Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[O:38]1[C:42]([NH2:43])=[CH:41][CH:40]=[N:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:43][C:42]3[O:38][N:39]=[CH:40][CH:41]=3)(=[O:24])=[O:25])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: Nc1ccno1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccno3)ccc21
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (44.1 mg, 0.080 mmol), isoxazol-5-amine (10.1 mg, 0.12 mmol, Matrix Scientific, Columbia, S.C.) and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (168 μl, 0.168 mmol) was added dropwise over 30 s to give a light-yellow solution. After 10 min, the flask was lowered into an ice bath for 45 min. Glacial acetic acid (1 drop) was added, and the mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(isoxazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (25.2 mg, 0.056 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.18 (br. s., 1 H), 8.42 (d, J=2.1 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H), 8.11 (dd, J=2.0, 8.9 Hz, 1 H), 7.76 (d, J=8.6 Hz, 1 H), 7.30 (d, J=2.2 Hz, 1 H), 7.23 (dd, J=2.2, 8.7 Hz, 1 H), 6.80 (d, J=8.6 Hz, 1 H), 5.77 (d, J=1.9 Hz, 1 H), 4.40-4.35 (m, 2H), 3.89-3.86 (m, 2 H). m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: [CH3:1]I.[C:3]([NH:7][C:8]([NH:10][C:11]1[C:12]([CH:28]([CH3:30])[CH3:29])=[N:13][C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[S:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([NH:7][C:8](=[N:10][C:11]1[C:12]([CH:28]([CH3:30])[CH3:29])=[N:13][C:14]([O:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])[S:9][CH3:1])([CH3:4])([CH3:5])[CH3:6]
Reactant: CI
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1NC(=S)NC(C)(C)C
Solvent: CCO
Product: CSC(=Nc1c(C(C)C)cc(Oc2ccc(Cl)cc2)nc1C(C)C)NC(C)(C)C

Procedure:
2.0 g of methyl iodide are added at room temperature to 2.50 g of 1-tert.-butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-thiourea in 30 ml of ethanol and the mixture is heated at +75° C. for 5 hours. The mixture is then concentrated by evaporation and the residue is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated. The crude product is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:3). 1-tert.-Butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-S-methyl-isothiourea is obtained in the form of a colourless crystalline powder, m.p. 95°-100° C.
Reaction SMILES: [CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[C:14]([O-])(=[O:16])[CH3:15].[Na+]>C(OC(=O)C)(=O)C>[C:14]([C:3]1[N:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[CH:1][C:2]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc2ccccn2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2ccccn2c1C(C)=O
Yield: 99.2 %

Procedure:
A stirred solution of 2-indolizinecarboxylic acid, methyl ester (91.42 g, 0.522 mole) and anhydrous sodium acetate (42.53 g, 0.52 mole) in acetic anhydride (1.1 L) was refluxed, under anhydrous conditions, for 48 hours. After cooling most of the acetic anhydride was evaporated in vacuo. The resulting residue (150 ml) was cooled in an ice water bath and methanol (140 ml) was added to destroy the remaining acetic anhydride. The resulting mixture was poured into water (1.1 L) and the product was extracted with diethyl ether, three times. The ethereal layer was washed with saturated sodium bicarbonate solution, three times, with water, two times, and was dried over magnesium sulfate. Evaporation of solvent yielded 112 g of crude 3-acetyl-2-indolizinecarboxylic acid, methyl ester which was chromatographed on silica gel (3 kg) using 10% acetone in benzene as eluant, to afford the pure compound (85.5 g). For analysis, the product was recrystallized from a mixture of diethyl ether and petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]([C:28]2[C:29](=[O:41])[N:30]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[N:31]=[CH:32][CH:33]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[S:17][C:10]=12.[CH3:42][NH:43][CH3:44].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:42][N:43]([CH3:44])[CH:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:25][C:26]([C:28]4[C:29](=[O:41])[N:30]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[N:31]=[CH:32][CH:33]=4)=[O:27])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:23][CH2:22]1
Reactant: CNC
Reactant: O=C1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(4-oxocyclohexyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 162, Step C, 3.2 mg, 0.0056 mmol), dimethylamine (1.3 mg, 0.028 mmol), NaBH(OAc)3 (3.6 mg, 0.017 mmol) and CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (30 mL) and H2O (30 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (2.1 mg, 62%). LRMS (APCI pos): m/e 602 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.43 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.60 (m, 2H), 7.38 (m, 1H), 7.21-7.32 (m, 4H), 6.45 (d, 1H), 3.22 (m, 1H), 2.30 (s, 6H), 2.22 (m, 1H), 1.55-1.94 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:7]=1.[Br:22]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[C:11]=2[Br:22])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COc1cc(COc2ccc(N)nn2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(COc2ccc(N)nn2)c(Br)c(OC)c1OC
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
3-Amino-6-(3,4,5-trimethoxybenzyloxy)pyridazine (Intermediate 1, 2.91 g, 10 mMol) in acetic acid (20 ml) was treated dropwise with a solution of bromine (1.59 g, 10 mMol) in acetic acid (2 ml) over 5 minutes. After 0.5 hours, the mixture was filtered to give a cream solid which was suspended in water and basified with sodium hydroxide solution. The mixture was extracted with chloroform and the extracts were washed with water, dried (Na2SO4) and evaporated in vacuo to yield a cream solid which was recrystallised from toluene to give the title compound (2.76 g) as cream needles, m.p. 160°-161° C., NMR δH(CDCl3) 6.93(1H,s,ArH) 6.91(1H,JAB,8.8 Hz,5H), 6.80(1H,JAB,8.8 Hz,4H), 5.49(2H,s,CH2), 4.95(2H, brs,NH2), 3.91(3H,s,OCH3), 3.90(3H,s,OCH3) and 3.89(3H,s,OCH3 ).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])C1C=CC=CC=1.[C:33]1([C:39]2[NH:40][C:41](C(OCC)=O)=[N:42][N:43]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:31][CH:30]([CH3:32])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:1]([C:41]4[NH:40][C:39]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[N:43][N:42]=4)=[O:8])=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([OH:29])=[O:28]
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: CCOC(=O)c1nnc(-c2ccccc2)[nH]1
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4nnc(-c5ccccc5)[nH]4)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 629 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 628.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[N:20][CH:21]=1.NN>C(O)C>[NH2:25][CH2:24][CH2:23][CH2:22][C:19]1[N:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:3])=[CH:17][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Agent: NN
Solvent: CCO
Product: NCCCCc1ccc(CCCN)nc1
Yield: 111.6 %

Procedure:
A mixture of 3-4 (14 g, 30.7 mmol) and hydrazine (5 mL) in ethanol (500 mL) was heated at reflux for 5 hours. The mixture was cooled and concentrated to ⅓ volume, diluted with 300 mL MTBE, and filtered. The filtrate was concentrated to give 7.1 g of 3-5 as a brown oil, contaminated with a small amount of phthalhydrazide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>O1CCCC1>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 2-hydroxynaphthalene (5 g, 34.7 mmol) in anhydrous tetrahydrofuran was added 2-fluoronitrobenzene (4.90 g, 34.7 mmol) at room temperature. The resultant mixture was heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water, the resulting mixture was extracted twice with methylene chloride and the combined extracts were dried (MgSO4). The resultant organic layer was concentrated under reduced pressure to yield 9.2 g of the title compound of Step A as an oil. Rf 0.45 (silica gel, 4:1 hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC)C3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)O)c4s3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (1h) (95 mg, 0.19 mmol) was dissolved in methanol (5 mL) and dichloromethane (2 mL). A 2 N aqueous lithium hydroxide solution (3 mL) was added, and the mixture was stirred at 70° C. for 1.5 hours. The organic solvent was evaporated under reduced pressure and 1 N hydrochloric acid was added until the pH of the solution was about 4. The resulting solid was collected by filtration and washed with distilled water to obtain 75 mg of the title compound as a white solid (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC)C(=O)OCC)c1

Procedure:
A mixture of 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (Intermediate 267; 110 mg; 0.32 mmol) and ethyl 2-bromobutyrate (50 μl; 0.35 mmol) in DME (2 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and refluxed for 18 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a colorless sticky solid which was not further purified before use.
Reaction SMILES: ClC1C=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)C=1.[CH2:12]([N:16]1[C:25](=[O:26])[C:24]2[N:23](CCC=C)[CH:22]=[N:21][C:20]=2[N:19]([CH2:31][CH2:32][CH2:33][CH3:34])[C:17]1=[O:18])[CH2:13][CH2:14][CH3:15]>C(Cl)(Cl)Cl>[CH2:12]([N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:6][CH2:5][CH:4]3[O:10][CH2:8]3)[CH:22]=[N:21][C:20]=2[N:19]([CH2:31][CH2:32][CH2:33][CH3:34])[C:17]1=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)c2c(ncn2CCC2CO2)n(CCCC)c1=O

Procedure:
39.4 g of m-chloroperbenzoic acid (70% pure) were added to a solution of 42.7 g of 1,3-dibutyl-7-(3-butenyl)xanthine in 900 ml of chloroform within 15 minutes, with stirring. After stirring at room temperature for 27 hours, the mixture was washed with 10% strength sodium dithionite solution, saturated sodium bicarbonate solution and water, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column with a mixture of methylene chloride/acetone (7:3, v:v) and recrystallized from petroleum ether.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(Cl)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-chloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.0 min; [M+H]+=371.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.C[Si](N[Si](C)(C)C)(C)C.C1C(=O)N([Br:33])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:33][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:9][C:10]=1[C:14]([OH:16])=[O:15]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1sc(-c2ccc(Cl)cc2)nc1CBr
Yield: 72 %

Procedure:
Following the procedure described in Part D of Example 1, 1.00 g of commercially available of 2-(4-chlorophenyl)-4-methylthiazole-5-carboxylic acid, 0.502 mL of HMDS, 0.702 g of NBS and 32 mg of AIBN in 3.40 mL of CCl4 afforded the title compound (0.940 g, 72% yield) as a yellow/orange solid: 1H NMR (500 MHz, DMSO-d6) δ 11.06 (1H, br. s.), 8.02 (2H, d, J=8.25 Hz), 7.61 (2H, d, J=8.80 Hz), 5.01 (2H, s); HPLC retention time: 3.591 min; LCMS (ES): m/z 334 [M+H]+.
Reaction SMILES: S(O)([O-])(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH2:37][CH:38]=[CH2:39])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([OH:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1.[C:40](=O)([O-:42])[OH:41].[Na+:44]>>[C:40]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:35][O:36][CH2:37][CH:38]=[CH2:39])[C:13]([NH:15][CH:16]2[C:33](=[O:34])[N:18]3[C:19]([C:30]([O-:32])=[O:31])=[C:20]([CH2:23][N+:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1)([O-:42])=[O:41].[Na+:44]
Reactant: O=C([O-])O
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NC(=O)[O-])n1

Procedure:
Sodium 7-[2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) was prepared by reacting 7-[2-(5-amino-1,2,4-thiadiazol-3yl)-2-allyloxyiminoacetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) (50 mg) and sodium hydrogencarbonate (21 mg) and detected according to a similar manner to that of Example 17.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22]C)=[O:21])=[CH:19][C:6]1=2)(=[O:4])=[O:3].[OH-].[Na+].Cl>O>[CH3:1][S:2]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:6]1=2)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc2c(c1)C(S(C)(=O)=O)c1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)C1c2ccccc2COc2ccc(C(=O)O)cc21

Procedure:
Reflux 1 gm. of the ester of Step A and 40 cc. of 1 N aqueous sodium hydroxide for 15 minutes. Strip to dryness and dissolve the residue in water. Acidify with aqueous hydrochloric acid. Separate the solids by filtration to obtain the title product (m.p. 251° C. dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH:13]=O.[C:15]([OH:25])(=O)[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:3]([CH:13]=[CH:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]3[O:25][C:3]4[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=4[CH:1]=3)=[CH:23][CH:22]=2)=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COc1cc(C)c(C=O)cc1C(=O)O
Product: COc1cc(C)c(C=Cc2ccc(-c3cc4ccccc4o3)cc2)cc1C(=O)O

Procedure:
When an equivalent amount of the anil derivative of 4-methyl-6-methoxyisophthalaldehydic acid is substituted for the anil derivative of terephthalaldehydic acid in the procedure described in Example 2 above, there is obtained as the product 2-[4-(6-methyl-4-methoxy-3-carboxystyryl)phenyl]benzofuran.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.Cl>C(OCC)C>[Cl:9][C:5]1[CH:4]=[C:3]([C:13]2([OH:17])[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]2)[CH:8]=[CH:7][CH:6]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC1CCCC(=O)C1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC1CCCC(O)(c2cccc(Cl)c2)C1
Yield: 42.8 %

Procedure:
For example, magnesium turnings (6.4 g, 0.26 mole) were flame-dried, the containing glassware was cooled, and 3-bromochlorobenzene (50 g, 0.26 mole), in 50 ml of diethyl ether was added. As the reaction began, an additional 200 ml of diethyl ether was added, and the reaction mixture was heated under reflux for 0.5 hour. To the refluxing reaction mixture was added dropwise, during a 0.5 hour period, 3-methylcyclohexanone (29.2 g, 0.26 mole) in 100 ml of diethyl ether. Upon complete addition, the reaction mixture was heated under reflux for an additional 0.5 hour, then poured into 500 ml of icewater containing 50 ml of hydrochloric acid. The mixture was extracted with three 200 ml portions of diethyl ether. The combined extract was washed twice with 100 ml portions of an aqueous solution saturated with sodium chloride. After separation, the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to an oil. The oil was purified by distillation using a Kugelrohr distilling system at 85°/0.05 mm for 2.5 hours to give 1-(3-chlorophenyl)-3-methylcyclohexan-1-ol (25 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.[CH2:10]=[O:11]>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][N:5]([CH2:10][OH:11])[N:4]=1
Reactant: C=O
Reactant: FC(F)(F)c1nc[nH]n1
Solvent: CC(C)=O
Product: OCn1cnc(C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
The mixture of 2.74 g of 3-(trifluoromethyl)-1H-1,2,4-triazole and 1.20 g of paraformaldehyde was stirred at 150° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 3.15 g of 3-(trifluoromethyl)-1H-1,2,4-triazole 1-ylmethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]=1)[CH2:8][NH:9][C:13](=[O:15])[CH3:14]
Reactant: NCc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NCc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of compound 13 (2.5 g, 10.82 mmol) in pyridine (20 mL) was added acetic anhydride (2 mL, 21.60 mmol) and the mixture was stirred at room temperature for 12 h. The reaction was added ethyl acetate (30 mL) and the organic layer was washed sequentially with H2O (20 mL), 1N HCl (15 mL×3), brine (15 mL) and dried over Na2SO4 and evaporated to get the title compound as an off-white solid (2.89 g, 98%). IR (KBr) νmax. cm−1: 3419 (NH), 3062 (Ar—H), 2925 (Alph-H), 1695 (C═O), 1604, 1564 (C═C), 1520, 1435 (NO2), 1232 (C—N), 1168 (C—O). 1H NMR (500 MHz, CDCl3) δ=2.19 (s, 3H, CH3); 5.50 (s, 2H, CH2); 7.63 (dd, 1H, J=2.3, 8.6 Hz, H-4); 7.75 (d, 1H, J=2.3, H-6), 8.00 (d, 1H, J=8.6 Hz, H-3). 13C NMR (125.7 MHz, CDCl3) δ=20.78 (CH3), 62.27 (CH2), 126.58 (C-3), 129.03 (C-1), 131.73 (C-6), 131.82 (C-4), 134.34 (C-5), 145.33 (C-2), 170.10 (CO). Calculated (%) for C9H9BrN2O3 (271.98); C, 39.58; H, 3.32; N, 10.26. found (%); C, 39.52; H, 3.36; N, 10.20.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:24][CH:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:24][CH:23]=1
Reactant: CCOC(=O)Cc1ccccc1Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1ccccc1Oc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
N-Bromosuccinimide (6.64 g) and azo(bisisobutyronitrile) (400 mg) were added to a solution of compound (B) (10.1 g) in carbon tetrachloride (100 ml). The mixture was heated under reflux for 20 hours and then cooled to ambient temperature. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:19 v/v), to give ethyl 2-(4-bromomethylphenoxy)phenylacetate (C) (5.9 g), as an oil; NMR (d6 -DMSO): 1.15(t, 3H), 4.1(q, 2H), 4.65(s, 2H), 6.0(s, 1H), 6.95(d, 2H), 7.3-7.5(m, 5H), 7.5-7.6(m, 2H).