Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=1)=[O:7].[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[NH:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.S1C=CC=C1>CC(O)C.[Pt].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:1])[F:34])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:50]2[CH2:51][CH2:52][N:47]([CH2:46][C:45]([NH:44][C:38]3[C:39]([CH3:43])=[CH:40][CH:41]=[CH:42][C:37]=3[CH3:36])=[O:53])[CH2:48][CH2:49]2)[CH2:10][C@@H:9]1[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=1)=[O:7].[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:1])[F:34])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:50]2[CH2:51][CH2:52][N:47]([CH2:46][C:45]([NH:44][C:38]3[C:39]([CH3:43])=[CH:40][CH:41]=[CH:42][C:37]=3[CH3:36])=[O:53])[CH2:48][CH2:49]2)[CH2:10][C@@H:9]1[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=1)=[O:7]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2cc(F)cc(C(F)(F)F)c2)C1
Agent: [Pt]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: c1ccsc1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3cc(F)cc(C(F)(F)F)c3)C2)CC1
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3cc(F)cc(C(F)(F)F)c3)C2)CC1
Yield: 10 %
Yield: 12 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoromethyl) phenyl]methyl]-4-piperidinone (0.01 mol) and N-(2,6-dimethylphenyl)-1-piperazine-acetamide (0.01 mol) in 2-propanol (150 ml) was hydrogenated at 50° C. with platinum on activated carbon (55), 2 g) as a catalyst in the presence of titanium(IV)isopropoxide (2.84 g) and thiophene solution (1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, washed several times with H2O, dried, filtered over dicalite and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2). Two pure factions were collected and their solvents were evaporated. The residue was dried, yielding 0.72 g (10%) of (±)-cis-4-[1-[3,5-bis (trifluoromethyl)benzoyl]-2-[[3fluoro-5-(trifluoromethyl) phenyl]methyl]-4-piperidinyl]-N—(2,6-dimethylphenyl)-1-piperazineacetamide (compound 140 ) and 0.88 g (12%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoro-methyl) phenyl]methyl]-4-piperidinyl]-N—(2,6-dimethylphenyl)-1-piperazineacetamide (compound 141).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH3:25])=[C:17](B(O)O)[CH:18]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:15]3[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=3[O:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CCCOc1ccc(Cl)cc1B(O)O
Product: CCCOc1ccc(Cl)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(5-chloro-2-propoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 5-chloro-2-propoxyphenylboronic acid in a manner analogous to Example 2c (0.46 g, 66%). MS=323 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20]>C(C(C)=O)C>[CH2:17]([NH:21][C:22]([NH:10][S:7]([C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)(=[O:9])=[O:8])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN=C=O
Reactant: Cc1cscc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cscc1C
Reaction time: 8 h

Procedure:
4-Methyl-3-thiophenesulfonamide (22 g), 125 ml of methyl ethyl ketone, 16.6 g of potassium carbonate and 14.3 g of butyl isocyanate was stirred at reflux for six hours, allowed to stand overnight and then evaporated to a syrup. Water (150 ml) was added to the residue and the mixture was filtered to remove a small amount of solid. The filtrate was acidified, cooled and the resulting intermediate was filtered off. It melted at 126°-131° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([N:9]1[C:10]2[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (7.7 g, 191.7 mmol) was added portionwise to a 0° C. solution of 4-methoxyindole (21.7 g, 147 mmol) in 750 mL of anhydrous DMF. After 15 min, the slurry was treated with benzyl bromide (17.5 mL, 147 mmol). The reaction mixture was allowed to warm to ambient temperature and stir overnight. The reaction mixture was poured into 1 L of H2O. The layers were separated, and the aqueous phase was extracted with EtOAc (2×200 mL). The combined organic layers were washed with H2O (4×500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2; hexanes) to give 32.9 g (138.6 mmol; 94%) of the title compound as a white solid. Electrospray MS 238 (M+1);
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate (0.11 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.11 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.070 g of methyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=[O:8].OC1C(=O)[NH:15][S:16](=[O:25])(=[O:24])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:11][C:6]1[C:7](=[O:8])[NH:15][S:16](=[O:24])(=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1NS(=O)(=O)C(c2ccccc2)=C1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NS(=O)(=O)C(c2ccccc2)=C1Cl
Temperature: 25 °C
Yield: 49.6 %

Procedure:
Dry DMF (1.2 ml) was added dropwise to a mixture of oxalyl chloride (4.96 g, 39.1 mmol) and 4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (2.2 g, 9.77 mmol) in DCM. The resulting solution was heated under reflux until it turned orange. The mixture was then cooled to room temperature and filtered affording the title compound (1.18 g, 50%) as white solid. 1H NMR (400 MHz, d6-DMSO): δ 7.41-7.54 (m, 3H), 7.77-7.80 (m, 2H), 12.70 (br.s, 1H); 13C-NMR (100 MHz, d6-DMSO): δ 126.1, 127.1, 128.3, 129.9, 130.6, 144.9, 162.2.
Reaction SMILES: [C:1]([Cl:5])(=[O:4])[CH2:2][CH3:3].C(O)(=[O:8])C>>[C:1]([OH:4])(=[O:8])[CH2:2][CH3:3].[C:1]([Cl:5])(=[O:4])[CH3:2].[C:1]([Cl:5])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(=O)O
Agent: CCC(=O)Cl
Product: CC(=O)Cl
Product: CCC(=O)O

Procedure:
If X is the carboxyl group O—C(O)—R5, carboxylic anhydrides are obtained. If R1 and R5 are each methyl, acetic anhydride is obtained, this being prepared industrially from acetic acid via the dehydration to give the ketene and subsequent addition of acetic acid (Weissermel, Arpe, Industrielle organische Chemie, 3rd edition, VCH, 1988, pages 193-194). Propionic anhydride can be obtained from propionic acid by dewatering, or by reaction with propionyl chloride. Mixed anhydrides in which R5 is not methyl or ethyl can be obtained from acetic acid or propionic acid via acetyl chloride or propionyl chloride with subsequent reaction of the corresponding carboxylic acid (Ullmanns Encyklopädie der technishen Chemie, 4th edition, 1980, Verlag Chemie GmbH, Volume 19, page 457).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Reactant: Cc1csc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (100 mg, 0.21 mmol) and (4-methyl-2-thienyl)boronic acid (60 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol) The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E110). MS (ES+) m/e 490 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[Cl:22])[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ccccc2Cl)CC1

Procedure:
The the hydrochloride of title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chlorophenyl)piperazine. Drying in vacuo at 50° C. for 3½ h gave the title compound; 1H NMR (DMSO-d6): δ8.61-8.55 (br, 1H), 8.29-8.20 (dd-like, 1H), 7.53-7.41 (m, 1H), 7.39-7.17 (m, 7H), 7.14-7.03 (m, 1H), 4.58 (br s, NH+water), 3.85-3.55 (br m, 4H), 3.12-2.99 (br m, 4H); HPLC-MS: m/z=478 (M+H); IR (KBr): ν 1733 (C═O) cm−1.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:17])[N:6]([CH2:18][CH2:19][CH3:20])[C:5](=[O:21])[CH:4]=1)[NH2:2].[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[CH3:22][NH:23][C:24]1[C:4]2[C:5](=[O:21])[N:6]([CH2:18][CH2:19][CH3:20])[C:7](=[O:17])[N:8]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3]=2[NH:1][N:2]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(CCc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(CCc2ccccc2)c1=O
Reaction time: 15 h

Procedure:
A solution of 6-hydrazino-1-phenethyl-3-propyluracil (1.5 g, 5.2 mM) and methyl isothiocyanate (1.1 ml, 16 mM) in DMF (15 ml) was stirred at 60° C. for 2 hours and then at 120° C. for 15 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless crystals (0.7 g, 41%), m.p. 256°-258° C.
Reaction SMILES: [CH:1]1([N:7]([CH:29]2[CH2:34][CH2:33][NH2+:32][CH2:31][CH2:30]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[C:36](Cl)(=[O:40])[CH2:37][CH2:38][CH3:39]>>[CH3:25][N:24]([CH3:26])[S:23]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:29]3[CH2:30][CH2:31][N:32]([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34]3)[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[N:15][CH:14]=2)[CH2:18][CH2:19]1)(=[O:28])=[O:27]
Reactant: CCCC(=O)Cl
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CC[NH2+]CC3)s2)CC1
Agent: [Cl-]
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCCCC2)CC1

Procedure:
Prepared in 70% (204 mg) yield as described in general procedure (N) from 4-{1-cyclohexyl-3-[5-(4-dimethylsulfamoyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium; chloride (275 mg) and butyryl chloride (64 mg, 0.6 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[O:14][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A solution of methyl 5-nitrosalicylate (10.0 g, 50.7 mmol) and imidazole (3.8 g, 55.8 mol) in DMF (50 mL) at 0° C. was treated with t-butylchloro-dimethyl-silane and stirred 16 h at room temperature. The reaction mixture was poured into water (100 mL) and extracted with ether (3×50 mL). The combined extracts were washed with water (4×100 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated. The crude residue was purified by flash chromatography (silica gel, 4×15 cm, eluted with 95/5 hexanes/EtOAc) to yield 2-(tert-butyl-dimethyl-silanyloxy)-5-nitro-benzoic acid methyl ester as a white solid (4.9 g, 31%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14](=O)[CH:15]([CH3:20])[CH2:16]C(O)=O.O.[NH2:23][NH2:24].[CH2:25]([OH:27])C>>[OH:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]1[CH:15]([CH3:20])[CH:16]=[N:24][NH:23][C:25]1=[O:27]
Reactant: CCO
Reactant: NN
Reactant: Cc1nn(-c2ccccc2)c(O)c1C(=O)C(C)CC(=O)O
Solvent: O
Product: Cc1nn(-c2ccccc2)c(O)c1C1C(=O)NN=CC1C

Procedure:
4.5 g (0.016 mole) of 4-(4-(5-hydroxy-3-methyl-1-phenylpyrazolyl)-4-oxo-3-methyl-butyric acid and 1.5 ml (0.031 mole) of hydrazine hydrate are heated under reflux in 30 ml of ethanol for 1 hour. After the mixture has been concentrated, the residue is boiled up with isopropanol, the mixture is filtered and the product which has crystallised out is separated off.
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH:3]1[O:8][CH:7]([C:9](Cl)([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17](Cl)=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>>[Cl:10][C:9]([Cl:11])=[C:7]1[C:6]2[CH:13]=[C:14]([C:17]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4][CH:3]([C:2]([Cl:20])([Cl:21])[Cl:1])[O:8]1
Reactant: O=C(Cl)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccc2c(c1)C(=C(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carbonyl chloride (2 g.) and diethylamine (25 ml.) was heated under reflux for 2 hrs., cooled, and filtered to remove diethylamine hydrochloride. The filtrate was evaporated to dryness under reduced pressure, and the residue was crystallised from ethanol to give 4-dichloromethylene-N,N-diethyl-2-trichloromethylbenzo[1,3]dioxin-6-carboxamide, m.p. 123°-124° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=3[F:27])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=3[F:27])[CH:13]=[N:12]2)[C:8]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1F

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,6-difluoro-3-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 84) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-3-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as a light yellow solid as a mixture of diastereomers (503.6 mg, 48%).
Reaction SMILES: Cl.C([NH:21][C@H:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([O-:33])=[O:32])=[C:26]([CH2:29][CH3:30])[CH2:27][S:28][C@H:23]12)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+](C)([O-])=O>[NH2:21][C@H:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH2:29][CH3:30])[CH2:27][S:28][C@H:23]12
Reactant: CCC1=C(C(=O)[O-])N2C(=O)[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: CCC1=C(C(=O)O)N2C(=O)[C@H](N)[C@H]2SC1

Procedure:
A current of gaseous hydrochloric acid was passed through a mixture of 527 mg of tert.-butyl DL cis 7-tritylamino-3-ethyl-3-cepheme-4-carboxylate in 10 ml of nitromethane at 0°C for 15 minutes and the mixture was evaporated to dryness under reduced pressure. The residue was taken up in ether and the solution was vacuum filtered. The recovered precipitate was dissolved in one ml of water and pyridine was added to adjust the pH to 4. The mixture was vacuum filtered and the precipitate was washed with water, then acetone and ether and dried to obtain 185 mg of DL cis 7-amino-3-ethyl-3-cepheme-4-carboxylic acid melting above 250°C. The product occurred in the form of colorless crystals slightly soluble in water and ethanol and insoluble in ether and acetone.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22].O>ClCCl>[CH3:19][N:20]([CH3:24])[C:21]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)=[O:22]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)N(C)C)CC1
Reaction time: 18 h

Procedure:
Ethyl isonipecotate (31.44 g, 200 mmol) and triethylamine (50.2 ml, 360 mmol) were dissolved in dichloromethane (200 ml), and under ice cooling, to the solution was added dropwise N,N-dimethylcarbamoyl chloride (27.6 ml, 300 mmol). The mixture was stirred for 18 hours while the temperature was elevating to room temperature. To the reaction mixture was added water (100 ml) under ice cooling, and the organic layer was taken by separatory funnel. The aqueous layer was extracted with dichloromethane (50 ml×2) and the extracts were mixed with the organic layer. The combined organic layer was washed with 1N-hydrochloric acid (100 ml×3), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (51.30 g, It was proved that N,N-dimethyl carbamoyl chloride is contained about 10 wt % by 1H NMR.) as a pale brown oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:20].[ClH:21]>C(O)C.[Ni]>[Cl-:21].[CH3:19][CH:17]([NH3+:20])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: Cl
Reactant: N
Reactant: CC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Ni]
Solvent: CCO
Product: CC([NH3+])CCc1ccc(OCc2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 40.0 g of methyl 2-(4-benzyloxyphenyl)ethyl ketone and 160 ml of anhydrous ammonia in 300 ml of ethanol was heated at 75° C. and stirred for two hours. After cooling the reaction mixture to room temperature, 4.0 g of Raney nickel was added in one portion, and the reaction mixture then was stirred at 25° C. for twelve hours under a hydrogen atomsphere at 300 psi. The reaction mixture next was filtered and the filtrate was concentrated by evaporation of the solvent under reduced pressure to provide an oil. The oil was dissolved in 120 ml of 3N hydrochloric acid, from which the product as a hydrochloride salt precipitated. The salt so formed was collected by filtration and recrystallized from methanol and toluene to provide 36.2 g of dl-1-methyl-3-(4-benzyloxyphenyl)propylaminium chloride. M.P. 195°-197.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([CH3:11])(O)[CH3:9])[CH:7]=1.[CH2:14]([O:16][C:17](=[O:25])[C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH3:15].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:14]([O:16][C:17](=[O:25])[C:18](=[O:19])[CH2:20][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13])([CH3:11])[CH3:9])[CH3:15]
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Reactant: COc1ccc(Br)cc1C(C)(C)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cc(Br)ccc1OC
Reaction time: 0.33 h
Yield: 37.9 %

Procedure:
9.8 g of 1-(5-bromo-2-methoxyphenyl)-1-methylethanol and 15.24 g of 2-(trimethylsilyloxy)-acrylic acid ethyl ester in 150 ml of dichloromethane are mixed at −70° C. with 5.6 ml of tin tetrachloride. After 20 minutes at −70° C., the solution is poured onto a semi-saturated potassium carbonate solution and mixed with dichloromethane. The dichloromethane phase is washed with potassium carbonate solution, 1 M hydrochloric acid and water, dried (Na2SO4) and concentrated by evaporation. After bulb tube distillation, 5.2 g of 4-(5-bromo-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid-ethyl ester is obtained. Boiling point: 160° C./0.04 hPa.