Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])/[CH:5]=[N:6]/[S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[CH2:18]([Mg]Br)[CH3:19].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CC[Mg]Br
Reactant: COc1ccc(/C=N/[S@@](=O)C(C)(C)C)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a solution of 66 (3.0 g, 12 mmol) in THF (30 mL) at −78° C. was added a solution of ethylmagnesium bromide in THF (1N, 18 mL, 18 mmol). After stirring for 4 h, the reaction mixture was warmed to 25° C. and stirred at RT overnight. The mixture was treated with NH4Cl, and diluted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:1) to afford 1.5 g (45%) of (S)—N—((R)-1-(3-fluoro-4-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide (68). LCMS (ESI) m/z: 288.1 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:13]([O-:16])([O-])=[O:14].[Na+].[Na+]>C(Cl)Cl.O>[C:6]([O:16][C:13]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([Br:2])=[CH:4][CH:5]=2)[CH2:10]1)=[O:14])([CH3:11])([CH3:7])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2c(c1)CNCC2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-bromo-1,2,3,4-tetrahydro-isoquinoline hydrochloride (1.0 g, 4.0 mmol) in DCM (18 mL) and 2M aqueous Na2CO3 solution (5.0 mL, 10.0 mmol) was added a solution of BOC-anhydride (1.0 g, 4.6 mmol) in DCM (7 mL). The reaction mixture was stirred at RT for 3 h and then diluted with water and DCM (1:1, 100 mL). The organic phase was then separated and washed with brine, dried (MgSO4) and filtered. The solvent was evaporated and then carried to next step without purification.
Reaction SMILES: [CH3:1][CH:2]([N:28]([CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=1)[C:29]([CH:31]([OH:40])[CH:32]([C:37]([O-:39])=[O:38])[CH2:33][C:34]([O-:36])=[O:35])=[O:30])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.[Na+].[Na+].O[C:55]([C:65](=O)N(C(C)C(C1C=CC2OCOC=2C=1)CC1OC(C(=O)NC2C=CC=CC=2)=CC=1)CC1C=CC2C(=CC=CC=2)C=1)=[C:56](C(OC)=O)CC(O)=O.C(Br)C=C.O>CN(C)C=O>[CH2:65]([O:38][C:37]([C:32](=[C:31]([OH:40])[C:29](=[O:30])[N:28]([CH:2]([CH3:1])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=1)[CH2:33][C:34]([OH:36])=[O:35])=[O:39])[CH:55]=[CH2:56]
Reactant: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)C(O)C(CC(=O)[O-])C(=O)[O-]
Reactant: COC(=O)C(CC(=O)O)=C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CC(=O)O)=C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 2.4 %

Procedure:
80 mg of disodium (3RS,4RS)-4-[N-[(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-(2-naphthylmethyl)carbamoyl]-3-carboxylato-4-hydroxybutanoate as the starting material of Example 28, was dissolved in 2 ml of dimethylformamide, and 37 μl of allyl bromide was added thereto, followed by stirring at room temperature for 3 days. The reaction solution was poured into water and extracted with ethyl ether and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2), and the obtained diallyl ester was treated in the same manner as in Example 25(2) and (3) to obtain 4.4 mg (yield: 2.4%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: CS([C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][N:5]=1)=O.CS(C1N=C(C2C=CC=CC=2)SN=1)(=O)=O.[CH2:30]([OH:34])[C:31]#[C:32][CH3:33].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[C:9]1([C:7]2[S:6][N:5]=[C:4]([O:34][CH2:30][C:31]#[C:32][CH3:33])[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC#CCO
Reactant: CS(=O)c1nsc(-c2ccccc2)n1
Agent: CS(=O)(=O)c1nsc(-c2ccccc2)n1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(-c2ccccc2)n1
Reaction time: 0.17 h

Procedure:
To 3 ml of N,N-dimethylformamide were added 300 mg of a mixture of 3-methylsulfinyl-5-phenyl-1,2,4-thiadiazole and 3-methylsulfonyl-5-phenyl-1,2,4-thiadiazole (integration ratio of 1H-NMR sulfonyl form:sulfinyl form=4:1) and 141 mg of 2-butyne-1-ol, and to the resulting mixture was added 80 mg of sodium hydride (60% oily) with ice-cooling. The mixture was stirred for 10 minutes with ice-cooling, and allowed to stand at room temperature for 18 hours. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The organic layer was concentrated, and the resulting residue was subjected to silica gel column chromatography to obtain 200 mg of 5-phenyl-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (2) of the present invention).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:27][C:28]([N:30]([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)[CH3:31])=[O:29])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH:17]([CH3:19])[CH3:18])=[O:12])[CH:8]=1)#[N:2].[ClH:42].O1CCOCC1.C(OCC)C>ClCCl>[ClH:42].[ClH:42].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:27][C:28]([N:30]([N:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40]2)[CH3:31])=[O:29])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][NH:16][CH:17]([CH3:18])[CH3:19])=[O:12])[CH:8]=1)#[N:2]
Reactant: Cc1ccc(C#N)cc1N(CC(=O)NCCN(C(=O)OC(C)(C)C)C(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(C#N)cc1N(CC(=O)NCCNC(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
The compound (2.81 g, 4.99 mmol) obtained in step B was dissolved in dichloromethane (15 ml), 4N hydrochloric acid-dioxane solution (15 ml, 60 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hr. Diethyl ether was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (2.60 g, yield 97%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[N+]([O-])([O-])=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[Li+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=3)=[N:27][N:28]3[CH:29]=[C:30]([F:34])[CH:31]=[CH:32][C:33]=23)[CH:5]=[CH:4][N:3]=1
Reactant: N[n+]1cccc(F)c1
Reactant: O=C(Nc1cccc(C#Cc2ccnc(Cl)n2)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.9 %

Procedure:
To a solution of N-[3-(2-chloro-pyrimidin-4-ylethynyl)-phenyl]-2,2,2-trifluoro-acetamide (5.0 g) in DMF (40 mL) were added 1-amino-3-fluoropyridinium nitrate (5.4 g) and potassium carbonate (6.0 g). The reaction was kept stirring at rt for 1.5 h. The DMF solution was poured into 5% LiCl solution (60 mL) and extracted with EtOAc (2×30 mL). The combined organic phase were dried (Na2SO4) and concentrated. The crude products were separated through silica gel column chromatography to afford two products. The first to elute was N-{3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (2.0 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (d, 1H, J=5.49 Hz), 7.45 (d, 1H, J=7.68 Hz), 7.55 (t, 1H, J=7.96 Hz), 7.73-7.79 (m, 1H), 7.83 (d, 1H, J=0.91 Hz), 7.95 (t, 1H, J=1.74 Hz), 8.41 (dd, 1H, J=9.97, 5.76 Hz), 8.49 (d, 1H, J=5.49 Hz), 9.27 (dd, 1H, J=4.30, 2.29 Hz); ES-LC/MS (M+H)+=436.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2ccc(O)cc2o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccc(OC(=O)c3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a stirred suspension of 2-methyl-1,3-benzoxazol-6-ol (2.99 g, 20 mmol) in dichloromethane (50 mL) was added triethylamine (4.05 g, 5.58 mL, 40 mmol). A solution of benzoyl chloride (3.09 g, 2.56 mL, 22 mmol) in dichloromethane (20 mL) was added dropwise over ca. 10 min. The reaction mixture was stirred at room temperature for 2.5 h, then washed with water (2×50 mL), and dried over Na2SO4, filtered and concentrated in vacuo to give the subtitled compound as a colourless solid (5.05 g, 20 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:26][C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(c2ccccc2N2CCNCC2)CC1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(c2ccccc2N2CCN(Cc3ccco3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg, 0.11 mmol) produced in Example (3c), furan-2-carbaldehyde (21 mg, 0.22 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (119 mg, 0.559 mmol), followed by stirring for 1 hour and 50 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was filtered through Celite. The solvent was distilled off by nitrogen stream to the filtrate. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-furan-2-ylmethylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Hexane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant hexane solution was removed and the resulting solid was dried to give 38 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>CO>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: Clc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
4-Chloroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullman conditions to give the novel intermediate 4-acetyl-4'-chloro-2-nitrobiphenyl, m.p. 103°-105° C. (from methanol). This compound was reduced with stannous chloride and concentrated hydrochloric acid to give 4-acetyl-2-amino-4'-chlorobiphenyl, m.p. 139°-140° C. (from methanol). This compound was converted to the novel intermediate 4-acetyl 4'-chloro-2-hydroxybiphenyl and thence to the novel intermediate 4-acetyl-4'-chloro-2-methoxybiphenyl, b.p. 167°-170° C./0.4 mm., by diazotization and methylation methods analogous to those described in Example 1.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH2:13][C:12](=O)[N:11]([N:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B>O1CCCC1.B(F)(F)F.C(OCC)C>[C:25]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[CH2:12][CH2:13]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(C=NN2C(=O)CN(C(c3ccccc3)c3ccccc3)CC2=O)n1
Agent: B#B
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(CNN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Reducing 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)-3,5-diketopiperazine using a mixture of diborane in tetrahydrofuran and boron trifluoride in diethyl ether to afford 1-diphenylmethyl-4-(6-methyl-2-pyridylmethylamino)piperazine followed by dehydrogenating to afford the desired 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)piperazine.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23](#[N:27])[CH2:24][C:25]#[N:26].CC(C)([O-])C.[K+].Cl>O1CCOCC1>[C:25]([CH:24]([C:23]#[N:27])[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16])#[N:26]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: N#CCC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C#N)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
2.7 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 1.1 g of malononitrile are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are added in portions. The mixture is warmed to 50° for 4 hours, cooled to room temperature, and acidified using HCl, and the red solid is isolated. It is recrystallized from glycol monomethyl ether.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([CH3:15])[S:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])(=[O:26])=[O:25])[CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Agent: Cl
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(F)cc1F

Procedure:
In analogy to example 11.9, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and 2,4-difluoro-benzenesulfonyl chloride (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-2,4-difluoro-N-methyl-benzenesulfonamide which was used directly in the next steps see Example 12.57-12.58 and 12.65 and 12.66.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N:7]([CH3:32])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O+]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)=[CH:10][N:9]=1.[S-2:33].[Na+].[Na+].Cl(O)(=O)(=O)=O>CC(C)=O.O.N1C=CC=CC=1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N:7]([CH3:32])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S+:33]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)=[CH:10][N:9]=1
Reactant: [S-2]
Reactant: CN(C)c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cn1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CN(C)c1ccc(-c2cc(-c3ccccc3)[s+]c(-c3ccccc3)c2)cn1

Procedure:
A mixture of 4 g of the pyrylium salt in 100 ml of acetone was stirred and 2 g of sodium sulfide in 50 ml of water is added. The solution was stirred for 1/2 hr and poured into dilute perchloric acid. The solid (which was the bis perchlorate salt) was dissolved in pyridine, the solution was diluted with alcohol and the solid which separated was collected, Mp 271°-272°, yield 3 g. The λmax (CH3CN) were 550 (58.0×103),~280 (17.0×103) and 265 nm (18.0×103).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=O)[CH:9]=[CH:8]2.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][C@@H:9]3[C@H:8]([C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH2:18][NH:17][CH2:16]3
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1cccc2ccc(=O)oc12
Product: COc1cccc2c1OC[C@H]1CNC[C@@H]21

Procedure:
From 8-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][S:14]([NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])=[O:15].[CH3:24][CH:25]([CH2:28]O)[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[S:14](=[O:15])(=[O:16])[N:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:26][CH:25]([CH3:28])[CH2:24]1
Reactant: CCOC(=O)CNS(=O)(=O)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(CO)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(C)CN(c2c(Cl)cc(C(F)(F)F)cc2Cl)S1(=O)=O
Temperature: -20 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
Ethyl 2-((N-(2,6-dichloro-4-(trifluoromethyl)phenyl)sulfamoyl)amino)acetate (300 mg, 0.76 mmol), 2-methylpropane-1,3-diol (75 mg, 0.76 mmol) and triphenylphosphine (498 mg, 1.90 mmol) were dissolved in anhydrous THF (30 mL), and then cooled down −20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (384 mg, 1.90 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (225 mg, 66%, light yellow solid). 1H NMR (300 MHz, CDCl3): δ 7.65 (s, 1H), 7.63 (s, 1H), 4.44-4.38 (m, 1H), 4.30-4.17 (m, 2H), 4.11-4.03 (m, 1H), 3.98-3.87 (m, 2H), 3.53-3.44 (m, 1H), 3.24-3.17 (m, 1H), 2.59 (m, 1H), 1.31 (t, 3H, J=7.1 Hz), 0.94 (d, 3H, J=6.7 Hz).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([C:12]1[CH:17]=[CH:16][C:15]([NH:18]/[C:19](=[C:26]2\[C:27](=[O:38])[NH:28][C:29]3[C:34]\2=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[S:8]([CH3:11])(=[O:10])=[O:9])=[O:5])C.[OH-].[Na+]>O1CCOCC1>[C:4]([CH2:6][N:7]([C:12]1[CH:13]=[CH:14][C:15]([NH:18]/[C:19](=[C:26]2\[C:27](=[O:38])[NH:28][C:29]3[C:34]\2=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[S:8]([CH3:11])(=[O:10])=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 8 by saponification of (Z)-3-{1-[4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone with sodium hydroxide solution in dioxane.
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:32])[C:15]([CH3:31])([O:17][C:18]1[CH:23]=[C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH3:16])[CH3:12].[F:33][C:34]([F:51])([F:50])[C:35]1[CH:49]=[CH:48][C:38]([CH2:39][O:40][C:41](N2C=CN=C2)=[O:42])=[CH:37][CH:36]=1>C(OCC)(=O)C>[F:33][C:34]([F:50])([F:51])[C:35]1[CH:49]=[CH:48][C:38]([CH2:39][O:40][C:41]([N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([C:22]3[CH:21]=[CH:20][C:19]([CH3:30])=[C:18]([O:17][C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:32])([CH3:31])[CH3:16])[CH:23]=3)[CH2:25]2)=[O:42])=[CH:37][CH:36]=1
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCNC2)ccc1C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
2-methyl-2-(2-methyl-5-piperidin-3-yl-phenoxy)-propionic acid ethyl ester L-tartaric acid salt (Example 11; 155 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 3 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (92 mg, 0.34 mmol) was added. The reaction was stirred for 18 h at room temperature under nitrogen. The reaction was flash chromatographed with 15% ethyl acetate/hexanes to yield 157 mg (91%) of the desired 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:4].P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.C[O-].[Li+].[Li].FC(F)(F)[C:42](O)=[O:43]>O1CCCC1.O.CO>[C:3]([NH:5][C@:6]1([O:43][CH3:42])[C:18](=[O:19])[N:8]2[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)(=[O:4])[CH3:2]
Reactant: COC(=O)C1=C(C)CS[C@@H]2[C@H](NC(=O)CBr)C(=O)N12
Reactant: O=C(O)C(F)(F)F
Agent: C[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(C)CS[C@H]2N1C(=O)[C@]2(NC(C)=O)OC
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Methyl 7β-(2'-bromo-1'-chloroethylidenimino)-3-methyl-3-cephem-4-carboxylate was prepared from methyl 7β-bromoacetamido-3-methyl-3-cephem-4-carboxylate(1.34 g), phosphorus pentachloride(1.5 g) and quinoline(1 ml) according to the same procedure as in Example 23 - (1) and dissolved in tetrahydrofuran(80 ml). To this solution was added a methanol solution of lithium methoxide prepared from lithium(200 mg) and methanol(20 ml) at -70°C. The reaction mixture was stirred at -70°C. for 30 minutes, then trifluoroacetic acid(2.5 ml) was added and stirring was continued at room temperature for 10 minutes. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 10 % dipotassium hydrogen phosphate solution and water, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel to afford 250 mg of methyl 7β-acetamido-7α-methoxy-3-methyl-3-cephem-4-carboxylate. IR νmaxliquid cm -1 : 3220, 1770, 1730, 1690. NMR(CDCl3) δ ppm: 2.13(6H, singlet), 3.20 and 3.37(2H, AB-quartet, J=17 Hz), 3.55(3H, singlet), 3.83(3H, singlet), 5.07(1H, singlet), 7.52(1H, singlet).