Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH3:25]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:25])[CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and Dimethylamine were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-dimethyl-amine as white semisolid, MS: 405(MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccccc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2ccccc2s1

Procedure:
A mixture of 4 g. (0.026 m.) of 2-methylbenzothiophene, 4.7 g. (0.027 m.) of N-bromosuccinimide, a catalytic amount of benzoyl peroxide and 250 ml. of carbon tetrachloride was stirred under irradiation for 30 minutes. The cooled and filtered mixture was evaporated to give an oily 2-bromomethylbenzothiophene.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(Nc2nc(Cl)nc3c2ncn3C(CC)CC)cc1
Reaction time: 22 h
Yield: 69.8 %

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 158 mg of ethyl 4-amino-benzoate in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for two days at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 209 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.CON(C)[C:18](=[O:20])[CH3:19]>C1COCC1>[CH3:6][O:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:18](=[O:20])[CH3:19]
Reactant: COCCn1ccnc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCn1ccnc1C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A solution of 30 ml (75 mmol) of 2.5 M n-butyllithium in hexanes was added slowly to a solution of 8.48 g (61.3 mmol) 1-(2-Methoxyethyl)-1H-imidazole (WO 2003055876 A1 in 200 ml THF cooled in a dry ice-acetone bath. After stirring 1 hour, 8 ml (75 mmol) of N-methoxy-N-methylacetamide was added quickly, and the solution was allowed to warm to room temperature over 30 min. After quenching with aqueous NH4Cl, the mixture was diluted with water and extracted twice with EtOAc, which was washed with brine, dried (MgSO4) and concentrated to give an oil that was chromatographed on silica gel (100% DCM followed by gradient elution to 50% EtOAc in DCM). Product (8.5 g) was obtained as a mobile oil. MS (ES) (M+H)+: 169 for C8H12CN2O2
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[Br:27]>>[Br:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[NH:20][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: COC(=O)c1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Product: COC(=O)c1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1
Yield: 41.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thiophene (646 mg, 2.04 mmol) and 5-amino-4-bromo-3-methylisoxazole (361 mg, 2.04 mmol). Purification by column chromatography using 10% MeOH/CHCl3 gave 384 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamide as a brown oil (41% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([C:31]([N:19]2[CH2:18][CH2:17][C@@:15]34[C:16]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1cccc2c1[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1[C@]13CCN(C(=O)C4CCC4)[C@H](C2)[C@@H]1CCC(=O)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a mixture of 2 g (7.37 mmol) 4-methoxymorphinan-6-one (H2O was removed azeotropic) and 3 g (21.71 mmol) K2CO3 in 20 ml dry DMF was dropped at room temperature during 15 min. a solution of 900 mg (7.59 mmol) cyclobutanecarboxylic acid chloride. This mixture was stirred at room temperature for 1 h, then poured on 200 ml ice water and extracted with ether. The organic layer was extracted with 2 N HCl and brine, dried and evaporated to give an oil, which was crystallized with benzene/u/hexane to yield 2.5 g (96%) N-cyclobutylcarbonyl-4-methoxymorphinan-6-one, m.p. 125°-126°, [α]D26 -204.5° (c 0.76, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(OCC)=O>O.C(#N)C>[C:25]1(=[O:34])[N:12]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH3:11])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: CCC(N)c1ccc(OC)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 38.1 %

Procedure:
To a stirred solution of 1-(4′methoxyphenyl)propylamine (2.5 grams, 15.2 mmol) and sodium carbonate (1.74 grams, 16.4 mmol) in a mixture of water (50 milliliters) and acetonitrile (50 milliliters) was added N-carbethoxyphthalimide (3.34 grams, 15.2 mmol). The resulting suspension was stirred for 4.5 hours at room temperature, the acetonitrile was removed in vacuo and a solid formed. The slurry was filtered and the solid was washed with water and air dried to afford 1.73 grams (39%) of crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 1.71 grams (38%) of the product as white crystals: mp 85-86° C.; 1H NMR (DMSO-d6) δ7.92-7.79(m, 4H), 7.46-7.28(m,2 H), 6.97-6.83(m, 2 H), 5.19-5.06(m, 1 H), 3.72(s, 3H), 2.56-2.13(m, 2 H), 0.87(t, J=7.3 Hz, 3 H);13C NMR (DMSO-d6) δ167.8, 1.5, 134.6, 131.7, 131.0, 128.6, 123.1, 113.7, 55.2, 54.9, 23.8, 11.3. Anal. Calculated for C18H17NO3. Theoretical: C,73.20; H,5.80; N, 4.74. Found: C,73.24; H, 5.74; N, 4.86. HPLC 100%.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:35][C:36]([O:39][C:40]([N:42]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:43]1[NH:44][C:45]([C:49](O)=[O:50])=[C:46]([Br:48])[N:47]=1)=[O:41])([CH3:38])[CH3:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:58][C:55]([O:54][C:52]([N:42]([C:43]1[NH:44][C:45]([C:49]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:50])=[C:46]([Br:48])[N:47]=1)[C:40]([O:39][C:36]([CH3:35])([CH3:37])[CH3:38])=[O:41])=[O:53])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
EDC (0.022 g, 0.116 mmol) and HOBT (0.016 g, 0.116 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.033 g, 0.106 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-bromo-1H-imidazole-5-carboxylic acid (0.043 g, 0.106 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated sodium bicarbonate was added and the reaction mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. Chromatography (MeOH:dichloromethane) gave the desired product (0.030 g, 34%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(Oc2cc(OC)ccc2C)cc1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(Oc2cc(OC)ccc2C)cc1C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 3-[4-(5-methoxy-2-methyl-phenoxy)-2-methyl-phenyl]-acrylic acid ethyl ester (1.18 g, 3.63 mmol) and palladium under carbon (10%) (0.39 g, 0.36 mmol) in ethanol (20 mL) and acetic acid (2 mL) is stirred under 1 atm of hydrogen. After stirring overnight, the mixture is filtered off through Celite and washed with methanol. The mixture is concentrated under reduced pressure and purified by flash chromatography by eluting with hexane:ethyl acetate 5:1 to afford the title compound (1.02 g, 85%). Rf=0.42 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.26 (t, 3H, J=6.9 Hz), 2.16 (s, 3H), 2.28 (s, 3H), 2.56 (t, 2H, J=7.3 Hz), 2.90 (t, 2H, J=7.3 Hz), 3.72 (s, 3H), 4.17 (q, 2H, J=6.9 Hz), 6.45 (d, 1H, J=2.4 Hz), 6.62 (dd, 1H, J=2.8, 8.5 Hz), 6.67 (dd, 1H, J=2.4, 8.1 Hz), 6.74 (d, 1H, J=2.4 Hz), 7.06 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=8.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[F:27][C:24]([F:25])([F:26])[O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: NNc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: O=C(NNc1nc2ccc(OC(F)(F)F)cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4e was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and 2-hydrazino-6-trifluoromethoxybenzothiazole (319 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 287 mg, 87%).
Reaction SMILES: [Cl-].[F:2][CH2:3][C@@H:4]([NH3+:24])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>CN(C)C=O>[Cl:34][CH:35]([Cl:39])[C:36]([NH:24][C@H:4]([CH2:3][F:2])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1)=[O:37]
Reactant: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@H]([NH3+])CF)cc2)on1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)on1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
To a dimethylformamide (3 ml) solution of (1R,2S)-3-fluoro-1-hydroxy-1-(4-(3-(methylsulfonamidomethyl)isoxazol-5-yl)phenyl)propan-2-aminium chloride (150 mg, 0.40 mmol) is added diisopropylethylamine (0.255 g, 2 mmol). After cooling the reaction mixture to 0° C. dichloroacetyl chloride (62 mg, 0.42 mmol) is added. The reaction is stirred at 0° C. for twenty minutes then quenched by the addition of water (1 ml). The reaction mixture is concentrated to a volume of approximately two milliliters and subjected to reverse phase HPLC purification to give the title compound (95 mg): 1H NMR (400 MHz, CDCl3) 3.06 (s, 3H) 4.30-4.43 (m, 1H) 4.49 (d, J=6.32 Hz, 2H) 4.56-4.67 (m, 2H) 4.93 (m, br, 1H) 5.19-5.24 (m, 1H) 5.87 (s, 1H) 6.61 (s, 1H) 7.03 (d, J=9.09 Hz, 1H) 7.52 (d, J=8.08 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H); m/z (CI) 454, 456, 458 ([M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:23][CH2:24][C:25]([O:27]C)=O)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[NH3:29]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:23][CH2:24][C:25]([NH2:29])=[O:27])[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)CCc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)o1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2oc(CCC(N)=O)nc2-c2ccc(F)cc2)cc1

Procedure:
Part 20) 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-oxazolepropionic amide is prepared by treating 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-oxazolepropionic acid, methyl ester with excess ammonia in methanol for 5 days, mp 193°-195° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][SH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS[C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][S:11][C:14]1=[CH:15][N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: SCCNCc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCN1Cc1ccccc1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
3.34 g (20 moles) of N-benzyl-cysteamine and 3.3 g of 1,1-bis-methylthio-2-nitro-ethylene are refluxed in 50 ml of ethanol for one hour. The gas evolution terminates after boiling for 20 minutes. The mixture is cooled and the precipitated product is isolated by filtration. 4.52 g of 3-benzyl-2-nitromethylene-thiazolidine are obtained, melting at 136° to 138° C. Crystallization of the product from 140 ml of ethanol yields 4.08 g of a purified product, melting at 139° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9].[C:12](Cl)([Cl:14])=[O:13]>C(Cl)Cl>[CH3:2][N:3]([CH2:4][CH2:5][O:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])[C:12]([Cl:14])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: C=C(C)C(=O)OCCNC
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OCCN(C)C(=O)Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-(2-methacryloyloxyethyl)amine hydrochloride (95.0 g, 0.529 mol) produced in Example 1 was suspended in methylene chloride (300 ml) and heated to 50° C. Phosgene (7.85 g, 0.793 mol) was introduced into the resultant suspension over two hours. The resultant reaction mixture was further stirred for one hour, and then the methylene chloride was removed from the mixture to produce N-methyl-N-(2-methacryloyloxyethyl)carbamoyl chloride (106.6 g, almost quantitative yield, purity: 98%) as a colorless transparent liquid. The product was analyzed through gas chromatography (column: silicone SE-30 20% glass column (2 m), injection temperature: 220° C., detection temperature: 230° C.). FIGS. 3 and 4 show the infrared spectrum and NMR spectrum of the product, respectively.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[OH:4].O=[C:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[F:14][C:11]([F:12])([F:13])[C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:16]([CH3:33])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 35.8 %

Procedure:
Following a procedure similar to that described in Example 2, but using 5.88 g of 2-amino-1-(3-trifluoromethylphenyl)ethanol (prepared as described in Preparation 42), 8 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 2), 200 ml of benzene, 150 ml of absolute methanol and 5.4 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 4.8 g of the title compound were obtained as crystals, melting at 100°-105° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]2)=[CH:11][C:10]=1[CH3:24])C1C=CC=CC=1.C(O)C.[H][H]>[OH-].[OH-].[Pd+2].C1COCC1>[CH3:24][C:10]1[CH:11]=[C:12]([N:15]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1O
Yield: 86.7 %

Procedure:
A mixture of 1-(4-(benzyloxy)-3-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (670 mg, 2.0 mmol), 20% palladium hydroxide on activated carbon (50 mg), ethanol (20 ml), and THF (20 ml) was shaken under 40 psi of hydrogen gas at the ambient temperature for 3 days and at +50° for 1 day, to drive reaction to completion. The reaction was filtered through a pad of Celite and the mother liquor was concentrated to obtain the target product as a colorless solid (420 mg, 86%). MS (M+1): 243.0.
Reaction SMILES: [C:1]([O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:10]([O:9][CH:1]1[CH2:2][CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:17][C:10](=[O:9])[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH3:29])(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCCCCCCCCC1CC(OC(=O)c2ccccc2)C(CCCCCC)C(=O)O1
Yield: 103.4 %

Procedure:
177.3 g of the δ-lactone from c) were suspended in 1250 ml of toluene while stirring. After the addition of 138.6 g of benzoic anhydride the mixture was stirred for 10 minutes. Then, 2.5 ml of perchloric acid were added. The mixture was stirred for a further 2.5 hours. The reaction solution was extracted in toluene with 1N sodium hydroxide solution and then with water. The combined toluene phases were dried, the drying agent was filtered off under suction and washed with toluene. Evaporation of the solvent gave 237.2 g (103.4%) of rac-(2RS,3RS,5SR)-3-benzoyloxy-2-hexyl-5-undecyl-δ-valerolactone, which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[C:15]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])#[N:16]>>[C:15]([CH2:17][S:18]([CH2:21][C:22]([NH:9][CH:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12)=[O:23])(=[O:20])=[O:19])#[N:16]
Reactant: N#CCS(=O)(=O)CC(=O)O
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC#N)[C@H]2SC1

Procedure:
When the t-butyl ester of 7-ADCA is acylated with cyanomethylsulfonylacetic acid by the procedure of Example 5, 7-cyanomethylsulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][CH3:11])([C:7]([O-:9])=[O:8])[C:4]([O-:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:10]([C:3]([CH2:1][CH3:2])([C:7]([O:9][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])[C:4]([O:6][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:5])[CH3:11]
Reactant: CCCCCCCCBr
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)C(CC)(CC)C(=O)OCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.7 %

Procedure:
To a stirring solution of diethylmalonate (16.0 g, 100 mmol) in THF (200 mL, 0.5 M) was added sodium hydride (2.4 g, 100 mmol). The solution began bubbling and an exothermic reaction occurred. The reaction eventually turned clear and then octyl bromide (17.3 mL, 100 mmol) was added. The reaction was refluxed for 20 hours and then cooled to room temperature. Another equivalent of NaH (2.4 g, 100 mmol) was added to the cloudy white mixture which was then stirred for 4 hours at room temperature. Another equivalent of octyl bromide (17.3 mL, 100 mmol) was added and the reaction was refluxed for 20 hours. The reaction was cooled to room temperature and filtered (NaBr). The mother liquor was collected and concentrated in vacuo to a yellow oil. The crude product was then distilled under vacuum (250° C.) to afford 23.4 g (64%) of pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]O.N1C=CC=CC=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Cl:23]
Reactant: COc1ccc(CO)c(OC)c1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCl)c(OC)c1OC
Temperature: 0 °C

Procedure:
5 g (24.47 mmol) of 2,3,4-trimethoxybenzyl alcohol (Aldrich, Steinheim, FRG) are dissolved, under argon, in 13.9 ml of abs. methylene chloride, and this solution is treated with 0.278 ml of pyridine. 3.05 ml of thionyl chloride in 6.94 ml of abs. methylene chloride are added dropwise to this solution, while cooling slightly (ice/water), within the period of 20 min. During this procedure, the internal temperature rises to approximately 18°-23° C. The mixture is left to react subsequently for 45 min and the slightly yellow solution is then poured onto ice/water. After the phases have been separated, the organic phase is washed once each with 1N sulfuric acid and water. After drying over Na2SO4, and removing the solvent, the oily residue is distilled under HV (b.p.: 93°-95° C./0.07 Torr) and the title compound is obtained. 1H-NMR (220 MHz, CDCl3): 7.05 (d, 1H); 6.65 (d, 1H); 4.61 (s, 2H); 3.97 (s, 3H); 3.85 (s, 3H). HPLC: tRet =8.1 min (gradient II).