Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH2:25]Br)[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]2)=[CH:14][CH:13]=1.[I-].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH2:25][C:3]3[NH:2][CH:6]=[CH:5][N:4]=3)[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]2)=[CH:16][CH:17]=1
Reactant: c1c[nH]cn1
Reactant: CCC1COC(CBr)(c2ccc(Oc3cccc(Cl)c3)cc2)O1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1COC(Cc2ncc[nH]2)(c2ccc(Oc3cccc(Cl)c3)cc2)O1
Temperature: 25 °C

Procedure:
1.2 parts of imidazole sodium salt, 4 parts of 2-[p-(3chlorophenoxy)phenyl]-2-bromomethyl-4-ethyl-1,3-dioxolane and a catalytic amount of potassium iodide are stirred in 50 ml of dimethyl formamide for 17 hours at a temperature of 125° C. The brown reaction mixture is cooled to room temperature, diluted with 150 ml of water and extracted with three 50 ml portions of ethyl acetate. The combined extracts are washed with two 50 ml portions of water, and dried over sodium sulfate. The solvent is removed by evaporation and the crude product is chromatographed over a 35 cm column of silica gel with acetone/ethyl acetate (1:1). The eluant is removed by evaporation and the oily residue is crystallised from petroleum ether in the form of slightly yellowish crystals with a melting point of 69°-71° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(-c2ccccc2)c2ccccc2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)c2ccccc2n1

Procedure:
2-methyl 4-(3-nitro phenyl) quinoline is prepared by nitration at 0° C. of 2-methyl 4-phenyl quinoline (1.36 10-1 mole) with sulfonitric mixture (90 ml nitric acid 60% and 90 ml concentrated sulfuric acid) and separation of isomers. It has a melting point of 157° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[OH:11])=[O:3].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[C:5]([O:11][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1ccc(Cl)cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(Cl)ccc3C(C)=O)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
4-Chloro-2-hydroxyacetophenone (45 mg), 4-chloro-6,7-dimethoxyquinoline (60 mg), and 4-dimethylaminopyridine (95 mg) are suspended in o-dichlorobenzene (10 ml) to prepare a suspension which was then stirred at 120° C. overnight and then at 140° C. for 5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (11 mg, yield 12%).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([I:19])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[O:28]1[CH2:33][CH2:32]C(=O)[CH2:30][CH2:29]1>ClCCCl>[I:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]3[CH2:9][CH2:8][NH:7][C:6]4([C:11]=3[NH:12]2)[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:17][CH:16]=1
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cc(I)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Ic1ccc2c3c([nH]c2c1)C1(CCOCC1)NCC3
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of [2-(6-Iodo-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (500.0 mg, 1.294 mmol) was stirred into a mixture of DCE (2.0 mL) and TFA (2.0 mL) for 10 min. Tetrahydro-4H-pyran-4-one (360.0 uL, 3.88 mmol) was added. The reaction mixture was stirred at 40° C. for one hour, then at 50° C. for two hours and finally at 60° C. for one hour. The reaction solution was then concentrated down and the product was used in the next step without further purification. MS m/z 369 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[N+:18]([O-])=O)#[N:2].[H][H]>[Pd].C(O)C>[NH2:18][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(C#N)c(N)c1

Procedure:
4.9 mg of palladium on carbon (10%) were added to a solution of 48.9 mg (0.18 mmol) of tert-butyl (2E)-3-(4-cyano-3-nitrophenyl)acrylate in 4.4 ml of ethanol. The reaction mixture was hydrogenated using a hydrogen pressure of 1 bar at RT overnight. The mixture was then filtered through celite and the filtrate was concentrated. This gave 43.5 mg (99% of theory) of the target compound of a purity of 85%.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH2:12]O)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:20])CC)C.C(=O)(O)[O-].[Na+].Cl>CCOC(C)=O.C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1([CH2:12][F:20])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)C1(CO)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)C1(CF)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a round-bottom flask equipped with a stir bar was added N-(tert-butyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide (8.66 g, 41.8 mmol) and CH2Cl2 (110 mL). The stirred solution was cooled to 0° C. and to the solution was added (diethylamino)sulfur trifluoride (11 mL, 84 mmol). The solution was allowed to warm to room temperature with stirring for 4 h. The solution was then slowly added to a stirred sat. aq. sodium bicarbonate (100 mL) and following the addition stirring was maintained for 18 h. The pH of the aqueous phase was adjusted to pH=4 using aq. HCl. The mixture was transferred to a separatory funnel and was twice extracted with CH2Cl2. The combined organics were washed with brine; dried over MgSO4; filtered; and then concentrated in vacuo to afford a brown solid residue. This material was subjected to SiO2 chromatography (hexanes:EtOAc, 90:10 to 40:60) to afford N-(tert-butyl)-1-(fluoromethyl)cyclopropane-1-sulfonamide as a colorless, crystalline solid (5.66 g, 65%). 1H NMR (400 MHz, CDCl3) δ 4.73 (s, 1H), 4.60 (s, 1H), 4.22 (br. s., 1H), 1.59-1.53 (m, 2H), 1.37 (s, 9H), 1.12-1.07 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH2:9][CH2:8]1)=[O:6].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]=O)=[CH:27][CH:28]=1.C([BH3-])#N.[Na+]>CO>[Cl:19][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:20])[C:13]=1[N:10]1[CH2:9][CH2:8][CH:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)=[O:6])[CH2:12][CH2:11]1
Reactant: NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: COc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCCNC(=O)C2CCN(c3c(Cl)cncc3Cl)CC2)cc1
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E13 (50 mg, 0.16 mmol) in MeOH (5 mL) was added anisaldehyde (19 μL, 0.16 mmol). After stirring for 2 h, sodium cyanoborohydride (20 mg, 0.32 mmol) was added and the mixture was stirred for a further 20 h. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (20 mL), washed with a saturated solution of sodium hydrogencarbonate (25 mL), brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a colourless oil (13 mg, 19%), umax (CHCl3)/cm−1 3008, 2839, 1660, 1513, 1249, 1174, 1036; m/z (ESI) C21H27Cl2N4O2 requires 437.1506, found [M+H]+ 437.1508.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][C@H:9]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:7].C(N(CC)CC)C.Cl.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([C:50](Cl)=[O:51])=[CH:42][CH:41]=1.Cl>C(Cl)Cl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:50]([C:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:40]=[CH:41][CH:42]=2)=[O:51])[CH2:10][C@H:9]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7]
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1ccnc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1)c1ccnc2ccccc12
Reaction time: 15 h

Procedure:
A solution of 1.70 g (3.65 mmol) of (2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidine4-amine and 1.5 ml (10.96 mmol) of triethylamine in 3 ml of methylene chloride is added dropwise at 0° C. to a solution of 0.915 g (4.01 mmol) of quinoline4-carboxylic acid chloride hydrochloride [Nicolai E, Gungor T, Goyard J, Cure G, Fouquet A, Teulon J M, Delchambre C, Cloarec A, Eur. J. Med. Chem., 1992, 27, 977] in 10 ml of methylene chloride. After 15 hours, a further 228 mg (1.0 mmol) of quinoline-4-carboxylic acid chloride hydrochloride and a further 0.1 ml (1.0 mmol) of triethylamine are added and the mixture is stirred for 3 hours. 1 N hydrochloric acid is added to the mixture which is then extracted with ethyl acetate. The organic phase is washed with 1 N sodium hydroxide solution and with brine, dried over sodium sulfate and concentrated. The residue is crystallised from toluene and yields the title compound in the form of white crystals. M.p. 204-207° C. (phase transition 135-140° C.); TLC: ethyl acetate: Rf =0.48, FD-MS: M+ =619(621). ##STR17##
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([SH:16])[CH2:14][SH:15]>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]1[S:16][CH2:13][CH2:14][S:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOC(=O)c1ccccc1
Reactant: SCCS
Solvent: Cc1ccccc1
Product: O=C(OCC1SCCS1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-benzoyloxyacetaldehyde (example (5.65 g), 1,2-ethanedithiol (3 ml) and paratoluenesulfonic acid (200 mg) in toluene (250 ml) was heated at refluxing under water removal conditions using a Dean Stark apparatus for 4 hours. The mixture was cooled to room temperature, washed first with saturated aqueous NaHCO3 solution (1×60 ml), then with water (2×60 ml), and dried over reduced pressure. The residue was purified by chromatography on silica gel using hexane:ethyl acetate (9:1) as eluant to give 5.2 g of pure product which was characterized by 1H- and 13C-NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](=[O:43])[CH:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)[CH3:33]>>[CH3:29][O:30][C:31](=[O:43])[CH:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:14](=[O:16])[CH:13]([N:12]2[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:37]([F:42])[CH:36]=1)[CH3:33]
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)C(C)Oc1ccc(N)c(F)c1
Product: COC(=O)C(C)Oc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
This compound was prepared in analogy to example 57, intermediate, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 2-(4-amino-3-fluoro-phenoxy)-propionic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:6][CH:7]=1.[SH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(C(C)C)C(C)C)C>>[O:18]([C:4]1[CH:3]=[C:2]([S:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:7]=[N:6][C:5]=1[NH:8][C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cnc(Nc2nc3cccnc3s2)c(Oc2ccccc2)c1
Reactant: COC(=O)CCS
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc3cccnc3s2)c(Oc2ccccc2)c1
Yield: 75 %

Procedure:
Prepared according to the method of Example 13 from N-(5-bromo-3-phenoxypyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine, methyl 3-mercaptopropanoate and N-ethyl-N-isopropylpropan-2-amine in 75% yield. 1H NMR (d6-DMSO) δ 2.59 (t, 2H), 3.09 (t, 2H), 3.56 (s, 3H), 7.12 (d, 2H), 7.20 (t, 1H), 7.38-7.46 (m, 4H), 7.91 (bs, 1H), 8.24 (s, 1H), 8.36 (d, 1H), 11.53 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[S:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c(=O)[nH]sc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc2c(Cl)nsc12
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 82.6 g (0.5 mol) of 7-methyl-1,2-benzisothiazol-3-one, 80.4 g (1.1 mol) of N,N-dimethylformamide and 200.0 g of toluene. While stirring, 83.3 g (0.7 mol) of thionyl chloride was added dropwise thereto at 70° to 80° C. over 1 hour, and the mixture was reacted at the same temperature for 3 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was distillated under reduced pressure of 0.40 kPa at 110° C. to give 81.7 g (0.45 mol) of 3-chloro-7-methyl-1,2-benzisothiazole. The yield based on 7-methyl-1,2-benzisothiazol-3-one was 89%.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>CO.O1CCCC1.[C].[Pd]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][C:39]([F:41])([F:42])[F:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(Cl)CS[C@H]23)cs1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(Cl)CS[C@H]23)cs1
Yield: 70.2 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 1.8 g.) and 10% palladium carbon (0.9 g.) in methanol (20 ml.) and tetrahydrofuran (20 ml.) was treated in a similar manner to that of Example 21-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([NH:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([NH:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(NC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(NC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][NH2:13]>C1COCC1.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:13][CH3:12])[S:3][C:4]=2[CH:10]=1
Reactant: CN
Reactant: Clc1ccc2nc(Cl)sc2c1
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichlorobenzo[d]thiazole (2 g, 10 mmol) in 10 mL THF was added 25% MeNH2 in water (3 mL) dropwise. After the addition complete, the reaction mixture was stirred at room temperature overnight. Filter off the product and washed with methanol. Drying in vacuo to yield 1.5 g of the desired compound. LC-MS: m/z 204.2 (M+H)+
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]4[CH2:20][O:21][C:22](=[O:23])[C:12]3=4)[CH:9]=2)[NH:4][N:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[CH3:19][C:15]1[NH:14][C:13]2[CH2:20][O:21][C:22](=[O:23])[C:12]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)[C:16]=1[C:17]#[N:18]
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(Br)c3c2)C2=C(COC2=O)N1
Reactant: OB(O)c1cccc(C(F)(F)F)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: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(-c4cccc(C(F)(F)F)c4)c3c2)C2=C(COC2=O)N1
Temperature: 95 °C
Reaction time: 12 h
Yield: 4.3 %

Procedure:
To a degassed solution of 120 mg (0.323 mmol) 4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile (Example 24) and 73.7 mg (0.388 mmol) [3-(trifluoromethyl)phenyl]boronic acid in anhydrous 1,4-dioxane (4.8 ml) were added under argon atmosphere 37.4 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution (2 M, 0.77 ml). The resulting mixture was stirred at 95° C. for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was subsequently washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (first run: acetonitrile/water gradient, final mixture 95:5 v/v; second run: methanol/water isocratic 75:25 v/v) to yield the title compound as a white solid (6 mg, 4% of th.).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[CH2:7].[CH:12]([Cl:15])(Cl)[Cl:13]>>[Br:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[CH2:7][C:12]1([Cl:15])[Cl:13]
Reactant: C=Cc1ccccc1Br
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: ClC1(Cl)CC1c1ccccc1Br
Temperature: 45 °C

Procedure:
A 20 ml solution of 50% sodium hyroxide was added dropwise to 2-bromostyrene (10.0 g, 54.9 mmol) in 100 ml of chloroform. The reaction mixture was warmed to 45° C. for 1 hour. After cooling the solution was separated and the organic layer was dried over magnesium sulfate and concentrated. The resulting liquid was flash chromatographed, affording 11.6 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1ccc(N2CCSCC2)cc1

Procedure:
A solution of 23.47 g of 4-(p-nitrophenyl)-tetrahydro-4H-1,4-thiazine in 1.5 l of dioxane is hydrogenated over Raney-nickel until the hydrogen uptake has finished. Thereafter, the catalyst is removed by filtration, washed well with dioxane and the filtrate is evaporated in vacuo. By recrystallization of the crude product from dichloromethane/ether, there is obtained 4-(p-aminophenyl)-tetrahydro-4H-1,4-thiazine of melting point 109°-111°.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][SH:25])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25][C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.6 g, 0.088 mol) was added to a cold solution of 2-chloro-5-nitrobenzoic acid (16.1 g, 0.08 mol) in dimethylformamide (200 mL) and the mixture was stirred for 5 min. The cold mixture was treated dropwise with a solution of 4-methoxy-α-toluenethiol (13.2 g, 0.08 mol) in dimethylformamide (80 mL) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the residue was diluted with water and acidified with dilute hydrochloric acid to pH 1. The resulting precipitate was filtered, washed with water and azeotroped to dryness from a mixture of methylene chloride-toluene. The residue was suspended in ethyl ether, filtered and washed with ethyl ether to give the title compound as a yellow solid (16 g, 63%), which was used without further purification. Mp 200-204° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]2[C:9]=1[C:10](=[O:28])[N:11]([CH2:19][C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:12]2=[O:18])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]2[C:9]=1[C:10](=[O:28])[N:11]([CH2:19][C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:12]2=[O:18]
Reactant: C[C@H](CN1C(=O)c2cc(Br)cc(NC(=O)OC(C)(C)C)c2C1=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CN1C(=O)c2cc(Br)cc(N)c2C1=O)c1ccccc1
Yield: 87.5 %

Procedure:
(S)-[6-Bromo-1,3-dioxo-2-(2-phenyl-propyl)-2,3-dihydro-1H-isoindol-4-yl]-carbamic acid tert-butyl ester (160 mg, 0.35 mmol) was stirred in a mixture of DCM (2 mL) and TFA (1 mL) for 3 h at rt. The mixture was concentrated, and the residue was diluted with satd. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give a yellow oil. Purification by flash chromatography (EtOAc/hexanes) gave 110 mg (87%) of the desired amine as a yellow foam. 1H NMR (500 MHz, CDCl3): 7.31-7.23 (m, 4H), 7.22-7.17 (m, 2H), 6.81 (d, J=1.5, 1H), 5.19 (br s, 2H), 3.78 (dd, J=13.6, 7.6, 1H), 3.71 (dd, J=13.6, 8.2, 1H), 3.30 (app sextet, Japp=7.5, 1H), 1.29 (d, J=7.0, 3H).