 ml of toluene at 0° C. under argon and stirred for 50 minutes at 0° C. Then, 20 ml of 2-propanol and 23 ml of water are instilled, stirred for 2 hours at 22° C. filtered washed with dichloromethane and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate/hexane (4+1), 2.1 g of cis-1,2-dihydroxymethyl-cyclopentane is obtained as colorless liquid.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:13][S:14]([O:12][C:8]1[CH:7]=[C:6]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:11]=[CH:10][N:9]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CSc1cc[nH]c(=O)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CSc1ccnc(OS(C)(=O)=O)c1
Yield: 91.6 %

Procedure:
1.3 g of 4-isobutylthio-2-pyridone (m.p. 119° to 120° C.) and 0.7 ml of methanesulfonyl chloride were dissolved in 10 ml of methylene chloride, and cooled below 10° C. 1.5 ml of triethylamine was added dropwise to the solution with stirring. By stirring at room temperature for 4 hours, the reaction was completed. The reaction solution was poured into 100 ml of water, followed by addition of 100 ml of methylene chloride for separation. The methylene chloride layer was washed with water and saturated aqueous solution of common salt, then distilled to remove the solvent. The obtained residue was purified by silica-gel column chromatography (developer: benzene and n-hexane) to obtain 1.7 g of the objective 4-isobutylthio-2-pyridyl methanesulfonate (yield: 91.6%) as a colourless oil, which were allowed to stand to crystallization.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH:23]1([NH:26][C:27](=[O:45])[C:28]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[C:31]([CH3:43])=[C:30]([F:44])[CH:29]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.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>[CH:23]1([NH:26][C:27](=[O:45])[C:28]2[CH:33]=[C:32]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:7][N:8]4[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=3)[C:31]([CH3:43])=[C:30]([F:44])[CH:29]=2)[CH2:24][CH2:25]1
Reactant: C[Si](C)(C)CCOCn1nc(S(C)(=O)=O)c2ccc(Br)cc21
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(S(C)(=O)=O)nn(COCC[Si](C)(C)C)c2c1
Yield: 66.1 %

Procedure:
A mixture of 6-bromo-3-(methylsulfonyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazole (Intermediate 76) (0.18 g) N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 62) (0.14 g) aqueous sodium carbonate (1M, 1.32 ml) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) in isopropanol (2 ml) was stirred at reflux under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (2:1) to give the title compound (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:17])[C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[CH3:16].[I:18][CH3:19]>CO>[I-:18].[OH:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:7]2[C:6]([CH3:17])=[CH:5][N+:4]([CH3:19])=[CH:3][C:2]=2[CH3:1])=[C:9]([CH3:16])[CH:10]=1
Reactant: CI
Reactant: Cc1cncc(C)c1-c1c(C)cc(O)cc1C
Solvent: CO
Product: Cc1cc(O)cc(C)c1-c1c(C)c[n+](C)cc1C
Product: [I-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 6 (0.113 g, 0.500 mmol) in anhydrous methanol (10 mL) was added dropwise iodomethane (0.5 mL, 0.660 g, 2.75 mmol) at room temperature under N2. The reaction mixture was then stirred at 60° C. under N2 overnight. After cooling to room temperature, the mixture was concentrated in vacuo to give the corresponding methylpyridinium iodide salt as an analytically pure yellow solid (0.184 g, 99.4%). mp 257-258° C.; 1H NMR (500 MHz, DMSO-d6): δ 9.562 (s, 1H), 8.898 (s, 2H), 6.645 (s, 2H), 4.295 (s, 3H), 2.015 (s, 6H), 1.760 (s, 6H); 13C NMR (125 MHz, DMSO-d6): δ 157.588, 157.448, 143.158, 136.942, 134.675, 124.179, 114.988, 47.297, 19.162, 16.527; MS (ESI): m/z 242.4 [(M−I)+, 100]; Anal. Calcd. For C16H20INO.H2O: C, 49.62; H, 5.73; N, 3.62; I, 32.77. Found: C, 50.08; H, 5.52; N, 3.65; I, 33.49.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][C:14]#[C:15][CH2:16][OH:17].O.[Na+].[Cl-]>C(Cl)Cl>[S:2]([O:17][CH2:16][C:15]#[C:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])(=[O:3])[CH3:1]
Reactant: OCC#CCOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Methanesulfonyl chloride (1.0 mL, 12.80 mmol) was added dropwise to a stirred solution of 4-(tetrahydro-pyran-2-yloxy)-but-2-yn-1-ol (1.9232 g, 11.30 mmol) and TEA (2.5 mL, 17.85 mmol) in DCM (40 mL) at ° C. for five minutes. And then the resulting mixture was stirred at room temperature for 5.5 hours. Water (20 mL) was added, followed by addition of saturated aqueous NaCl solution (70 mL). The organic phase was separated and washed again with brine (60 mL), dried over Na2SO4, concentrated. The residue was separated by flash column chromatography on silica gel using 5-25% EtOAc/hexane to afford 1.542 g of product (yield 55%, oil), along with 400 mg of Di-4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl ether (yield 22%). 1H-NMR (CDCl3): δ 4.88 (t, J=1.8 Hz, 2 H), 4.76 (t, J=3.0-3.3 Hz, 1 H), 4.37-4.24 (m, 2 H), 180-3.76 (m, 1 H), 3.54-3.50 (m, 1 H), 3.11 (s, 3 H), 1.78-1.51 (m, 6 H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:25][CH:26]1[C:44](=[O:45])[N:28]2[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])[C:15]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH2:31][S:32][C@H:27]23)=[O:17])[N:13]=1)=[O:7]
Reactant: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC=O)n3)[C@H]2SC1
Yield: 58.8 %

Procedure:
N,N-Dimethylformamide (0.207 g.), phosphoryl chloride (0.436 g.), 2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetic acid (syn isomer, 0.65 g.), 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.85 g.), trimethylsilylacetamide (2.71 g.) and ethyl acetate (20 ml.) were treated in a similar manner to that of Example 5-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.80 g.).