Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]([C:22]([CH3:28])([CH3:27])[C:23]([O:25]C)=O)=[C:19](O)[N:20]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:39]>C(#N)C>[F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]3[C:22]([CH3:28])([CH3:27])[C:23](=[O:25])[NH:39][C:19]=3[N:20]=2)=[N:6]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3cccc(F)c3F)c3nc(C)ncc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncc2c(-c3nnc4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
160 mg (purity 89%, 0.313 mmol) of methyl 2-{3-[1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 4 ml (42.913 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 20 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 40 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. The residue was stirred with hot ethanol/water and filtered with suction, and the solids were dried under high vacuum. 70 mg of the target compound were obtained (52% of theory).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH2:1]([NH:5][S:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)(=[O:23])=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of isobutylamine (5 mL, 0.052 mol) in CH2Cl2 (100 mL) was added Et3N (5.07 mL) and 4-nitrobenzenesulfonyl chloride (11.7 g, 0.052 mol) and the mixture was stirred at room temperature overnight. The resulting solution was washed with H2O (3×), dried and concentrated to afford the desired product (9.41 g, 70%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].[Cl:12][CH:13]=[CH:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:12]/[CH:13]=[CH:14]/[CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH2:1][CH3:2]
Reactant: ClC=CCCl
Reactant: CCNCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCN(C/C=C/Cl)Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 34.96 g (0.231 moi) of N-ethyl-3-hydroxybenzylamine in 200 ml of dimethylsulfoxide were added 25.64 g (0.231 mol) of 1,3-dichloropropene (E/Z=2/1) and 16.7 g (0.121 mol) of ground potassium carbonate under ice cooling. The mixture was stirred for 4 hours at 50° C., poured into 250 ml of ethyl acetate, washed with 200 ml ×2 of water and 200 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to-silica gel chromatography (n-hexane→n-hexane/ethyl acetate =9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 26.2 g (yield: 50%) of the above identified compound as an oil.
Reaction SMILES: C(OC([N:6]=[S@@:7]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])[C:22]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[CH:21][N:20]=2)=[CH:14][CH:13]=1)([CH:9]1[CH2:11][CH2:10]1)=[O:8])=O)C.CC[O-].[Na+]>>[OH:28][CH2:27][C@H:26]([NH:25][C:23]1[C:22]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:21][N:20]=[C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([S@@:7]([CH:9]3[CH2:11][CH2:10]3)(=[NH:6])=[O:8])=[CH:13][CH:14]=2)[N:24]=1)[CH3:29]
Reactant: CCOC(=O)N=[S@@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Agent: CC[O-]
Agent: [Na+]
Product: C[C@H](CO)Nc1nc(Nc2ccc([S@@](=N)(=O)C3CC3)cc2)ncc1-c1cccs1
Yield: 63 %

Procedure:
In the reaction of (S)—N-(ethoxycarbonyl)-S-(4-{[4-{[(R)-2-hydroxy-1-methylethyl]-amino}-5-(2-thienyl)pyrimidine-2-yl]amino}phenyl)-S-cyclopropylsulfoximide with sodium ethylate according to procedure 14, the desired product is obtained in 63% yield after chromatographic purification (silica gel, dichloromethane/ethanol (0-10% ethanol)).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:29]=1[O:30][CH3:31])[C:24]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:25]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (442 mg) and 37% formalin (0.29 mL) in the same manner as in Example 1 was dissolved in chloroform (8 mL), and triethylamine (0.49 mL) and 3-chloro-4-methoxy-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (f).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([NH2:14])=O)=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:16][CH3:17].N1C(Cl)=NC(Cl)=NC=1Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]#[N:14])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc2c(=O)c(C(N)=O)c[nH]c2cc1F
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)c(C#N)c[nH]c2cc1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 7-fluoro-6-methoxy-4-oxo-1,4,-dihydro-3-quinolinecarboxamide (700 mg, 3.0 mmol) and cyanuric chloride (341 mg, 1.65 mmol) in 15 mL of N,N,-dimethylformamide is heated at 65° C. for 6 hours then cooled to room temperature and an additional 206 mg of cyanuric chloride is added. The mixture is heated at 65° C. for 4 hours then stirred overnight at room temperature. The reaction mixture is poured into ice water and neutralized with saturated sodium bicarbonate. The solids are collected by filtration washing with water and hexane to provide 610 mg of crude product. Purification by flash column chromatography eluting with a gradient of 3% methanol in dichloromethane to 10% methanol in dichloromethane, provides 272 mg of 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarbonitrile, mp 147-149° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:29][CH2:28][CH2:27]4)=[C:21]([CH:25]=3)[C:22](O)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C[CH2:32][N:33]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CN>CN(C=O)C.C(OCC)(=O)C.CO.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH3:30])=[CH:19][C:20]([CH:26]4[CH2:27][CH2:28][CH2:29]4)=[C:21]([CH:25]=3)[C:22]([NH:33][CH3:32])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(C2CCC2)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)c(C)cc1C1CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
To a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoic acid (compound 234, 50 mg, 0.124 mmol) in DMF (2 mL) were added EDCI (36 mg, 0.186 mmol), HOBt (10 mg, 0.5 mmol), diisopropylethyl amine (54 mg, 0.434 mmol), and methyl amine (125 ul, 2.5 M in THF). The reaction mixture was stirred for 12 hours at room temperature and quenched with saturated aqueous NaHCO3 (50 mL). After extraction with ethyl acetate (2×50 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification via SiO2 flash chromatography with ethyl acetate to ethyl acetate/methanol=98/2 afforded 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide (28.3 mg, 55% yield) as a white solid. m/z (ES+) 416 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 8.13 (q, J=4.5 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.55-7.45 (m, 2H), 7.26 (br s, 1H), 7.12 & 6.99 (2 singlets, amide rotamers, Ar—H, 1H), 4.70 (br d, J=11.9 Hz, 1H), 3.86-3.72 (m, 1H), 3.50-3.35 (m, 1H), 3.13 (t with fine structure, J=12.3 Hz, 1H), 2.99-2.78 (m, 2H), 2.72 (d, J=4.6 Hz, 3H), 2.39-2.17 (m, 5H), 2.17-1.98 (m, 2H), 1.98-1.81 (m, 2H), 1.81-1.35 (m, 4H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O.O>[OH:13][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 3-aminobenzenesulfonamide (2.35 g, 13.6 mmol) in 30% sulfuric acid (18 mL) stirred in a 0° C. ice-water bath was added dropwise a solution of sodium nitrite (1.22 g, 17.7 mmol) in water (10 mL). The resulting reaction solution continued to stir in an ice-water bath for 30 min. The solution was then stirred in a 100° C. oil bath for 30 min. After cooling to room temperature, the reaction solution was partitioned between ethyl acetate and brine. After shaking, the aqueous phase was extracted with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate, filtered, and concentrated to a yellow solid (2.11 g, 89% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[K+].CO>O>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCC(F)(F)F
Yield: 98 %

Procedure:
To 160 g of ethyl 4,4,4-trifluorobutyrate, a mixed solution of 123 g of potassium hydroxide, 900 ml of methanol and 80 ml of water was added under ice cooling and the mixture was further reacted at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was then partitioned between water and diethyl ether. The ether layer was extracted once with water and the water layer was combined with the aqueous layer which had already been partitioned. After adjusting the pH to about 1 by the addition of an aqueous 10% ice-cooled hydrochloric acid solution, the mixture was extracted three times with diethyl ether. The layers were combined and the combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 131 g of 4,4,4-trifluorobutyric acid (yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[N:6]1[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])=[O:4].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:16]2([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4]
Reactant: COC(=O)C1Cc2ccc(OC)cc2N1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(OC)cc2n1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the solution of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid methyl ester (0.65 g, 1.31 mmol) in 10 mL toluene was added DDQ (0.51 g, 2.23 mmol). The reaction mixture was stirred at room temperature for 6 hour. And the mixture was washed with water (3×10 mL). The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was purified with chromatography to give white solid. MS: 495 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:27])([F:26])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:8].CO>C(Cl)Cl>[F:27][C:6]([F:5])([F:26])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1cccs1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCc2cc(O)ccc2C1c1cccs1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.66 ml, 0.66 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-(6-methoxy-1-thiophen-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (0.150 g, 0.439 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The resulting red solution was stirred at 0° C. for 30 min, then warmed to rt and stirred at rt for 20 hr. MeOH (5 ml) was slowly added to the reaction mixture with stirring and the resulting solution was concentrated in vacuo to give 0.138 g of a black residue. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.006 g (4% yield) of white solid.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8](=[O:33])[C:9]([CH3:32])=[C:10]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[O:11]2)=[CH:6][CH:5]=1>CO>[OH:3][C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([C:8](=[O:33])[C:9]([CH3:32])=[C:10]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=4)[CH2:17][CH2:16]3)[O:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CN2CCC(c3oc4c(C)c(O)ccc4c(=O)c3C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C2CCN(Cc3ccc(C(=O)O)cc3)CC2)oc2c(C)c(O)ccc2c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A 1 N aqueous sodium hydroxide solution (4 mL) was added to a solution of methyl 4-{[4-(7-hydroxy-3,8-dimethyl-4-oxo-4H-chromen-2-yl)piperidin-1-yl]methyl}benzoate (140 mg, 0.33 mmol) obtained in Example 23-1 in methanol (4 mL), and the mixture was heated with stirring at a bath temperature of 50° C. for 4 hours. Methanol in the reaction solution was distilled off under reduced pressure. Then, a 1 N aqueous hydrochloric acid solution (4 mL) and water (10 mL) were added to the residue, and insoluble matter was collected by filtration to obtain 125 mg of the title compound (yield: 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[S:35])[NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1
Reactant: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: S=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Temperature: 85 °C
Yield: 116 %

Procedure:
A solution of 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (10 g, 0.023 mol) in anhydrous 1,4-dioxane (400 mL) was treated with Lawesson's reagent (7.44 g, 0.018 mol) and heated at 85° C. for 4 h. The orange solution was cooled to room temperature and concentrated in vacuo. The crude product was washed with CH2Cl2 and then dried to give 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbothioamide as a yellow solid (9.41 g, yield 91%). ESI-MS: 449.9.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[K+:44]>C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:27]([O-:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+:44]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C([O-])C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A mixture of 2.88 g of the said ester and 4.3 ml of dioxane was stirred under an inert atmosphere at room temperature until dissolution occured and then 30.6 ml of a solution of 0.5 M potassium hydroxide in ethanol were added thereto over 3 minutes at 20°-25° C. The mixture was stirred at room temperature under an inert atmosphere for 24 hours and after 2 or 3 hours a potassium salt crystallized. The mixture was vacuum filtered at room temperature and the recovered product was rinsed with 1 ml of ether and 3 times with 2 ml of methylene chloride to obtain 1.6 g of the syn isomer of potassium 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].N(OC(C)C)=O.[C:33]1([CH:39](N)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C.CC(N(C)C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CC(C)ON=O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 3 h

Procedure:
3-Acetoxymethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylic acid (3.96 g, 10 m.moles) was dissolved in acetonitrile (50 ml) and dimethylacetamide (5ml). To this solution was added a mixture of isopropyl nitrite (2.4 g, 27 m.moles) and diphenylmethylamine (2.21 g, 12 m.moles) dissolved-suspended in acetonitrile (20 ml). The resulting slurry was stirred for 3 hours at 35°, after which time a solution resulted. The solvents were removed in vacuo and the gum redissolved in chloroform (50 ml). The resulting solution was washed with 5% sodium bicarbonate solution (50 ml), then water (50 ml) and the chloroform removed in vacuo. The gum was crystallised from hot isopropyl alcohol (28 ml), the crystals washed with cold isopropyl alcohol (25 ml) and then dried in vacuo at room temperature to give the title compound. Yield 3.19 g (56.8% based on the input acid); m. pt. and mixed m. pt. 140° - 140.5° with an authentic sample of the ester. The bicarbonate extract was washed with ethyl acetate (10 ml) and then acidified with 2N sulphuric acid at 5° to pH 1.2. The suspension was stirred for 30 minutes, filtered and washed with cold water (70 ml). The recovered starting material was dried in vacuo at room temperature, (0.9 g, single spot on t.l.c. by u.v. detection).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=O.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:8]
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.7 %

Procedure:
(R)-2-(Cyclohexylmethyl)succinic acid 1-methyl ester (1.00 g, 4.38 mmol) was dissolved in 10 mL of DMF and cooled to 0° C. with an ice-water bath. EDC (1.12 g, 5.69 mmol) then 1-hydroxybenzotriazole (0.77 g, 5.69 mmol) were added and stirring continued, under argon, for 25 min. Morpholine (0.76 mL, 8.76 mmol) was added and stirring was continued overnight (16 h). The solution was diluted with 200 mL of EtOAc and washed with a 1.0 M solution of HCl (3×100 mL), a saturated solution of NaHCO3 (3×100 mL), water (100 mL), then with brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated by rotary evaporation to give (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid 1-methyl ester (1.26 g, 99%) as a white solid. The product was used in the following step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: Nc1ccccn1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)Nc3ccccn3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Yield: 1.7 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 120 mg, 0.317 mmol) and 2-aminopyridine (448 mg, 4.76 mmol) in 5 mL of DCM at 0° C. was added 244 μL (3.17 mmol) of TFA. The mixture was allowed to warm to room temperature, at which time it was cooled in an ice bath and filtered. The filtrate was concentrated in vacuo with MeOH (10 mL) and purified by preparative thin layer chromatography ((2×) with 10% MeOH—CHCl3) to afford 2.5 mg (2%) of the title compound as a white solid. 1H-NMR (CDCl3-CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.6 Hz), 7.88 (m, 1H), 7.64 (s, 1H), 7.29 (m, 1H), 7.18 (d, 1H, J=2.0 Hz), 7.16-7.11 (m, 1H), 7.47-7.44 (m, 1H), 5.81 (d, 1H, J=8.6 Hz), 5.66 (m, 1H), 2.16-2.13 (m, 2H), 1.99 (m, 2H), 1.59 (s, 6H), 1.52-1.44 (m, 2H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H30N6O 455.2 (M+H). found 455.1.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:19]=[C:14]1[N:13]([CH2:12][CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[C:2](=[O:1])[O:3][CH2:4][C:5]=3[CH:10]=2)[CH2:18][CH2:17][N:16]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:15]1
Reactant: O=C1OCc2cc(CCN3CCNCC3=O)ccc21
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3)COC4=O)C(=O)C1)C2

Procedure:
The title compound was prepared from 1-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 416 [M+1]+.