Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[CH:12][NH:13]3)=[CH:9][CH:8]=2)[CH2:2]1.[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH3:16][C:17]1[C:22]([CH:23]([C:11]2[C:10]3[C:14](=[CH:15][C:7]([O:6][CH:3]4[CH2:4][CH2:5][O:1][CH2:2]4)=[CH:8][CH:9]=3)[NH:13][CH:12]=2)[CH2:24][N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1cc2ccc(OC3CCOC3)cc2[nH]1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(OC3CCOC3)ccc12
Yield: 46.4 %

Procedure:
6-(Tetrahydrofuran-3-yloxy)-1H-indole (0.632 g, 3.11 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (0.800 g, 2.56 mmol) were dissolved in THF (50 mL). The solution was then concentrated under vacuum to dryness. The solid mixture was melted at 130° C. and heated at this temperature for 6 hr. The mixture was subjected to ISCO (120 g silica gel, solid loading, 25-65% ethyl acetate/hexane) to afford the desired product (0.612 g, 1.187 mmol, 46.3% yield) as a beige solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[C:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[CH2:22][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)#[N:26]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(Cc2ccccc2C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a microwave vial equipped with a stir bar was added tert-butyl (3R)-piperidin-3-ylcarbamate (3000 mg, 14.98 mmol), Potassium Carbonate (6211 mg, 44.9 mmol), and 2-(bromomethyl)benzonitrile (3230 mg, 16.48 mmol). The vial was sealed and stirred at room temperature. The LCMS taken after 2.5 hours indicates the formation of the desired product. The crude reaction mixture was filtered and concentrated in vacuo. The material was dry loaded onto a 50 g column. The column was run from 100% dichloromethane to 15% methanol. The desired product eluted and the fractions were collected and concentrated in vacuo.
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][NH2:1]
Reactant: NN
Reactant: CN1CCNCC1CCc1cccc2c1C(=O)NC2=O
Solvent: CO
Product: CN1CCNCC1CCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 2-(N-methylpiperazinyl)ethylphthalimide (218 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:27][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:20][CH:19]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCCCCCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC(=O)Nc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
91 g (375 mmol) of 1-hexadecanol were added to a solution of 50 g (375 mmol) of p-tolyl isocyanate in 50 ml of toluene, and the resulting solution was heated under reflux for 8 h. After cooling to room temperature and stirring at this temperature for 12 h, the precipitated solid was filtered off. The colourless solid was washed twice with 10 ml of toluene each time and then dried in vacuo. 80 g (213 mmol, 57%) of the desired carbamate were obtained in the form of a colourless solid with a melting point of 75° C. The melting point agreed with literature data (75-76° C., Microchem J. 1962, 6, 179).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CCOCC1)N1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 258.7 %

Procedure:
To a solution of 13 g (41.7 mmol) of 4-(tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester in DCM (260 mL) were added 32.5 mL of trifluoroacetic acid. The reaction was stirred for 6 h at room temperature. The solvent was removed under reduced pressure. The residual oil was azeotroped with DCM (3×20 mL), chloroform (2×20 mL) and toluene (3×20 mL) to afford 22.9 g of [1,4]diazepan-1-yl-(tetrahydro-pyran-4-yl)-methanone as triple trifluoroacetic acid salt; ES−MS: m/z 213 [M+H+]
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc3oc4c(c3c2)CCCC4)cc1
Yield: 69.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), 4-t-butylbenzoyl chloride (1.1 mL, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided 4-tert-butyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.2 g). Mp 185-186° C.; Anal. Calcd. for C23H25NO2: C, 79.51; H, 7.25; N, 4.03; Found: C, 79.33; H, 7.27; N, 3.94.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>ClCCl>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:23][CH:22]=3)=[O:26])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)CNc1ccc2nc(S)sc2c1
Solvent: ClCCl
Product: CC(C)CN(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc2nc(S)sc2c1
Reaction time: 8 h
Yield: 64.1 %

Procedure:
Into 50 ml round bottomed flask were added 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (52.36 mg, 0.22 mmol), dichloromethane (10 ml), and α,α,α-trifluoro-p-tolyl isocyanate (41.1 mg, 0.22 mmol). The reaction mixture was stirred 8 h, filtered, and the solid that was obtained was triturated with chloroform, followed with chloroform/methanol (9:1 mixture) to give 60 mg (64%) of the title compound. 1H NMR (DMSO-d6) δ=0.84 (d, 6H), 1.66 (m, 1H), 3.49 (d, 2H), 7.30 (s, 2H), 7.50 (d, 2H), 7.60 (d, 2H), 7.71 (s, 1H); ESIMS: m/z 424 (M−H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:37][CH:36]=2)[CH2:29][CH2:30][S:31][CH2:32][CH2:33]1
Reactant: Nc1ccc(CN2CCSCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCSCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(thiomorpholin-4-yl-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=15:1) C28H27N3O3S
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:6][OH:7])=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a mixture of 4-chloro-2,6-difluoro-benzaldehyde (5.7 g, 32 mmol), tetrahydrofuran (150 mL) and ethanol (20 mL) was added sodium borohydride (1.2 g, 32 mmol) at 0° C. The mixture was stirred for 30 minutes, warmed to ambient temperature, and additional sodium borohydride (0.40 g, 11 mmol) was added to drive the reaction to completion (TLC). The mixture was concentrated in vacuo, diluted with ether and treated cautiously with 1M aqueous HCl. The aqueous phase was extracted 3× with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated. Trituration of the residue with pentane afforded 4.8 g (83%) of (4-chloro-2,6-difluoro-phenyl)-methanol as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.04 (d, 2H, J=7.1 Hz), 4.73 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].CS([C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1)(=O)=O>C(Cl)Cl.N1C=CC=CC=1>[CH3:12][S:9]([C:26]1[CH:25]=[CH:30][C:29]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:32])=[O:33])=[C:28]([O:35][CH3:36])[CH:27]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(C)(=O)=O)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(S(C)(=O)=O)ccc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.4 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 5-methanesulfonyl-2-methoxybenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 330 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-methanesulfonyl-2-methoxy-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.06 min; MS: 553.8 (M+1)+.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH3+:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C([O-])(=O)C.[Na+].C(O)(=O)C>C(O)C>[CH3:2][C:3]1[CH:4]=[C:5]([N:10]2[C:12]([OH:17])=[CH:13][C:14]([CH3:16])=[N:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N[NH3+])cc1C
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2ccc(C)c(C)c2)n1
Yield: 71 %

Procedure:
2-(3,4-Dimethylphenyl)hydrazinium chloride (900 g, 5.21 mol), ethyl acetoacetate (678 g, 5.21 mol), sodium acetate (428 g, 5.21 mol) and glacial acetic acid (10 L) were stirred at 118° C. for about 24 hours. The resulting mixture was cooled and concentrated, and the residue was dissolved in dichloromethane (10 L) and carefully washed with saturated sodium bicarbonate (3×3 L). The organic layer was concentrated to afford a solid. The solid was dissolved in ethanol (450 mL) under reflux. Petroleum ether (7.2 L) was slowly added, and the resulting mixture was cooled and filtered to afford the title compound (748 g, 71%). PXRD analysis provided the diffractogram as shown in FIG. 31.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C1C(=O)N([I:19])C(=O)C1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([I:19])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1[nH]cnc1C
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(I)nc1C

Procedure:
A solution of 5 g 5-Methyl-3H-imidazole-4-carboxylic acid ethyl ester and 7.2 g NIS in 50 ml THF were refluxed for 10 h. After cooling, the solvent was removed under reduced pressure and the residue taken-up in ethyl acetate, washed with sat. NaS2O3 solution and dried over MgSO4. After removal of the solvent under reduced pressure the product was purified by recrystallisation from ethyl acetate. Yield: 7 g
Reaction SMILES: [Na].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])CCC.[C:18]([NH2:24])(=[O:23])[CH2:19][C:20]([NH2:22])=[O:21]>C(O)C>[O:21]=[C:20]1[C:19]([C:18]([NH2:24])=[O:23])=[CH:7][CH:8]=[C:9]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[NH:22]1
Reactant: CCCCOC=CC(=O)C(F)(F)C(F)(F)F
Reactant: NC(=O)CC(N)=O
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1ccc(C(F)(F)C(F)(F)F)[nH]c1=O

Procedure:
0.22 g (9.7 mmol) of sodium was dissolved in 50 ml of ethanol, 2 g (8.1 mmol) of 1-butoxy-4,4,5,5,5-pentafluoropent-1-en-3-one and 0.86 g (8.1 mmol) malonamide were added and the mixture was heated under reflux for 7 h. The mixture was concentrated, and 1N hydrochloric acid was added. The resulting precipitate was filtered off with suction and dried. This gave 1.9 g (94% of theory) of a yellow powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].FC(F)(F)C(O)=O.[F:28][C:29]([F:42])([F:41])[C:30]1[S:34][C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:32][N:31]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:38]2[CH2:37][CH2:36][N:35]([C:33]3[S:34][C:30]([C:29]([F:41])([F:28])[F:42])=[N:31][N:32]=3)[CH2:40][CH2:39]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an off-white solid (yield 52%). MS (m/e): 533.0 (M+H+, 100%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[CH3:30][N:31]([CH3:46])[CH2:32][CH2:33][N:34]([S:42]([CH3:45])(=[O:44])=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[CH3:30][N:31]([CH3:46])[CH2:32][CH2:33][N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:19](=[C:6]2\[C:5](=[O:29])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=3)/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:39][CH:40]=1)[S:42]([CH3:45])(=[O:44])=[O:43]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4)ccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Cl:18][C:19]1[S:23][N:22]=[C:21]([C:24]2[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=2)[N:20]=1>ClCCl.N1C=CC=CC=1>[Cl:18][C:19]1[S:23][N:22]=[C:21]([C:24]2[S:28][C:27]([S:29]([NH:14][C:13]3[CH:15]=[C:9]([N:4]4[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]4)[CH:10]=[CH:11][C:12]=3[O:16][CH3:17])(=[O:31])=[O:30])=[CH:26][CH:25]=2)[N:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2nsc(Cl)n2)s1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2nsc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (33 mg, 0.14 mmol) in dichloromethane (2 ml) and pyridine (0.5 ml) was treated with 5-(5-chloro-1,2,4-thiadiazol-3-yl)-2-thiophenesulfonyl chloride (50 mg, 0.17 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo, co-evaporated with toluene and the crude product purified by mass directed autoprep HPLC to afford the desired product which was characterized as the hydrochloride salt. MS (ES+) m/e 500/502 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[Br:35][C:36]([CH2:42][CH3:43])([CH:39]([Br:41])[CH3:40])[CH:37]=O.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Br:35][C:36]([CH2:42][CH3:43])([CH:39]([Br:41])[CH3:40])[CH:37]=[N:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: CCC(Br)(C=O)C(C)Br
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCC(Br)(C=N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@H]12)C(C)Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of benzhydryl 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (2.47 g, 5.00 mmol) in methylene chloride (35 ml) was added under ice-cooling a solution of 2,3-dibromo-2-ethylbutanal (1.42 g, 5.50 mmol) in methylene chloride (5 ml) followed by addition of anhydrous magnesium sulfate. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and, after addition of benzene (20 ml) and thorough stirring, insolubles were filtered off. The filtrate was concentrated to dryness under reduced pressure and the reside was made powdery by the addition of ether (10 ml). The resulting powder was recovered by filtration and dried under reduced pressure to give 3.12 g (85%) of the title compound as a pale brown powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([Cl:34])=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:43])=[O:42]>>[ClH:34].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:51][CH2:50]3)=[O:33])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)Cl)cc1
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: C#Cc1ccc([C@@H]2[C@H](c3ccc(C#C)cc3)N=C(c3ccc(C(C)(C)C)cc3OCC)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)cc1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12c) and 1-(2-methanesulfonylethyl)-piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 665.5 [(M+H)+]
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl.[CH3:7][CH:8]1[CH2:12]OC(=O)[O:9]1>>[OH:9][CH:8]([CH3:12])[CH2:7][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CC1COC(=O)O1
Agent: Cl
Product: CC(O)Cn1cncn1
Temperature: 0 °C

Procedure:
The starting material may be prepared as follows. A mixture of 1,2,4-triazole (5 g.) and 4-methyl-1,3-dioxolan-2-one was heated at 150° for 18 hours. Concentrated aqueous hydrochloric acid (8 ml.) was added dropwise to the ice-cooled mixture and the mixture was washed with chloroform. The aqueous phase was neutralised with aqueous potassium carbonate solution and extracted with chloroform, and the chloroform extract was dried and evaporated to dryness to give 1-(2-hydroxypropyl)-1,2,4-triazole (7.8 g.) which was characterised as the hydrogen oxalate, m.p. 110°-112° (after crystallisation from EtOH).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]1)=[O:7].O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH2:11][CH:10]([C:24]2[O:25][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=2)[CH2:9]1)=[O:7]
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: CC(C)C(N)=NO
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C(C)C)no2)C1
Yield: 51.4 %

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 51 mg (0.497 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Diastereomer separation of 83 mg of the cis/trans isomer mixture according to Method 14C gave 60.5 mg of the title compound and 6.7 mg of the trans isomer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][OH:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][O:17][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Methyl (4S)-4-[(tert-butoxy)carbonylamino]-5-hydroxypentanoate (9.11 mmol, 2.25 g) was dissolved in 30 mL of methylene chloride. p-Toluenesulfonyl chloride (9.1 mmol, 1.7 g) and triethylamine (27.33 mmol, 3.8 mL) were added and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and crude was purified by column chromatography (SiO2, 4:1 n-hexanes/ethyl acetate to 7:3 n-hexanes/ethyl acetate) to yield the title compound (1.98 g, 54% yield). ES-MS: 402 (M+1).