Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([OH:17])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:39]=[C:40]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)[CH2:41][NH:42][C:43](=[O:57])[C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:46][CH:45]=1>CN(C=O)C.O>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:61]1[CH2:62][CH2:63][N:58]([C:40](=[O:39])[CH2:41][NH:42][C:43](=[O:57])[C:44]2[CH:45]=[CH:46][C:47]([O:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[CH:48][CH:49]=2)[CH2:59][CH2:60]1)=[O:17]
Reactant: O=C(O)c1ccco1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccco2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
DIPEA (0.091 mL, 0.53 mmol) was added drop wise to furan-2-carboxylic acid (23 mg, 0.21 mmol) in DMF (5 mL). EDCI (84 mg, 0.44 mmol) and HOBT (28 mg, 0.21 mmol) were added consecutively and, after 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.18 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the resulting solid was filtered under reduced pressure to afford N-{2-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 65% yield. LC-MS purity: 92%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 8 (t, 3H), 7.4 (t, 2H), 7.2 (t, 1H), 7 (m, 4H), 6.6 (s, 1H), 4.2 (d, 2H), 3.6 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24](Cl)=[C:23]([Cl:30])[N:22]=1)COCC[Si](C)(C)C)(=[O:11])=[O:10].[C:31]([NH:34][CH2:35][CH2:36][NH2:37])(=[O:33])[CH3:32].C(N(CC)CC)C>C(#N)C>[Cl:30][C:23]1[C:24]([NH:37][CH2:36][CH2:35][NH:34][C:31](=[O:33])[CH3:32])=[N:25][C:26]([O:27][CH3:28])=[C:21]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])[N:22]=1
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CC(=O)NCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc(NCCNC(C)=O)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 48 h

Procedure:
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.26 g) was dissolved in acetonitrile (1.0 mL) and N-acetylethylenediamine (0.055 mL) and triethylamine (0.19 mL) added. After 48 h, the reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate gave the title compound protected with the SEM group, as an oil (0.13 g). The oil was dissolved in dichloromethane (2.0 mL) and boron trifluoride etherate (0.14ml) added. After 2 h, ethyl acetate (20 mL) was added and the mixture washed with 5% aqueous citric acid (5 mL), dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate gave the title compound as a solid (0.031 g).
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].S(Cl)([Cl:18])=O>>[Cl:11][C:7]1[N:6]=[C:5]2[N:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[NH:2][C:10]2=[CH:9][C:8]=1[Cl:18]
Reactant: O=S(Cl)Cl
Reactant: On1c(C(F)(F)F)nc2nc(Cl)ccc21
Product: FC(F)(F)c1nc2nc(Cl)c(Cl)cc2[nH]1

Procedure:
1-Hydroxy-5-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine (100 milligrams) was mixed with 10milliliters of thionyl chloride and the mixture refluxed on a steam bath for ten hours. The thionyl chloride was then evaporated and the residue, the desired 5,6-dichloro-2-(trifluoromethyl) -1H-imidazo [4,5-b] pyridine product, was shaken with water and separated by filtration, m.p. 222° -24° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]([C:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:15](C(OC(C)(C)C)=O)[CH:14]=1)=O.[N+]([O-])([O-])=O.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([NH2:45])=[NH2+:44]>COCCO>[NH:15]1[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:13]([C:11]2[CH:10]=[CH:9][N:45]=[C:43]([NH:42][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:35])[N:44]=2)=[CH:14]1
Reactant: Cc1ccccc1NC(N)=[NH2+]
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)C#C[Si](C)(C)C)c2cnccc21
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: COCCO
Product: Cc1ccccc1Nc1nccc(-c2c[nH]c3ccncc23)n1

Procedure:
173 mg (1.25 mmol) of potassium carbonate are added to a solution of 171 mg (0.50 mmol) of tert-butyl 3-(3-trimethylsilylpropynoyl)pyrrolo[3,2-c]pyridine-1-carboxylate and 265 mg (1.25 mmol) of 2-methylphenylguanidinium nitrate (prepared by the method of J. L. Hughes et al., J. Med. Chem. 1975, 18, 1077-1088) in 2.5 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 18 hours. After cooling, the reaction mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving [4-(1H-pyrrolo-[3,2-c]pyridin-3-yl)pyrimidin-2-yl]-o-tolyl-amine (“A6”) as beige crystals; ESI 303;
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](OC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCOCC3)co2)C1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (1.00 g, 2.29 mmol) (obtained as described in Reference Example 70(8)) in toluene (50 ml) was added a solution of 0.67 M morpholine-trimethylaluminium in toluene (6.87 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred in an oil bath (80° C.) for 4 hours. After checking the completion of the reaction, to the reaction mixture were added 10% aqueous acetic acid (50 ml) and ethyl acetate (100 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-morpholinocarbonyl-1,3-oxazol-2-yl)azetidine (400 mg, yield 36%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2(O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]2([F:35])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2-c2ccc(Cl)cc2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
A solution of EXAMPLE 263E (2.0 g) and diethylaminosulfur trifluoride (1.39 mL) in dichloromethane (40 mL) was stirred for 24 hours. The reaction was quenched with water (30 mL), extracted twice with ether, and the combined extracts were washed with water, and brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][OH:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Na+].[CH3:37]I>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][O:30][CH3:37])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h

Procedure:
{8-(3,4-Difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (100 mg) was added to a suspension of sodium hydride (60%, 9.4 mg) in DMF (1 mL) under ice-cooling, and the mixture was stirred for 30 min. Methyl iodide (14.7 μL) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and diluted with ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (80.0 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(C)nc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2cc[nH]c2n1
Yield: 89.5 %

Procedure:
The synthesis was performed with reference to the known literature (US 2006/0148801). A solution of 6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.17 g, 0.60 mmol) in ethanol (5.0 mL) was added with 5 N aqueous sodium hydroxide (1.0 mL), and the mixture was refluxed for 8 hours by heating. The solvent was evaporated under reduced pressure, the residue was extracted with chloroform, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (80:20→60:40)) to obtain 6-methyl-1H-pyrrolo[2,3-b]pyridine (0.071 g, 90%).
Reaction SMILES: [N:1]1([CH:6]([CH:14]([OH:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:10]([O:9][C:7](=[O:8])[CH:6]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH:14]([O:23][C:24](=[O:27])[CH2:25][CH3:26])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)C(C(O)c1ccc(Cl)cc1Cl)n1cncn1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)OC(c1ccc(Cl)cc1Cl)C(C(=O)OC(C)(C)C)n1cncn1
Yield: 76.3 %

Procedure:
3.15 gms of t-butyl α-(1,2,4-triazol-1-yl)-β-hydroxy-β-(2,4-dichlorophenyl)propionate were added to 50 mls of chloroform along with 1.1 gms of 4-dimethylaminopyridine. 1.25 gms of propionyl chloride were then added to the system. The reaction mixture was then refluxed for 18 hours. The reaction solution was then first washed with aqueous 5 wt. % hydrochloric acid and then with aqueous sodium hydroxide. The organic phase was dried over sodium sulfate and then filtered. The filtrate was evaporated to dryness under vacuum affording 2.78 gms of the title compound as a yellow wax.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([OH:18])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:19]([N:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]([OH:18])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:11])=[CH:9][C:2]=1[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([N:21]([CH2:19][CH3:20])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30])#[N:5]
Reactant: CCN(C(=O)c1cccc(O)c1)c1ccccc1
Reactant: Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cccc(Oc2cc(C(C)(O)c3cncn3C)ccc2C#N)c1)c1ccccc1
Temperature: 60 °C

Procedure:
2-Fluoro-4-[1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile (0.054 g, 0.220 mmol), N-ethyl-3-hydroxy-N-phenyl-benzamide (0.053 g, 0.220 mmol) and Cs2CO3 (0.143 g, 0.440 mmol) were dissolved in anhydrous DMF (5 mL) and heated at 60° C. under Ar for 4 days. The reaction was diluted with EtOAc, washed with satd. NaHCO3 solution, water, and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (1-3% MeOH/CH2Cl2) to give the title compound. FAB MS (M+1)=467.
Reaction SMILES: OC([C:6]1([O:16][CH3:17])[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:7]1[C:8]([NH2:10])=[O:9])C(C)C.S(Cl)(Cl)=O>C(OCC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([O:16][CH3:17])=[C:7]([C:8]2[O:9][CH2:6][C:7]([CH3:11])([CH3:8])[N:10]=2)[CH:11]=1
Reactant: COC1(C(O)C(C)C)C=CC(Cl)=CC1C(N)=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(Cl)cc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 5-chloro-o-anisic acid (50 g) in toluene (100 mL) was added thionyl chloride (50 mL). The reaction mixture was heated under reflux for 2 hrs and distilled using a short path distillation apparatus to give 5-chloro-o-anisyl chloride, which was used in the next step. To a solution of 2-amino-2-methyl-1-propanol (38 mL) in dichloromethane (200 mL) was added a solution of 5-chloro-o-anisyl chloride in dichloromethane (150 mL) dropwise. The reaction mixture was stirred at ambient temperature for 1 hr, dichloromethane was added and the mixture was washed with 2 N hydrochloric acid. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give N-(2-(1-hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide, which was used in the next step. To N-(2-(1 -hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide was added thionyl chloride (40 mL) at 0° C. The reaction mixture was stirred for 30 min, warmed to ambient temperature, diluted with diethyl ether (200 mL), and the mixture was stirred for 10 mins. The mixture was decanted, 10% sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to afford 41 g (64%) of product, mp 50-51° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][C:3]=1[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH:7]=1
Reactant: CC(C)COc1ccc(N)c(C(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)COc1ccc(N)c(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C

Procedure:
In methanol (12 ml) was dissolved 2-amino-3′-tert-butoxycarbonylaminomethyl-5-isobutyloxy-benzophenone (0.38 g). To the solution was added, while stirring at room temperature, sodium borohydride (50 mg). The reaction mixture was concentrated, to which was added water, followed by extraction with ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 2-amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-isobutyloxy-benzyl alcohol as a yellow oily product (0.36 g).
Reaction SMILES: C(O)C.[C:4]([C:6]1[CH:7]=[C:8]([NH:26][C:27]([C:29]2[CH:30]=[N:31][N:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:33]=2[CH3:34])=[O:28])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:21]=[N:22][O:23][C:24]=2[CH3:25])=[O:19])[CH2:14][CH2:13]1)#[N:5].[OH-].[Na+]>O>[C:4]([C:6]1[CH:7]=[C:8]([NH:26][C:27]([C:29]2[CH:30]=[N:31][N:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:33]=2[CH3:34])=[O:28])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:19])/[C:20](/[C:21]#[N:22])=[C:24](\[OH:23])/[CH3:25])[CH2:14][CH2:13]1)#[N:5]
Reactant: Cc1oncc1C(=O)N1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(F)cc4)c3C)cc2C#N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(O)=C(\C#N)C(=O)N1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(F)cc4)c3C)cc2C#N)CC1
Reaction time: 2 h
Yield: 47.4 %

Procedure:
A mixed solvent of ethanol (10 ml) and water (10 ml) containing N-{3-cyano-4-[4-(5-methylisoxazol-4-ylcarbonyl) piperazin-1-yl]phenyl}-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (0.95 g) and sodium hydroxide (0.1 g) was stirred at a refluxing temperature for 2 h. The solvent was evaporated under reduced pressure. Dilute hydrochloric acid was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (0.45 g), melting point: 210° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][NH2:15].O1CCCC1>C(Cl)Cl>[CH3:14][NH:15][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A solution of 2-nitrobenzene-1-sulfonyl chloride (4 g, 18.05 mmol) in DCM (60.2 mL) was cooled down to 0° C. with an ice water bath. TEA (7.55 mL, 54.1 mmol) and 2 M methylamine in tetrahydofuran (13.54 mL, 27.1 mmol) were added. The resulting solution was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM, washed with sat. NaHCO3 (2×100 mL), brine (100 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure, and triturated in ether to afford N-methyl-2-nitrobenzenesulfonamide (3.12 g, 14.44 mmol, 80% yield). LCMS (m/z): 217.1 (MH+), 0.53 min.
Reaction SMILES: [NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:17])=[C:6]([S:9][CH2:10][C:11]3[N:12]=[N:13][S:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.[ClH:34].CC(C)=O.C(OCC)(=O)C>C(O)=O>[ClH:34].[NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([S:9][CH2:10][C:11]3[N:12]=[N:13][S:14][CH:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3csnn3)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O=CO
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3csnn3)CS[C@H]12
Reaction time: 1.5 h

Procedure:
To a solution of diphenylmethyl 7β-amino-3-[(1,2,3-thiadiazol-4-yl)methylthio]-3-cephem-4-carboxylate (4.68 g, 9.42 m mol) in formic acid (18.7 ml) was added conc. HCl (3.93 ml) at room temperature and the mixture was stirred at the same temperature for 1.5 hours. The mixture was poured into a cooled mixture of acetone (140 ml) and ethyl acetate (280 ml) and the precipitates were collected by filtration, washed with acetone and dried in vacuo to give 7β-amino-3-[(1,2,3-thiadiazol-4-yl)methylthio]-3-cephem-4-carboxylic acid hydrochloride (2.63 g).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:3]=1[NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[N:37]=[C:36]([C:38]([NH:41][C:42]2[C:47]([CH2:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:50][CH3:51])([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1(C)C=CC=CC=1.CO>[CH2:50]([C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH2:48][CH3:49])[C:42]=1[NH:41][C:38]([C:36]1[N:37]=[C:32]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH2:5][NH:4][C:3]2[C:2]([CH3:1])=[CH:28][C:27]([CH3:29])=[CH:26][C:25]=2[CH3:30])[CH:33]=[CH:34][CH:35]=1)([CH3:40])[CH3:39])[CH3:51]
Reactant: CCc1cccc(CC)c1NC(C)(C)c1cccc(Br)n1
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
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: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1NC(C)(C)c1cccc(-c2c(CNc3c(C)cc(C)cc3C)ccc3ccccc23)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.43 g (6.00 mmol) of 2,4,6-trimethyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 2.10 g (6.00 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,6-diethylaniline, 4.33 g (15.10 mmol) of Na2CO3×10H2O, 65 ml of water, 18 ml of methanol, and 80 ml of toluene was purged with argon for 30 min. To this solution 0.35 g (0.30 mmol) of Pd(PPh3)4 was added. In argon atmosphere, this mixture was stirred for 12 h at 80° C. Then, it was cooled to room temperature, the organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 2.66 g (82%) of yellow oil. Anal. calc. for C39H43N3: C, 84.24; H, 8.00; N, 7.76. Found: C, 84.36; H, 8.15; N, 7.61. 1H NMR (CDCl3): δ 7.87 (m, 1H. 8-H in naphtalene), 7.82 (d, J=8.4 Hz, 1H, 4-H in naphtalene), 7.78 (t, J=7.7 Hz, 1H, 4-H in pyridine), 7.70 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.35-7.47 (m, 4H, 3, 5, 6, 7-H in naphtalene), 7.21 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 6.93-7.00 (m, 3H, 3, 4, 5-H in 2, 6-Et2C6H3), 6.74 (s, 2H, 3, 5-H in mesityl), 3.96 (m, 2H, CH2N), 3.70 (br.s, 2H, NH), 2.47 (sep, J=7.6 Hz, 1H, CHMe2), 2.43 (sep, J=7.6 Hz, 1H, CHMe2), 2.21 (s, 3H, 4-Me in mesityl), 2.03 (s, 6H, 2, 6-Me in mesityl), 1.54 (s, 3H, CMeMe′), 1.47 (s, 3H, CMeMe′), 1.02 (t, J=7.6 Hz, 6H, CHMe2).