Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.O[C:14]1C=CC(C)=CC=1S>>[NH2:1][C@H:2]1[CH2:8][S:7][C:6]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: Cc1ccc(O)c(S)c1
Reactant: N[C@@H]1COc2ccccc2SC1
Product: Cc1ccc2c(c1)SC[C@H](N)CO2

Procedure:
The title compound (Ib) is prepared according to a reaction sequence identical to that employed for the synthesis of 3-(R)-amino-3,4-dihydro-2H-1,5-benzoxathiepine (Ia-1) but using, as starting material, 2-hydroxy-5-methylthiophenol (IVb) instead of 2-hydroxythiophenol. The title compound (Ib) is obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([S:39]([NH:1][C:2]2[CH:10]=[C:9]3[C:5](/[C:6](=[C:12](/[NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:22][CH:21]=4)\[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)/[C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1Nc2cc(NS(=O)(=O)c3ccccc3)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and benzenesulphonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: COc1ccccc1-c1cc2cnc(N)nc2nc1N
Reactant: CC(C)(C)N=C=O
Product: COc1ccccc1-c1cc2cnc(N)nc2nc1NC(=O)NC(C)(C)C

Procedure:
The title compound was prepared from 0.203 g of 6-(2-methoxy-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 100 and 0.093 mL of tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with 1:1 CHCl3 :EtOAc; mp 300-301° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 367 (MH+ +1, 67), 368 (MH+ +2, 14), 236 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=CC=[C:46]([O:49]C)C=3)CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[C:21]([O:49][CH3:46])[CH:20]=3)[CH2:25][CH2:26]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCc3ccc(OC)cc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCc2ccc(OC)cc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.21, 1.29, 1.94, 2.51, 2.67, 2.80, 2.92, 3.01, 3.81, 4.69, 5.80, 6.86, 6.95, 7.22, 7.29–7.36, 7.51; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1443.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][C:3]1=[O:15].I[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[H-].[Na+]>O1CCCC1>[Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:3]1=[O:15]
Reactant: CC(C)(C)OC(=O)CI
Reactant: O=C1NC(c2ccccc2)CCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(Br)CCCC1c1ccccc1

Procedure:
A solution of 15.5 g of the lactam from Step A and 14.7 t-butyl iodoacetate in 150 ml tetrahydrofuran was added dropwise to a slurry of 1.45 g sodium hydride in 20 ml tetrahydrofuran. After 3 hr at room temperature the reaction was quenched by the addition of 15 ml sat. NH4Cl solution. The mixture was filtered and concentrated and the residue partitioned between CHCl3 and H2O. The crude product was obtained after drying and concentrating the CHCl3 solution. Chromatography over silica gel with hexane: ethyl acetate (4:1) afforded two isomers of 3-bromo-1-t-butoxycarbonylmethyl-7-phenylperhydroazepin-2-one: isomer A (minor, elutes first), and isomer B (major, elutes second).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C:22]4=[O:26])=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][C:22]5=[O:26])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: O=C1CCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)cn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A suspension of 103 (270 mg, 0.581 mmol), iron (649 mg, 11.63 mmol), and ammonium chloride (187 mg, 3.49 mmol) in MeOH (10 mL) and water (1 mL), was heated to reflux for 3 h, then cooled to RT. The mixture was then filtered through celite and the cake was rinsed with methanol. The mother liquor was concentrated, and partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The aqueous phase was extracted 3 times with DCM. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, re-dissolved in ethyl acetate, washed with 1N NaOH, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 50 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 104 (220 mg, 0.50 mmol, 87% yield) as beige solid. MS (m/z): 435.5 (M+H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=3)[CH2:35][CH2:34]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2C(C)(C)C)cc1

Procedure:
143 mg (89%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(3,4-dichlorophenyl)piperazine (69 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1.C(OCC)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][C:13]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1cccc1S(=O)(=O)NC(C)(C)C
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccn(C)c1S(=O)(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a solution of 2.5 g (11.5 mmol) of N-(1,1-dimethylethyl)-1-methyl- 1H-pyrrole-2-sulfonamide in 50 mL THF under nitrogen atmosphere cooled to below -70° C. was added dropwise 13 ml, (32.5 mmol) of 2.5M n-butyllithium at such a rate as to keep the temperature below -58° C. After stirring at -20° C. to -10° C. for 30 min then 1 h at 0° C., the mixture was recooled to -70° C. and treated with a solution of 1.63 g (17.3 mmol) of methyl chloroformate in 6 mL THF causing an exotherm to -57° C. The reaction mixture was stirred overnight at ambient temperature then diluted with 200 mL of ethyl acetate. This solution was washed successively with two 60 ml, portions of 1N HCl, brine, then dried (Na2SO4) and evaporated to a dark oil. The crude product was purified by chromatography on silica gel (30% ethyl acetate/70% hexanes) then collected from hexanes to afford 0.45 g of the title compound, m.p. 105°-108° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[CH3:18][C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:24]=[CH:25][C:26]([F:27])=[C:21]([Cl:20])[CH:22]=3)=[CH:19][C:6]1=2
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid generally according to the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.13 (s, 1H), 7.86 (dd, J=6.8, 2.0 Hz, 1H), 7.64 (m, 2H), 7.55 (m, 2H), 7.48 (t, J=8.8 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 6.99 (dd, J=4.9, 3.4 Hz, 1H), 6.91 (dd, J=3.4, 1.0 Hz, 1H), 4.16 (d, J=16.1 Hz, 1H), 4.06 (d, J=16.1 Hz, 1H), 2.08 (s, 3H); MS (ES) m/z 388 (M+H)+; Anal. Calc. For C20H15ClFNO2S: C, 61.93; H, 3.90; N, 3.61. Found: C, 61.88; H, 3.99; N, 3.35.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.F[O:10][C:11](=O)[CH3:12]>>[C:11]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)(=[O:10])[CH3:12]
Reactant: Cc1ccnc(O)c1
Reactant: CC(=O)OF
Product: CC(=O)Oc1cc(C)ccn1

Procedure:
As a process for the preparation of 2-hydroxy-4-methylpyridine, a process whereby [iv]-4-methylpyridine is reacted with acetyl hypofluorite at −10° C. to obtain a 2-acetoxy-4-methylpyridine, and thereafter the 2-acetoxy-4-methylpyridine is hydrolyzed to obtain 4-methyl-2-pyridone is reported [Journal of the American Chemical Society, 109, 3789-3790, (1987): Non-Patent Reference 2].
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:10][S:11]([O:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([N:8]([S:11]([CH3:10])(=[O:13])=[O:12])[CH3:9])[CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: CN[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN([C@H]1CC[C@@H](OS(C)(=O)=O)CC1)S(C)(=O)=O

Procedure:
Prepared by reacting cis-1-hydroxy-4-methylamino-cyclohexane with methanesulphonic acid chloride in tetrahydrofuran in the presence of triethylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[C:17]([OH:18])=[CH:16][C:15]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=2)=[C:14]([F:33])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[C:17]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][C:15]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=2)=[C:14]([F:33])[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(O)c(Cl)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cn3)c(Cl)cc2F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (952 mg, 6.01 mmol) and N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-(1-cyano-1-methylethyl)benzamide (2.00 g, 6.01 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.24 g, 9.01 mmol), and the mixture was stirred at 80° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (200 mL and 100 mL). The combined organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (2.28 g, 83%) as a yellow oil.
Reaction SMILES: [S:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1)([CH3:4])(=[O:3])=[O:2].[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:16]([CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][C:6]([O:5][S:1]([CH3:4])(=[O:2])=[O:3])=[CH:7][CH:8]=2)[C:12]1=[O:15])[CH:17]=[CH:18][CH3:19]
Reactant: CS(=O)(=O)Oc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(OS(C)(=O)=O)cc2C1=O
Yield: 50 %

Procedure:
A solution of 18.3 g of 6-mesyloxy-1-indanone, 16.7 ml of 3-buten-2-ol and 300 mg of p-toluenesulfonic acid in 400 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). In addition to 8.31 g of educt, there were obtained 11.3 g (50%) of (RS)-2-(2-buten-1-yl)-6-mesyloxy-1-indanone as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C:13]([O:23][CH3:24])([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:25])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].ClC(Cl)(Cl)C[O:29][C:30]([N:32]=C=O)=O>>[C:30]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C:13]([O:23][CH3:24])([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:25])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])(=[O:29])[NH2:32]
Reactant: O=C=NC(=O)OCC(Cl)(Cl)Cl
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(CO)CS[C@@H]21
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@@H]21

Procedure:
When 3-hydroxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid is reacted with 2,2,2-trichloroethoxycarbonyl isocyanate and the resulting imidodicarboxylate is deblocked following the procedures described in Example 5, 3-carbamoyloxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:28][C:23]=2[S:24][C:25]=1[CH2:26][CH3:27])=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NC
Yield: 56.7 %

Procedure:
This material was prepared by reacting 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (87 mg, 0.35 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (99 mg, 0.42 mmole) and Cs2CO3 (342 mg, 1.05 mmole) in a manner analogous to that described for example 1 to give a yellow solid (89 mg, 37%). 1H NMR (DMSO-d6, 300 MHz), δ 8.52 (1H, d, J=5.56 Hz), 8.33 (1H, m), 7.98 (1H, d, J=2.27 Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.59 Hz), 7.40 (1H, s), 7.33 (1H, dd, J=2.27, 8.84 Hz), 7.02 (1H, s), 6.97 (1H, d, J=5.31 Hz), 3.98 (3H, s), 3.00 (2H, q, J=7.58 Hz), 2.83 (3H, d, J=4.80 Hz), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: Cl.[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].S(Cl)(C)(=O)=O>>[OH:2][CH:3]([CH:9]1[O:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(O)C1CNCCO1
Agent: CS(=O)(=O)Cl
Agent: Cl
Product: CCOC(=O)C(O)C1CN(S(=O)(=O)c2ccc(C)cc2)CCO1
Yield: 35.5 %

Procedure:
According to the Step 28-1 in synthetic method for EXAMPLE 28, compound 115-3 (0.2 g) and tosylchloride (203 mg) were used instead of 26-5 and mesyl chloride to obtain compound 116-1 (108 mg) as a pale yellow amorphous solid.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=1>C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2[NH:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:5])([CH3:4])[S:6]2)[CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: CC(C)(S)C(N)C(=O)O
Solvent: CCO
Product: CC1(C)SC(c2cccnc2)NC1C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.9 %

Procedure:
To a suspension of DL-penicillamine (50 g, 335 mmol) in 1:1 aqueous ethanol (500 mL) was added 3-pyridinecarboxaldehyde (36 g, 335 mmol). The resulting clear-yellow solution was stirred for 17 hours at ambient temperature during which time a white precipitate formed. The white solid was filtered off and rinsed with 3:1 H2O, ethanol and ether to give 2-(3-pyridinyl)-5,5-dimethyl-4-thiazolidinecarboxylic acid (51 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([OH:13])[CH:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9]2)=[C:4]([N+:29]([O-:31])=[O:30])[CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:10]3[CH2:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[N+:29]([O-:31])=[O:30])[CH2:12][CH:11]3[O:13][C:39](=[O:41])[CH3:40])[CH2:19][CH2:18]2)=[O:21])=[CH:23][CH:24]=1
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(c3ccc(Cl)cc3[N+](=O)[O-])CC2O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CN(c2ccc(Cl)cc2[N+](=O)[O-])CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of {4-[1-(4-chloro-2-nitro-phenyl)-4-hydroxy-pyrrolidin-3-yl]-piperazin-1-yl}-(4-chloro-phenyl)-methanone (300 mg, 0.64 mmol) in CH2Cl2 (5 mL) at 0° C., was added Et3N (0.2 mL, 1.42 mmol) and acetyl chloride (112 mg, 1.42 mmol). The mixture was stirred at RT for overnight. The organic phase was washed with Saturated NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product (160 mg, 50% yield) as a yellow oil. MS: (ESI), M/Z, 507(M+1). Retention time: 2.59 min (FA-polar).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][CH2:16][N:17]1[C:21]2[CH:22]=[N:23][NH:24][C:25](=[O:26])[C:20]=2[C:19]([C:27](O)([CH3:29])[CH3:28])=[CH:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:8]([O:15][CH2:16][N:17]1[C:21]2[CH:22]=[N:23][NH:24][C:25](=[O:26])[C:20]=2[C:19]([CH:27]([CH3:29])[CH3:28])=[CH:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.2 %

Procedure:
To 13 ml of dichloromethane solution containing 2.47 g of triethylsilane was added 1.31 ml of boron trifluoride diethyl ether complex under ice-cooling, then 30 ml of dichloromethane solution containing 1.65 g (5.3 mmol) of 1-benzyloxymethyl-3-(1-hydroxy-1-methylethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 21-(d) was added dropwise to the mixture, and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.98 g of the title compound as a white solid. (Yield: 62%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[N:31]1([C:38]2[S:39][C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][CH2:37][N:31]([C:38]4[S:39][C:40]5[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=5[N:42]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCCN(c4nc5ccccc5s4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1B(O)O.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Solvent: CCCCCC
Product: CCOC(=O)Cc1c(C)cc(C)cc1C

Procedure:
Ethyl 2,4,6-trimethylphenylacetate was prepared according to the general experimental method from 2,4,6-trimethylphenylboronic acid (164 mg, 1.00 mmol). After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 2,4,6-trimethylphenylacetate is obtained as a colourless liquid in a yield of 62% of theory. 1H NMR (200 MHz, CDCl3): δ=6.89 (s, 2H), 4.10-4.25 (m, 2H), 3.67 (s, 2H), 2.27-2.37 (m, 9H), 1.27 (t, J=7.1 Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3): δ=171.9, 137.4, 136.8, 129.3, 129.2, 61.1, 35.6, 21.3, 20.6, 14.7 ppm; MS (70 eV), m/z (%): 206 (23) [M+], 160, (7), 133 (100), 105 (10) 91 (11); IR (NaCl): ν=2978 (m), 2867 (w), 1732 (s), 1157 (m), 1031 (m) cm−1.