Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][CH:20]=[C:21]([CH:29]=[CH:30][C:31](OCC)=[O:32])[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[NH:19][CH:20]=[C:21]([CH:29]=[CH:30][CH2:31][OH:32])[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: ClCCl
Product: OCC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 93 %

Procedure:
27.6 ml (27.6 mmol) of a 1M solution of diisobutylaluminum hydride in dichloromethane were added dropwise to a solution of 3.88 g (12.5 mmol) of ethyl 3-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrol-4-yl]acrylate in 120 ml of dichloromethane at −78° C. with stirring. The resulting mixture was stirred at the same temperature for 3 hours. At the end of this time, the reaction mixture was added to a saturated aqueous solution of sodium hydrogencarbonate and the resulting mixture was filtered. The filtrate was extracted with dichloromethane and the organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 9:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 3.42 g (yield 93%) of the title compound as a pale brown powder.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:26])=O>>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 4'-n-octylbiphenyl-4-carboxylic acid (3.2 g) and an excessive amount of thionyl chloride were heated under refluxing for 6 hours, unaltered thionyl chloride was distilled off to obtain 4'-n-octylbiphenyl-4-carboxylic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=1)([O-])=O>[Pd].CO>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1
Reactant: C[Si](C)(C)CCOCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc(N)n1
Temperature: 30 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Into a 2 L round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 3-nitro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (125.0 g, 513.69 mmol, 1.00 equiv.), MeOH (1 L), and Pd/C (13.0 g). The suspension was the placed under an atmosphere of hydrogen. The resulting solution was stirred at 30° C. for 4 h. The solids were then filtered and the filtrate was concentrated under vacuum to afford of 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-amine (110 g 80% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([CH3:10])=[CH:8][N:7](S(N(C)C)(=O)=O)[N:6]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([CH3:10])=[CH:8][NH:7][N:6]=1
Reactant: COCCc1nn(S(=O)(=O)N(C)C)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCc1n[nH]cc1C
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2-methoxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.3, 440 mg, 1.78 mmol) in dioxane (10 mL). HCl (10 mL, 6 M, 30 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 h at 85° C., then cooled to room temperature and carefully neutralized with NaHCO3 aq (sat.) to pH=8. The aqueous phase was extracted with 3×50 mL of EtOAc and the combined organic layers were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=2)[O:2]1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([O:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2c1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3c2OCO3)cc1
Temperature: 60 °C

Procedure:
A solution of 2,3-methylenedioxyphenol (17.45g) and benzyl bromide (27.5 mL) in dimethylformamide (200 ml) was treated with potassium carbonate (35 g), and the mixture was heated at 60° C. overnight. After cooling and filtering, the mixture was evaporated. The residue was dissolved in ethyl acetate and washed with 1 M hydrochloric acid. The organic extract was dried, filtered and evaporated to afford 1-benzyloxy-2,3-methylenedioxybenzene, mp 62°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.CCOC(C)=O>C(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:33])=[CH:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(S(C)=O)cc2)c(-c2ccc(F)cc2)s1
Yield: 85.5 %

Procedure:
To a solution of 5-(4-fluorophenyl)-4-(4-(methylthio)phenyl)-thiophene-2-carboxylic acid methyl ester (5.60 g) in CH2Cl2 (84.0 mL) at 0° C. was added portionwise m-CPBA 50 to 60% (5.39 g). After TLC showed completion (50% EtOAc in hexane), the reaction mixture was extracted with saturated NaHCO3, dried over Na2SO4, filtered and evaporated to dryness to provide the title compound as a white foam (5.00 g).
Reaction SMILES: COC1C=CC(NC(N)=S)=CC=1.C1(NC(NC)=S)C=CC=CC=1.[C:24]1([N:30]([CH3:34])[C:31]([NH2:33])=[S:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CNC1SC2C=CC=CC=2N=1>>[CH3:34][N:30]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:32][C:31]1=[NH:33]
Reactant: CN(C(N)=S)c1ccccc1
Agent: CNC(=S)Nc1ccccc1
Agent: CNc1nc2ccccc2s1
Agent: COc1ccc(NC(N)=S)cc1
Product: Cn1c(=N)sc2ccccc21

Procedure:
When using, instead of 4-methoxyphenyl-thiourea of Examples 89 and 90, equivalent amounts of N-phenyl-N'-methyl-thiourea or N-phenyl-N-methyl-thiourea, the other conditions remaining the same, 2-methylamino-benzthiazole (m.p. 137° C.) or 3-methyl-2-imino-benzthiazoline (m.p. 122°) is obtained in an equally good yield and in a high purity.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18])(C)(C)C.[NH:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30]1>>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH:8]([NH:7][S:38]([C:33]1[C:32]2[CH:31]=[CH:30][NH:29][C:37]=2[CH:36]=[CH:35][CH:34]=1)(=[O:39])=[O:40])[C:19]([N:21]1[CH2:22][CH2:23][CH:24]([CH3:27])[CH2:25][CH2:26]1)=[O:20])#[N:18]
Reactant: O=S(=O)(Cl)c1cccc2[nH]ccc12
Reactant: CC1CCN(C(=O)C(CCc2ccccc2C#N)NC(=O)OC(C)(C)C)CC1
Product: CC1CCN(C(=O)C(CCc2ccccc2C#N)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 70 is prepared from tert-butyl{3-(2-cyanophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate and indole-4-sulfonyl chloride in the same manner that Example 5 is synthesized. ESI MS Calc. 464.2; Found: 465.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]O)[CH:30]=1>>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:19][C:18]([C:17]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:28])[C:10]3[C:15]([C:16]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=3)=[O:20])[CH:30]=1
Reactant: OCc1cccnc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Product: O=C(OCc1cccnc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 3-pyridinemethanol. A colorless powder (100 mg).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH:22]=O)=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[NH3:30].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CCOCC>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]#[N:30])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: N
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Solvent: CCOCC
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
A solution of 4.8 g (0.015 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde [see Example 1 a)] in abs. benzene is saturated with ammonia. After cooling of the solution to 0°, an addition is made portionwise, with a light flow of ammonia gas and in the course of 45 minutes, of 14.0 g (0.030 mole) of lead tetraacetate. The reaction mixture is then stirred for a further 24 hours at 25°; it is subsequently diluted with ether and filtered through kieselguhr. The filtrate is washed with 1N hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed through silica gel with the use of ethyl acetate as eluant. The fractions containing the desired nitrile [Rf = 0.63 in the eluant system ethyl acetate/isopropanol (7:1)] are combined, and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([NH2:10])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccccc1)c1ccc(Br)cc1N
Temperature: 90 °C
Yield: 107.3 %

Procedure:
Dissolving 6.8 g (29 mmol) 4-bromo-N-methyl-2-nitroaniline obtained in the above step (1) into 20 milliliter of pyridine, further adding 5.0 g (35 mmol) benzoyl chloride, the resultant solution was refluxed with heating at the temperature of 90° C. under an atmosphere of argon gas for 7 hours. After completing the reaction, 200 milliliter of ethyl acetate was added and the resultant solution was washed with 10% HCL, with 10% K2CO3 and with a saturated solution of sodium chloride and then, dried with the use of magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure and the residue was refined with silicagel column chromatography (hexane:ethyl acetate=10:1 at primary stage→2:1 from middle stage) resultantly obtaining 9.5 g of 4′-bromo-N-methyl-2′-amino-benzanilide as greenish white solids (yield: 96%).
Reaction SMILES: Cl.[F:2][C:3]1([F:31])[CH2:5][CH:4]1[CH2:6][N:7]1[C:15]2[C:10](=[N:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[N:9]([CH3:28])[S:8]1(=[O:30])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:56]1[CH:60]=[CH:59][C:58]([C:61](O)=[O:62])=[N:57]1.CCN(C(C)C)C(C)C>CO.CN1C(=O)CCC1>[F:31][C:3]1([F:2])[CH2:5][CH:4]1[CH2:6][N:7]1[C:15]2[C:10](=[N:11][C:12]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:61]([C:58]5[CH:59]=[CH:60][O:56][N:57]=5)=[O:62])[CH2:26][CH2:27]4)=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[N:9]([CH3:28])[S:8]1(=[O:29])=[O:30]
Reactant: O=C(O)c1ccon1
Reactant: CN1c2nc(-c3ccc(N4CCNCC4)cc3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN1CCCC1=O
Product: CN1c2nc(-c3ccc(N4CCN(C(=O)c5ccon5)CC4)cc3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(4-piperazin-1-ylphenyl)-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide hydrochloride (8-3) (0.028 g, 0.059 mmol), HATU (0.029 g, 0.077 mmol), isoxazole-3-carboxylic acid (0.0087 g, 0.077 mmol), NMP (1 mL), and finally DIPEA (0.060 mL, 0.344 mmol). The reaction mixture was then stirred at room temperature for 1 hour. The crude reaction mixture was then diluted with methanol, then filtered. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 1-[(2,2-difluorocyclopropyl)methyl]-5-{4-[4-(isoxazol-3-ylcarbonyl)piperazin-1-yl]phenyl}-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (34-1) as a tan solid. HRMS (M+H)+: observed=531.1613, calculated=531.1621.
Reaction SMILES: CN(C)P(N(C)C)(N(C)C)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]I)=[CH:15][CH:14]=1.CSC.[O:25]=[C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:27]=[CH:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].C[Si](Cl)(C)C>O1CCCC1.C(OCC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:28]([C:29]2[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])[CH2:27][C:26](=[O:25])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(C=CC(=O)c2ccccc2)c1
Reactant: Clc1ccc(CCI)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CSC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1cccc(C(CCc2ccc(Cl)cc2)CC(=O)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of SmI2 (48 mL, 0.1N, 4.4 mmol) in tetrahydrofuran is treated with hexamethylphosphoramide (HMPA) (3.75 mL, 2.19 mmol) and stirred 5 minutes. A solution of 1-chloro-4- (2-iodoethyl) -benzene (0.6 g, 2.25 mmol) in tetrahydrofuran (5 mL) is added, stirred 10 minutes and cooled to -78° C. A catalytic amount of CuBr.DMS (45 rag, 0.225 mmol) is added to the reaction mixture which is stirred 5 minutes before a solution of 3-(3-oxo-3-phenyl-1-propenyl)-benzoic acid, methyl ester (0.4 g, 1.5 mmol) and trimethylsilyl chloride (0.75 mL, 5.58 mmol) in tetrahydrofuran (6 mL) is added. The reaction is stirred in the cold for 30 minutes, diluted with diethyl ether (400 mL), and filtered over a 2" cake of Al2O3. The ethereal solution is washed with water, dried (MgSO4), and stirred with a few drops of tetrabutylammonium fluoride for 2 hours. The reaction mixture is concentrated and columned over SiO2 eluting with dichloromethane to collect 0.5 g of an oil which is clean by PMR.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N:23]([O-])=[O:24].[Na+]>C(OC(=O)C)(=O)C>[N:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:24]
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)N(Cc2ccccc2)N=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of N-benzyl-p-toluenesulphonamide (21 g, 80 mmol) and acetic acid (100 ml) in acetic anhydride (400 ml) was added solid sodium nitrite (120 g, 1.7 mol) in portions over a period of 12 hours at 5° C. The temperature was kept below 10° C. all the time. After the addition was finished the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured over an excess of ice water and stirred for 1 hour. The pale yellow precipitate was filtered and washed several times with water. The crude product was recrystallized from ethanol to give the title compound as a tiny yellow needles (19.1 g, 82% yield, m.p. 92°-93° C., (Lit.1 89°-90° C.). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(2H,s); 2.40(3H,s)ppm.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:14]([F:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:6]=1[C:7](OC)=[O:8]>CCO>[F:15][C:14]1[CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=[C:6]2[C:5]=1[NH:3][N:2]=[C:7]2[OH:8]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(F)c2[nH]nc(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydrazine monohydrate (1.91 ml) was added to an EtOH (40 ml) solution containing methyl 2,3-difluoro-5-nitrobenzoate (1.71 g) obtained in the 2nd step, followed by stirring at room temperature for 10 minutes. An insoluble precipitate was removed by filtration and washed with EtOH. 7-Fluoro-5-nitro-1H-indazol-3-ol (956 mg) was thus obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:20])[O:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14]1>C(Cl)Cl>[CH3:12][C:13]1([CH3:20])[O:19][CH2:18][CH:17]2[CH:16]([O:9]2)[CH2:15][O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)OCC=CCO1
Solvent: ClCCl
Product: CC1(C)OCC2OC2CO1
Yield: 80 %

Procedure:
To a suspension of m-chloroperbenzoic acid (74% pure; 78.15 g; 0.33 mole) in methylene chloride (600 ml), was added a solution of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (II) (41.0 g, 0.32 mole) in methylene chloride (200 ml) during 30 min at room temperature. The mixture was refluxed for 8 hrs and then cooled in ice for 1 hr. The precipitated solid was filtered off and the organic filtrate was washed with 10% aqueous sodium sulfite (2×100 ml), saturated aqueous sodium bicarbonate (3×500 ml), 5% aqueous sodium hydroxide (2×250 ml) and brine (2×200 ml) and dried (MgSO4). Removal of the solvent followed by vacuum distillation of the residual oil gave the epoxide product (III) as a colorless liquid. 36.94 g (80% yield). b.p. 90°-92°/11 mm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].I[CH2:33][CH3:34]>CN(C)C=O>[CH2:33]([N:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[O:28][CH3:29])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])[CH3:34]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3OC)CC2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C)c(C)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
1-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.2 g, 0.5 mmole) was dissolved in dimethylformamide(15 ml), and thereto sodium hydride(12 mg, 0.5 mmole) was added slowly. The resulting mixture was stirred at room temperature for 15 min. After iodoethane(78 mg, 0.5 mmol) was added, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([NH:21][C:22]([CH3:23])=[O:24])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Temperature: 25 °C
Yield: 60 %

Procedure:
5-(6,7-Dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)pyridin-2-amine 142 (60 mg, 0.2 mmol) was heated in 1 ml of acetic anhydride at 85° C. for 60 min. The reaction mixture was then cooled to room temperature, the precipitate filtered out, washed with cold ethanol and dried in high vacuum to yield 308 (44 mg, 60%). MS: (ESI+) 338.1
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O.CCOCC>[CH2:15]([O:14][CH2:13][N:2]1[N:3]=[N:4][CH:5]=[N:1]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1nnn[nH]1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCn2ncnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tetrazole (1 mmole) and powdered K2CO3 (1.5 mmole) in 1 mL DMF cooled to 0° C. was added benzyl chloromethyl ether (1.2 mmole) and the resulting mixture stirred for 30 min at 0° C. and then for 16 h at rt. The mixture was diluted with water and ether. Extraction and chromatography provided 2-benzyloxymethyltetrazole as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[NH:10][C:9]([C:11](O)=[O:12])=[C:8]([CH3:14])[CH:7]=1)([OH:3])=[O:2].C(OCC)(OCC)OCC>O>[CH:11]([C:9]1[NH:10][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][C:8]=1[CH3:14])=[O:12]
Reactant: Cc1cc(CCC(=O)O)[nH]c1C(=O)O
Solvent: O
Solvent: CCOC(OCC)OCC
Product: Cc1cc(CCC(=O)O)[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
A solution of 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid (e.g, 6.59 mmol) in trfluoroacetic acid (6 mL) was stirred at room temperature for 10 minutes. It was then cooled to 0° C. and to it was added triethyl orthoformate (6 mL). The mixture was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes. The reaction was poured into water (50 mL) and extracted with ethyl acetate. The extract was dried and concentrated to give 1.2 g of 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 12.17 (brs, 1H), 11.50 (brs, 1H), 9.44 (s, 1H, CHO), 5.85 (s, 1H), 2.74 (t, J=7.4 Hz, 2H, CH2), 2.54 (t, J=7.4 Hz, 2H, CH2, CH2), 2.23 (s, 3H, CH3). MS 182 [M++1].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1c(F)ccc(O)c1F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(OCC)c1c(F)ccc(Oc2ccc(F)cc2)c1F
Temperature: 25 °C
Reaction time: 40 h
Yield: 35.3 %

Procedure:
To a solution under Ar of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (320 mg) in CH2Cl2 (10 ml) was added copper(II)acetate (230 mg), 4-fluorobenzeneboronic acid 516 mg) and powdered MS4 Å (2 g). After addition of triethlyamine (622 mg) the mixture was stirred 40 h at rt. The solids were filtered away and the solvent was evaporated. Column chromatography (CC) (AcOEt:Hept 1:9 to 1:1) afforded 154 mg of (RS)-[2,6-difluoro-3-(4-fluoro-phenoxy)-phenyl]-ethoxy-acetic acid ethyl ester as a brownish oil.