Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:15][CH2:16][Cl:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[K+].[Br-]>>[Cl-:17].[C:7]([O:15][CH2:16][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCCl)c1ccccc1
Reactant: c1ccncc1
Agent: [Br-]
Agent: [K+]
Product: O=C(OC[n+]1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
A mixture containing 0.79 g (0.01 mol) pyridine and 1.7 g (0.01 mol) chloromethyl benzoate was allowed to react at ambient temperature for 24 hr. Trituration in anhydrous ether followed by filtration under nitrogen gave 1.2 g (0.005 mol), 50%, 29, mp 197°-199° (dec); ir (KBr) 3440, 3020, 1710, 1610, 1475, 1265, 1150, 1085, 870 and 700 cm-1 ; pmr (D2O) δ 7.0-10.0 (m, 10H) and 6.6 (s, 2H) ppm.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.CC(C)=O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:7]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-2-methylpiperazine (13.85 g, 138 mmol) and sodium bicarbonate (52.3 g, 622 mmol) were partially dissolved in a mixture of water (182 ml) and acetone (112 ml). A solution of benzoyl chloride (17.7 ml, 152 mmol) in acetone (56 ml) was added dropwise over 1 hour with vigorous stirring. After stirring for 16 hours at RT, the acetone was stripped on the rotovap, water (400 ml) was added, and the solution acidified (6M HCl) to a pH less than 2. The aqueous phase was washed three times with dichloromethane (200 ml) and then 5M sodium hydroxide was added to bring pH over 12. The resulting solution was extracted three times with dichloromethane (200 ml), dried (MgSO4) and evaporated to give (R)-(3-methylpiperazin-1-yl)(phenyl)methanone 62 as a yellow oil, 15.1 g (54% of theoretical). LC/MS m/z=205 (M+H+).
Reaction SMILES: [CH2:1]([CH:4]1[NH:10][C:9](=S)[CH2:8][CH2:7][S:6][CH2:5]1)[CH2:2][CH3:3].F[B-](F)(F)F.C[O+](C)C.[Cl-:21].[NH4+:22]>>[ClH:21].[NH:22]=[C:9]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[NH:10]1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCCC1CSCCC(=S)N1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Product: CCCC1CSCCC(=N)N1
Product: Cl

Procedure:
Employing the procedure described in Example 2, step D, tetrahydro-3-propyl-(2H)-1,4-thiazepin-5-thione was reacted with Meerwein's salt and ammonium chloride to yield hexahydro-5-imino-3-propyl-1,4-thiazepine, hydrochloride.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5](Cl)(=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[CH2:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].Cl>CC(C)=O>[CH2:16]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]([NH:3][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[S:1])[CH2:17][CH2:18][CH3:19]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: N#C[S-]
Reactant: CCCCNCCCC
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCN(CCCC)C(=S)NC(=O)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 38.87 g (0.40 mol) of potassium thiocyanate in 630 ml of acetone was added dropwise over 15 min, 68.24 g (0.40 mol) m-anisoyl chloride. The mixture was heated to reflux and maintained at reflux for 20 mins. To this mixture was added 51.7 g (0.40 mol) of dibutylamine over 10 min. The mixture was stirred overnight. The mixture was added to a mixture of 103 ml of conc. HCl in 840 ml of ice water. The oily residue was extracted with methylene chloride, dried over magnesium sulfate and concentrated. The yield of product was 94.62% and was used without further purification. Anal. Calcd. for C17H26N2O2S: C, 63.3; H, 8.1, N, 8.7; S, 9.9. Found: C, 62.54; H, 8.38; N, 8.66: S, 9.19.
Reaction SMILES: [CH2:1]([N:8]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[C:26]([CH:34]=[CH2:35])=[CH:27][N:28]=[CH:29]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.CO>[CH2:1]([N:8]([CH:16]1[CH2:21][CH2:20][CH:19]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[C:26]([CH:34]=[CH2:35])=[CH:27][N:28]=[CH:29]3)[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCC(=O)CC1
Reactant: C=Cc1cncc2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: C=Cc1cncc2cccc(NC3CCC(N(Cc4ccccc4)C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of Intermediate 9 (5.73 g), Intermediate 1 (2.92 g), and para-toluenesulfonic acid monohydrate (163 mg, Wako Pure Chemical Industries) in toluene (50 ml) was refluxed by heating for 1 hour. The reaction mixture was cooled to room temperature, then added with methanol (75 ml) and sodium borohydride (6.48 g), and stirred at room temperature for 1 hour. The reaction mixture was added with water (5 ml), and then the solvent was evaporated under reduced pressure. The residue was added with ethyl acetate (100 ml), and the organic layer was washed twice with water (50 ml), and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (2.2 g of trans-isomer, 1.8 g of cis-isomer).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]([NH:28][C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=4[F:36])=[O:27])[CH:23]=[CH:22][C:21]=3[F:37])[CH:16]=[CH:15][N:14]=2)[NH:10][CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C.Br[CH2:48][C:49]([O:51][CH3:52])=[O:50].O>CN(C=O)C>[F:37][C:21]1[CH:22]=[CH:23][C:24]([C:26]([NH:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=2[F:36])=[O:27])=[CH:25][C:20]=1[O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:11]2[NH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:7])[CH:12]=2)[CH:18]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)c2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CNCCCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (100 mg, 0.20 mmol) and N,N-diisopropylethylamine (52 mg, 0.40 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (30 mg, 0.20 mmol). The mixture was stirred at room temperature for 50 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of MeOH in CHCl3 to afford methyl ({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}amino)acetate as white solid. Yield: 40 mg, 35%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:22])[NH:17][CH2:18][N:19]=[C:20]=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:23](=[C:25]1[N:29]=[CH:28][N:27]=[C:26]1[C:30]([NH2:32])=[O:31])=[N-:24]>CS(C)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:22])[NH:17][CH2:18][N:19]3[C:20](=[O:21])[N:29]4[CH:28]=[N:27][C:26]([C:30](=[O:31])[NH2:32])=[C:25]4[N:23]=[N:24]3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C=NCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: NC(=O)c1ncn2c(=O)n(CNC(=O)OCC3c4ccccc4-c4ccccc43)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Isocyanatomethyl-carbamic acid 9H-fluoren-9-ylmethyl ester (1.13 g, 3.83 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.5 g, 3.65 mmol) in dry dimethylsulfoxide (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the pouring onto crushed ice. The resultant precipitate was collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a white solid (600 mg, 33.9%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.86 (1H, s), 8.61 (1H, t-broad), 7.89-7.26 (9H, m), 5.55 (2H, t, J=6.8 Hz), 4.40-4.19 (5H, m), 2.01 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13](SC)=[CH:12][CH:11]=2)=[CH2:9])[CH:3]=1.O[O:19][S:20]([O-:22])=O.[K+].[CH3:24]O>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([S:20]([CH3:24])(=[O:22])=[O:19])=[CH:14][CH:15]=2)=[CH2:9])[CH:3]=1
Reactant: CO
Reactant: C=C(c1ccc(SC)cc1)c1cccc(Br)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: C=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 1-bromo-3-(1-[4-methylsulfanyl-phenyl]-vinyl)-benzene (0.5 g, 0.16 mmol, 1 eq) in methanol (15 mL) was added over 5 min Oxone® (2.0 g, 0.32 mmol, 2.0 eq) dissolved in water (15 mL). After stirring at 25° C. for 2 h, the reaction mixture was diluted with water (40 mL) and extracted with dichloromethane (3×40 mL). The organic layer was washed with brine (20 mL) and dried on magnesium sulfate. After filtration and concentration, the crude material was chromatographed (silica gel: cyclohexane/ethyl acetate, 4:1) to give an oil (0.3 g, 56% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[C:3]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:22])([CH3:23])[C:4]=3[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
5-tert-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (2.0 g, 6.16 mmol) was dissolved in THF (40 ml), treated first with N,N-diisopropylethylamine (5.4 ml, 30.80 mmol) and then, at 0° C., with 4-fluorobenzoyl chloride (800 μl, 6.77 mmol) dissolved in THF (8 ml) dropwise. The reaction mixture was stirred at room temperature for 5 hours, concentrated and dissolved in DCM, washed with saturated sodium hydrogencarbonate aqueous solution and with brine. The organic phase was dried over sodium sulfate, evaporated and purified by flash chromatography (eluent hexane/EtOAc 80/20) to afford 2.5 g of the title compound in 90% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH2:25])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25][S:32]([CH3:31])(=[O:34])=[O:33])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Yield: 31.8 %

Procedure:
7-(2-Thienyl)acetamido-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.46 g.) was suspended in methylene chloride (100 ml.). To the suspension was added bis(trimethylsilyl)acetamido (4.06 g.) and the mixture was stirred to give a solution. To the solution was added methanesulfonyl chloride (1.15 g.) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was added to 5% hydrochloric acid at 0°-5° C. White precipitates in the solution were collected by filtration, dried and then recrystallized with aqueous acetone to give 7-(2-thienyl)acetamido-3-(5-mesylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (910 mg.). m.p. 139°-145° C (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:11]([O-])=O.[Na+].[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][C:19]=1[NH2:20])[CH3:16]>O.Cl>[CH2:26]([O:25][C:22]1[CH:21]=[C:19]([N:20]=[N:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:18]([O:17][CH2:15][CH3:16])=[CH:24][C:23]=1[NH2:11])[CH3:27]
Reactant: O=N[O-]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1ccc(OCC)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOc1cc(N=Nc2ccc([N+](=O)[O-])cc2)c(OCC)cc1N

Procedure:
4-Nitroaniline (6.9 g, 0.05 mol) is suspended in water (150 ml) and 35% HCl (17.3 g) is added. To this is added a solution of sodium nitrite (3.6 g, 0.053 mol) at 0-5° C., pH<1. Once all solid has dissolved, excess nitrous acid is destroyed by addition of sulfamic acid and the solution is then added dropwise to a solution of 2,5-diethoxyaniline (9.4 g, 0.052 mol) in water (300 ml) and 35% HCl
Reaction SMILES: [I-].[Na+].C[Si](C)(C)Cl.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>C(#N)C.CCOCC.O>[CH2:15]([O:14][C:8](=[O:13])[CH:9]([CH2:23][C:22]1[CH:17]=[CH:18][C:19]2[O:27][CH2:26][O:25][C:20]=2[CH:21]=1)[C:10](=[O:11])[CH3:12])[CH3:16]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(C)=O
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
To a solution of 117.2 g sodium iodide in 700 ml of acetonitrile, first 85.9 g trimethylchlorosilane and then 20.56 g ethyl acetoacetate were dropped in at room temperature. After cooling down to 0-5° C., a solution of 23.65 g Piperonal in 50 ml of acetonitrile was dropped in. Then the mixture was stirred at room temperature for 5 hours and then at 60° C. overnight. After the mixture was cooled down to room temperature it was diluted with ether and water. The organic phase was separated and washed with saturated sodium thiosulfate until the color of the iodine was gone. Then the organic phase was washed with water, dried, filtered and evaporated to dryness. The resulting dark oil was purified by chromatography to yield 13.7 g of a yellow oil.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:21])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(Cl)Cl.C(OCC)(=O)C>[O:21]=[C:9]1[NH:8][C:12]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=2[N:10]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)n(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.6 %

Procedure:
Part 1. To a chilled solution of methyl 1-[(tert-butyl)oxycarbonyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (0.37 g, 1.28 mmol) in CH2Cl2 (8 mL) and N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) was added a solution of benzyl chloroformate (0.208 mL, 1.46 mmol) in CH2Cl2 (2 mL). The reaction was stirred at room temperature for 2.5 hr, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. This residue was dissolved in CH2Cl2 (9 mL) and treated with neat trifluoroacetic acid (2 mL) at 0° C. for 40 min, diluted with ethyl acetate, washed with 5% NaHCO3, water and brine, dried over sodium sulfate and concentrated to yield methyl 2-oxo-3-[benzyloxycarbonyl]-(3H)—benzimidazole-5-carboxylate (0.37 g, 89%) as an off-white solid. 1H NMR (CDCl3) δ: 3.51 (s, 3H); 5.14 (s, 2H); 6.67-6.69 (d, 1H); 6.97-7.06 (m, 5H); 7.17-7.18 (d, 1H); 7.51-7.53 (d, 1H); 8.07 (s, 1H). ES-MS (M+Na)+=349.0.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1>C1COCC1.CO.O>[OH:3][CH:4]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: O=C1CC(C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
NaBH4 (215 mg; 5.68 mmol) was added to the solution of benzyl 3-oxocyclobutanecarboxylate (2.3 g; 11.3 mmol) in THF (30 mL) and MeOH (1.5 mL). The reaction mixture was stirred for 0.5 hour at 0° C., diluted with water (20 mL), and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase flash chromatography to afford 1.24 g (53%) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:20]1([C:3]2[C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][NH:6][C:2]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1-c1ccccc1
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+]
Product: COC(=O)c1c[nH]c(-c2ccccc2)c1-c1ccccc1
Yield: 75.9 %

Procedure:
Using methyl 5-bromo-4-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.01 g), phenylboronic acid (439 mg), sodium carbonate (771 mg) and tetrakis(triphenylphosphine)palladium (420 mg), a procedure as in Reference Example 56 was performed to give the title compound as pale-yellow crystals (yield 506 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][C:32]=4[CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1cnccc1Br
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ccncc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-(4-bromo-pyridin-3-yl)-4-phenyl-butan-1-ol.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:20]([CH:30]=1)[C:21]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:20]([CH:30]=1)[C:21]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A solution of DIAD (252 mg, 1.249 mmol) in toluene (1 ml) was added dropwise to a stirred solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 160 mg, 0.50 mmol), 2-(dimethylamino)ethanol (49.0 mg, 0.549 mmol) and Ph3P (328 mg, 1.25 mmol) in toluene (4 ml) under nitrogen at 0° C. The reaction mixture was stirred at 115° C. overnight. The mixture was then cooled and concentrated. The residue was added to water and extracted with ethyl acetate (3×60 ml). The organic phase was washed with saturated brine (30 ml), dried over sodium sulphate and evaporated in vacuo to give crude product. The crude product was added to a silica gel column (40 g) and was eluted with a 20:1 mixture of DCM/methanol (2 l) to yield the title compound as a yellow solid. 50 mg.
Reaction SMILES: C([N:8]1CC=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:21].Cl.[O:23]1[CH2:28][CH2:27]OCC1>>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:27][CH:28]1[OH:23]
Reactant: C1COCCO1
Reactant: Cl
Reactant: Cc1ccccc1C1=CCN(Cc2ccccc2)CC1
Product: OC1CNCCC1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Tert-butyl (3RS,4RS)-4-(2-chlorophenyl)-3-hydroxypiperidine-1-carboxylate was obtained as a colorless amorphous substance in the same manner as in Production Example 12-2, for which, however, the compound obtained in the above 2 was used in place of 1-benzyl-4-o-tolyl-1,2,3,6-tetrahydropyridine used in Production Example 12-2 and the step of converting the product into its hydrochloride was omitted. In a nitrogen atmosphere, 4 N hydrogen chloride-dioxane solution was added to the above compound, and stirred at room temperature for 1.5 hours. The solvent was evaporated off under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to obtain (3RS,4RS)-4-(2-chlorophenyl)piperidin-3-ol as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:23][CH2:22][CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1CNC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 41.3 %

Procedure:
A mixture of 0.6 g (2.2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.25 g (4.4 mmol) of azetidine and 1 ml of triethylamine in 8 ml of pyridine is heated to 110° C. in a closed vessel for 2 hours. The mixture is allowed to cool and is filtered and the product is washed with water, ethanol and ether. 0.275 g of 1-cyclopropyl-6-fluoro-7-(1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point 291°-4° C., is thereby obtained.