Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28](O)=[O:29])[CH:21]=[CH:22][CH:23]=1.S(Cl)(Cl)=O>>[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28]([N:1]([CH2:8][C:9]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CNc1ccccc1)OCC(F)(F)F
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OCC(F)(F)F)c2ccccc2)c1
Yield: 14.4 %

Procedure:
The procedure is carried out in a manner analogous to that described in Example 1, but using 2.3 g of 2,2,2-trifluoroethyl 2-anilinoacetate, 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 0.7 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 40 g of silica (0.063-0.200 mm) contained in a column 1.5 cm in diameter [eluent: methylene chloride/ethanol (98/2 by volume)], collecting 10-cm3 fractions. Fractions 5 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diisopropyl ether, 0.6 g of 2,2,2-trifluoroethyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 172° C. is obtained.
Reaction SMILES: [Cl-].[C:2]1([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([CH:44]=O)[CH2:40][CH2:39]1>CCOCC>[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([CH:44]=[CH:12][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:40][CH2:39]1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CN1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1CCC(C=Cc2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, a 250 mL three-necked round bottomed flask was fitted with a reflux condenser, an addition funnel and a gas inlet tube. A gentle flow of nitrogen was maintained throughout the reaction. To a stirred suspension of 1-naphthylmethyltriphenylphosphonium chloride (4.39 g, 0.01 mole) in 125 mL of anhydrous ether was added, dropwise through a syringe at 0°, an ethereal solution of n-butyllithium (3.85 mL of a 2.6M solution in hexanes). After the addition, the solution was stirred at room temperature for 2 hours as an orange-yellow precipitate formed. A solution of 1-methylpiperidine-4-carboxaldehyde (1.27 g, 0.01 mole) in 25 mL of ether was added dropwise. The reaction mixture became colorless and a white precipitate separated. The mixture was heated under reflux overnight, allowed to cool to room temperature, and the precipitate was removed by filtration. The precipitate was washed with 2×50 mL portions of ether. The combined ethereal filtrates were washed with 3×50 mL portions of water until the washings were neutral. The organic solution was dried (MgSO4) and evaporated in vacuo. The residue was dissolved in petroleum ether and the small amount of triphenyl phosphine oxide (0.1 g) that precipitated was removed. The petroleum ether solution was concentrated to give 1-methyl-4-(1-naphthylvinyl)piperidine as a thick syrup. (1.822 g, 73%): IR (KBr) 3060, 3040, 3000, 2940, 2850, 2780, 2740, 2680, 1920 (W), 1800 (W), 1725 (W), 1640 (W), 1590, 1510, 1465, 1445, 1380, 1280, 1200, 1140, 1120, 1070, 970, 850, 780, 720 and 700 cm-1 ; NMR (CDCl3) δ1.70 (m, 5H), 1.33 (m, 2H), 2.20 (s, 3H), 2.68 (m, 2H), 6.13 (d.d, J=6 Hz, 2H), and 7.40 (m, 7H). The strong absorption at 970 cm-1 in the IR spectrum and the NMR peak at δ6.13 indicated that the major product was the trans-naphthylvinylpiperidine. Gas chromatographic analysis showed that the product contained 87.3% of the trans and 12.7% of the cis isomer.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]=1[OH:15].C(N(CC)CC)C.[P:23](=[O:32])(Cl)([S:27][CH2:28][CH2:29][CH3:30])[O:24][CH2:25][CH3:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:23](=[O:32])([S:27][CH2:28][CH2:29][CH3:30])([O:15][C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=1)[O:24][CH2:25][CH3:26]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: Oc1ccc2cc3ccccc3cc2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCSP(=O)(OCC)Oc1ccc2cc3ccccc3cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Anthrol (3.0 grams; 0.015 mole), triethylamine (2.1 ml) and toluene (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to about 0° C. and O-ethyl S-propyl phosphorochloridothioate (3.01 grams; 0.015 mole) dissolved in toluene (38 ml) was added with stirring over a period of about 1/2 hour. After the addition was completed stirring was continued at room temperature overnight. After this time the reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate stripped of solvent leaving solid residue. This residue was subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-ethyl O-(2-anthryl) S-propyl phosphorothioate as a light tan solid melting at 79° to 83° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][CH2:4]1.CC1C=CC(S(O[CH2:30][C@@H:31]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][N:32]2[S:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)(=[O:43])=[O:42])(=O)=O)=CC=1.[Cl-].[NH4+]>CC(OC)(C)C>[CH3:50][C:47]1[CH:48]=[CH:49][C:44]([S:41]([N:32]2[C@H:31]([CH2:30][CH:10]([C:9]([N:6]3[CH2:5][CH2:4][O:3][CH2:8][CH2:7]3)=[O:18])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)(=[O:42])=[O:43])=[CH:45][CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3ccccc3CN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)N1CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CC(C(=O)OC(C)(C)C)C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1 g of NaH (60%) (25.08 mmol) in 30 mL of MTBE there are added, dropwise, a solution of 5 g of tert-butyl 3-morpholino-3-oxopropanoate (21.81 mmol) in 20 mL of anhydrous MTBE. This suspension is stirred at ambient temperature for 1 hour and then the compound obtained in Step A is added in the form of a powder. The batch is stirred at 60° C. for 30 hours. 100 mL of saturated aqueous ammonium chloride solution are added. The resulting solution is extracted with dichloromethane. The organic phase is then dried over MgSO4, filtered and concentrated to dryness. After purification by chromatography over silica gel (dichloromethane/MeOH gradient), the expected product is obtained in the form of an oil.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:43]1[C:44]([CH:56]2[CH2:58][CH2:57]2)=[CH:45][C:46]([O:53][CH2:54][CH3:55])=[C:47]([CH:52]=1)[C:48]([O:50][CH3:51])=[O:49]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:56]1([C:44]2[C:43]([CH:1]3[CH2:3][CH2:2]3)=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:46]([O:53][CH2:54][CH3:55])[CH:45]=2)[CH2:58][CH2:57]1
Reactant: OB(O)C1CC1
Reactant: CCOc1cc(C2CC2)c(Br)cc1C(=O)OC
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1cc(C2CC2)c(C2CC2)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
Cyclopropylboronic acid (1.76 g), a 2 M aqueous sodium carbonate solution (20 mL), tris(dibenzylideneacetone)dipalladium(0) (874 mg), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (840 mg) were added at room temperature to a toluene (70 mL) solution of methyl 5-bromo-4-cyclopropyl-2-ethoxybenzoate (4.08 g), and the mixture was stirred at 100° C. for 18 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.27 g).
Reaction SMILES: N.C([O:5][CH2:6][CH2:7][CH2:8][CH:9]([F:17])[CH2:10][CH2:11][CH2:12][O:13]C(=O)C)(=O)C>CO>[F:17][CH:9]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:7][CH2:6][OH:5]
Reactant: CC(=O)OCCCC(F)CCCOC(C)=O
Agent: N
Solvent: CO
Product: OCCCC(F)CCCO
Temperature: 25 °C
Reaction time: 28 h
Yield: 99.8 %

Procedure:
Methanol (15 ml) saturated with anhydrous NH3 gas was added to acetic acid, 7-acetoxy-4-fluoro-heptyl ester (500 mg, 2.13 mg) contained in round-bottomed flask closed by glass stopper. The mixture was allowed to stir for over 28 hours at room temperature and then concentrated. Purification of the residue by column chromatography on silica gel, using 5% methanol in CH2Cl2, gave the title compound (320 mg, 100%) as pure colorless oil. 1H NMR (CDCl3) δ 1.59–1.83 (m, 8H), 3.67 (t, 4H, J=5.7 Hz), 4.47–4.67 (m, 1H); 13C NMR (CDCl3) δ 28.73, 28.75, 31.78, 32.06, 62.88, 93.56, 95.98; ES-MS m/z 173.2 (M+Na).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][C:19]=1[CH3:44]>O1CCCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][C:19]=1[CH3:44]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(C(=C(C=CC=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)c(C)c1)c1ccc(F)c(C)c1)c1nnnn1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A solution of the dianion of ethyl acetoacetate (1.42 mL, 11.1 mmoles) in dry tetrahydrofuran (15 mL) was generated as described in Example 10 using 450 mg (11.3 mmoles) of NaH (60% in mineral oil) and 4.5 mL (11.1 mmoles) of 2.5M n-BuLi in hexane at 0° C. under argon. The orange dianion solution, after being chilled to -78° C., was transferred via a cannula into a tetrahydrofuran (15 mL) solution containing 5,5-bis(4-fluoro-3-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (2.12 g, 5.6 mmoles) at -78° C. The reaction mixture was stirred at -78° C. for 15 minutes. Analytical TLC eluted once with 50% (v/v) ethyl acetate in hexanes showed a major product at Rf =0.16. The reaction mixture was diluted with 20 mL of 1N HCl and the organic residues were extracted with ethyl acetate (30 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give a pale syrup. The crude product was chromatographed on a silica gel column eluted with 35% (v/v) ethyl acetate in hexanes to give 1.39 g (48.7%) of the title compound. MS (CI): m/e=511 for (M+H)+ ;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1>C(O)C>[CH:17]1([CH2:20][NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH2:19][CH2:18]1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CC1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c([N+](=O)[O-])c1
Yield: 54.6 %

Procedure:
A mixture of 1-chloro-4-(isopropylsulfonyl)-2-nitrobenzene (Step C, 849 mg, 3.2 mmol), and cyclopropylmethylamine (333 μL, 3.8 mmol) in ethanol (15 mL) was stirred under reflux for 16 h. After removal of solvent, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1 as eluent) to afford the title compound (521 mg, 55%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].Br[C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:28]1[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:1]([NH:5][CH2:6][C:7]1[S:11][C:10]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:29][CH2:30][N:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])[CH2:32][CH2:33]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCCCNCc1ccc(B(O)O)s1
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: [K+]
Product: CCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 24 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), butylamine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 49 mg of crude {5-[(butylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(butylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 27.2 mg of the title compound (24%).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH3:20])[N:14]=1)C.[OH-].[Na+].Cl>CO.O>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH2:5][C:4]([OH:27])=[O:3])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(CCCCCCc1cccc(NC)n1)c1cncnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1cccc(CCCCCCC(CC(=O)O)c2cncnc2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 6-13a (0.215 g, 0.580 mmol) in TBf/MeOH/H2O 3:1:1 (10 mL)) was added NaOH (1.16 mL of 1N solution in water, 1.16 mmol). After 30 minutes, the mixture was neutralized with HCl (1.16 mL of 1N solution in water, 1.16 mmol) and the solvents were evaporated. The residue chromatographed on silica gel (15% MeOH/CHCl3) to give 6-14a as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6](=O)[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O.[NH2:21][C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>C(O)(=O)C>[C:27]([C:26]1[CH:30]=[C:22]([N:21]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=[C:6]2[C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=2)[CH:23]=[CH:24][C:25]=1[OH:31])([OH:29])=[O:28]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3cccc(C(F)(F)F)c3)cc3c2CCCC3)ccc1O

Procedure:
A mixture of 12.0 g. (0.042 mole) of 2-(m-trifluoromethylphenacyl)cyclohexanone, 6.45 g. (0.042 mole) of 5-aminosalicylic acid, and 30 ml. of glacial acetic acid was heated under reflux for 4 hours and filtered. The filtrate was diluted with water and the supernatant was decanted from the oil which separated. Trituration with cyclohexane gave 7.7 g. of solid, m.p. 215°-225°. Recrystallization from isopropyl alcohol-water afforded 4.1 g. (47%) of crystals, m.p. 223°-225°.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13]>CN(C)C=O>[C:1]([N:17]1[CH2:18][CH2:19][N:14]([CH:12]=[O:13])[CH2:15][CH2:16]1)(=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: O=CN1CCNCC1
Solvent: CN(C)C=O
Product: O=CN1CCN(C(=O)C=Cc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 50 %

Procedure:
trans-Cinnamic acid (1.48 g) and N-formylpiperazine (2.28 g) were dissolved in N,N-dimethylformamide (20 mL), and the atmosphere was purged with nitrogen. While the solution was stirred in an ice-water bath, triethylamine (2.53 g) and diphenylphosphoryl azide (5.78 g) were added thereto, and stirring was continued for 1 hour and 45 minutes. The reaction mixture was poured in a mixture of ice and saturated sodium hydrogencarbonate solution, followed by extraction twice with ethyl acetate. The organic layers were combined and sequentially washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate solution, and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure, and the residue (colorless, oily) was purified through silica gel chromatography (silica gel 45 g, eluent; chloroform:methanol=200:1-100:1). The thus-purified product was dissolved in ethyl acetate, and the solution was sequentially washed with saturated sodium hydrogencarbonate solution and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby yield 1.22 g of the product of interest as a colorless oil (yield 50.0%).
Reaction SMILES: C([NH:3][CH:4]1[C:36](=[O:37])[N:6]2[C:7]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][S:10][C@H:5]12)=O.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[NH2:3][CH:4]1[C:36](=[O:37])[N:6]2[C:7]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Yield: 79.1 %

Procedure:
To a suspension of benzhydryl 7-formamido-3 -[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (69.8 g) in methanol (350 ml) was added conc. hydrochloric acid (40.7 ml). The mixture was heated at 30°-35° C. for 2 hours. The mixture was poured into a mixture of ethyl acetate (2 l) and water (1 l) and adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo to a crystal. The crystal was washed with diethyl ether to give benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (52.3 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCO.C[O-].[Na+]>CO.[Pd]>[CH3:13][O:12][C:10]1[C:9]([O:14][CH3:15])=[C:8]2[C:3]([CH2:4][CH2:5][NH:6][CH:7]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:2][CH:11]=1
Reactant: COc1cc(Br)c2c(c1OC)C(c1ccccc1)=NCC2
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1ccc2c(c1OC)C(c1ccccc1)NCC2
Yield: 100 %

Procedure:
A solution of 5-bromo-7,8-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (450 mg), EtOH (30 mL), 10% palladium-supported carbon (80 mg) and 28% sodium methoxide in MeOH (0.1 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The insoluble materials were subjected to filtration and the filtrate was concentrated to obtain 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg).
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][P:11]=[O:12]>CO>[OH:9][C:2]([P:11]([OH:12])[OH:10])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=PO
Reactant: CCCCCCC(C)=O
Solvent: CO
Product: CCCCCCC(C)(O)P(O)O
Temperature: 25 °C

Procedure:
A mixture of octan-2-one (3.76 g, 0.29M) and hypophosphorus acid (91.5%, 2.09 g, 0.029M) is heated at 100° C. for 12 hours in the presence of Dowex 50W x 2 ion exchange resin (1 ml, aqueous slurry). The mixture is cooled to room temperature, methanol (50 ml) is added and the Dowex is removed by filtration. The filtrate is evaporated to an oily residue, which is dissolved in ethyl acetate, washed with water, brine, then dried (MgSO4). Removal of the solvent gives 1-hydroxy-1-methylheptylphosphonous acid.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([CH2:19][O:20][C:21]2[CH:50]=[CH:49][C:24]([C:25]([N:27]4[CH2:48][CH2:47][C:30]5([NH:34]/[C:33](=[N:35]/[C:36]([C:38]6[C:43]([NH2:44])=[N:42][C:41]([NH2:45])=[C:40]([Cl:46])[N:39]=6)=[O:37])/[NH:32][CH2:31]5)[CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:22]=2)[CH:13]=[CH:12]3)[CH2:4][O:3]1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][O:20][C:21]1[CH:50]=[CH:49][C:24]([C:25]([N:27]3[CH2:28][CH2:29][C:30]4([NH:34]/[C:33](=[N:35]/[C:36]([C:38]5[C:43]([NH2:44])=[N:42][C:41]([NH2:45])=[C:40]([Cl:46])[N:39]=5)=[O:37])/[NH:32][CH2:31]4)[CH2:47][CH2:48]3)=[O:26])=[CH:23][CH:22]=1)[CH:13]=[CH:12]2
Reactant: CC1(C)OC[C@@H](COc2ccc3cc(COc4ccc(C(=O)N5CCC6(CC5)CN/C(=N\C(=O)c5nc(Cl)c(N)nc5N)N6)cc4)ccc3c2)O1
Solvent: CO
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4ccc(OCc5ccc6cc(OC[C@@H](O)CO)ccc6c5)cc4)CC3)N2)nc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [8-{4-[6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoyl}-1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (0.16 g, 0.22 mmol) in MeOH (10 ml) is added SCX-2 resin (˜2 g), the resultant slurry is stirred for 0.5 hours and then the solvent is removed in vacuo. The slurry is loaded onto a column of SCX-2 resin (˜3 g) and eluted with MeOH and then with 2 M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and the residue is triturated with diethyl ether to obtain 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [8-{4-[6-((S)-2,3-dihydroxy-propoxy)-naphthalen-2-ylmethoxy]-benzoyl}-1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide as yellow solid; [M+H]+ 675
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=NC2C=CC=CC=2)=[CH:13][CH:12]=1>CCOCC>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[N+:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O-:9])=[CH:13][CH:12]=1
Reactant: Clc1ccc(C=Nc2ccccc2)cc1
Reactant: ONc1ccc(F)cc1
Solvent: CCOCC
Product: [O-][N+](=Cc1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
N-p-fluorophenylhydroxylamine (0.052 moles) was dissolved in ether (20 cc). This solution was treated with N-p-chlorobenzylideneaniline (0.05 moles) and dissolved in ether (50 cc). The product which separated was filtered and washed with ether to give α-p-chlorophenyl-N-p-fluorophenylnitrone.