Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([O:38]CC)=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCOCC1.Cl>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(-c4c(F)cc5c(=O)c(C(=O)O)cn(C6CC6)c5c4C)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 3 ml of ethanol was suspended 0.30 g of ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate, and 3 ml of 1N aqueous sodium hydroxide solution and 3 ml of dioxane were added to the suspension, after which the resulting mixture was stirred at room temperature for two hours. To the reaction mixture was added 3 ml of 1N hydrochloric acid, and the crystals thus formed were collected by filtration, to obtain 0.27 g of colorless, crystalline 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Clc1ncccn1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)CN(c1ncccn1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.1 %

Procedure:
A mixture of the amine from example 4 (200 mg, 0.53 mmol), 2-chloropyrimidine (66 mg, 0.58 mmol) and potassium carbonate (72 mg, 0.53 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 18 hours. TLC analysis showed starting materials remained, so additional 2-chloropyrimidine (66 mg, 0.58 mmol) was added, and the reaction was stirred at 80° C. for a further 72 hours. The cooled mixture was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and brine, and the layers were separated. The organic layer was washed with water, wash with ammonium chloride solution, dried over magnesium sulphate and then evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluant, to afford the title compound as a yellow oil (117 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[CH:33]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:32][C:31]([CH2:43]Br)=[CH:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[CH:33]([CH2:34][OH:35])[CH2:32][C:31]([CH2:43][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:30]1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2=CC(CO)C(CO)C2)c(=O)[nH]c1=O
Yield: 19.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (53 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (5.0 g, 27.0 mmol) in 70 mL DCM is added thionyl chloride (12.1 mL, 162 mmol). The reaction mixture is stirred at 50° C. for 1.5 h and overnight at RT. The reaction mixture is concentrated in vacuo, the residue is taken up in fresh DCM and concentrated in vacuo again. Yield: 5.12 g.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[BH4-].[Na+].Cl>C(O)C.O>[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0° C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.57 mL, 52.4 mmol). The mixture is heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.77 (s, 2H) 7.09 (m, 1H) 7.19 (t, J=7.96 Hz, 1H) 7.38 (m, 1H); LC/MS: MS (ES+) m/e 257.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A 2.5 L 4-necked round-bottomed flask (suspension tank in the sketch) equipped with a mechanical stirrer was charged with 236.4 g of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione, (0.5 mol), 196.6 g of 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-diethyl ester (0.75 mol) and 750 g of Dowtherm A (20 w %, apparent density 1.132 g/ml). This mixture was stirred for ca. 2 h at room temperature until a homogeneous suspension was formed. The temperature of the tube reactor was set to 230° C. and was controlled automatically. When the temperature was reached, pumping of the reactant suspension was started at a flow rate of 4.8 ml/min. The effluent was collected with stirring in the collection tank which contained 2300 ml of ethanol. After 2 h, 661 g (i.e. 584 ml) of product solution had passed through the reactor, which corresponds to 132.2 g (0.28 mol) of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione. Crystallization of the product in the collection tank took place almost immediately after the addition of the effluent to the ethanol had started. Finally, the suspension was stirred for additional 14 h at room temperature and in an ice bath at ca. 2° C. for 4 h. The precipitate was filtered with suction, the filter cake was washed twice with a total of 1500 ml of cold (0° C.) ethanol and dried to constant weight (60° C., 25 mbar, 17 h) to afford 124.9 g (yield: 95.9%, 99.9% purity based on HPLC assay) of 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione as a yellowish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[OH:11].[CH2:12]([O:14][C:15](N1C2C(=C(Br)C=CC=2)C(O)=N1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([OH:11])=[N:6]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)n1nc(O)c2c(Br)cccc21
Reactant: Oc1n[nH]c2ccc(Br)cc12
Product: CCOC(=O)n1nc(O)c2cc(Br)ccc21

Procedure:
5-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CCVIII was prepared from 5-bromo-1H-indazol-3-ol using the procedure described for preparation of 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV (Example 37).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16]>O.C(O)(=O)C>[NH:5]1[C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)[CH:16]=[N:1]1
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
A solution of sodium nitrite (836 mg, 59.1 mmol) in water (2 ml) was added to a solution of methyl 4-amino-3-methylbenzoate (2.00 g, 12.1 mmol) in acetic acid (80 ml) at room temperature and stirred at room temperature for 5 hours. The reaction solution was concentrated and the resulting residue was diluted with chloroform and washed with a 5% aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain methyl 1H-indazole-5-carboxylate (645 mg, 30%).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][CH:14]([CH2:17][CH2:18][NH2:19])[CH2:15][NH2:16]>>[CH3:13][CH:14]([CH2:17][CH2:18][NH:19][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:15][NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: CC(CN)CCN
Product: CCCCCCCCCC(O)CNCCC(C)CNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 2-methyl-1,4-butanediamine affords N,N'-(2-methyl-1,4-butylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8R' = H, X = CH2CH(CH3)CH2CH2, Z = H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2
Reactant: COc1ccc2cc(F)cnc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2cc(F)cnc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Fluoro-7-methoxyquinoline (130 mg, 0.74 mmol) was taken up in dichloromethane (2 ml) under nitrogen and treated with boron tribromide (4 ml of a 1.0M solution of in dichloromethane). The reaction mixture was stirred for 24 hours at ambient temperature followed by quenching the reaction by the slow addition of excess methanol. The solution was stirred for a further 2 hours and evaporated to dryness to give 3-fluoro-7-hydroxyquinoline which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH3:23].O>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([N:22]([CH3:23])[CH3:21])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To the product from Example 168b (2.0 g, 6.4 mmol) in THF (25 mL) was added dimethylamine (0.6 g, 13.3 mmol) and the reaction stirred for 16 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with 5% HCL, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.9 g, 87%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[OH:13]>C(O)C.C1COCC1.[OH-].[Pd+2].[OH-]>[NH2:10][C:4]1[C:3]([OH:13])=[C:2]([F:1])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(N)c(O)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
A suspension of 2-fluoro-3-methoxy-6-nitrophenol (300 mg) and 5% palladium hydroxide (40 mg) in ethanol (10 mL) and THF (5 mL) was stirred at room temperature for 15 hr under a hydrogen atmosphere (1 atm). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (220 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]1[C:30]([F:31])=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:27][C:24]=1[CH:25]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:25][C:24]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[C:30]([F:31])[C:23]=1[F:22]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1F
Product: O=C(C=Cc1ccc(C(F)(F)F)c(F)c1F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 2,3-difluoro-4-(trifluoromethyl)benzaldehyde (91 ul, 0.633 mmol) similar to Example 18 as a yellow solid (66 mg, 20%). 1H NMR (CDCl3): 7.78 (d, J=15.9 Hz, 1H), 7.64 (d, J=16.2 Hz, 1H), 7.51-7.38 (m, 2H), 7.35 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.95 (d, J=9.3 Hz, 1H), 4.47-4.35 (m, 4H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1>C(#N)C>[S:1]([O:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCc1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Product: NS(=O)(=O)OCCc1ccccc1
Yield: 68 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 12 with 12.2 g (0.1 mole) of β-phenethyl alcohol using 40.4 g (0.4 mole) triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 12 through the first evaporation. The crude oily residue was purified by chromatography (10×80 cm glass column; 700 g silica gel; eluents methylene chloride followed by 10:1 methylene chloride/acetone). Fractions containing the title compound were combined and solvents evaporated under reduced pressure to give 13.6 g (68% yield) of title compound as light-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>CS(C)=O>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ncccc2[N+](=O)[O-])c(Cl)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 5-amino-2-chloro-4-fluorophenol (0.64 g), powdered potassium hydroxide (0.24 g), and 2-chloro-3-nitropyridine (0.76 g) in dimethylsulfoxide (15 ml) was heated at 110° C. with stirring for 2 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with methanol:methylene chloride, 3:97, to yield 2-(5-amino-2-chloro-4-fluorophenoxy)-3-nitropyridine (Intermediate IIa) as a yellow semi-solid (0.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:22][C:21]([C:23]([OH:25])=O)=[CH:20][CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][CH:39]([NH2:43])[CH2:40][CH2:41][CH3:42]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:22][C:21]([C:23](=[O:25])[NH:43][CH:39]([CH3:38])[CH2:40][CH2:41][CH3:42])=[CH:20][CH:19]=1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(=O)O)s1
Reactant: CCCC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCC(C)NC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 4.4 g (12.1 mmol) 5-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-thiophene-2-carboxylic acid in 80 ml THF were added 2.2 g (13.6 mmol) carbonyldiimidazol. The reaction mixture was stirred at 45° C. for 1 h and then cooled to rt. After addition of 1.05 g (12 mmol) 2-pentylamine the reaction mixture was kept at rt for 12 h. The solvent was evaporated and the residue was dissolved in 150 ml CH2Cl2. The solution was washed twice with 150 ml water each and dried over magnesium sulfate. The solvent was evaporated and the residue was washed with diethyl ether to yield (2-{[5-(1-methyl-butylcarbamoyl)-thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester as a white solid, mp. 183° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[O:17]1CCOCC1>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:17])[N:10]=2)[CH:12]=1
Reactant: C1COCCO1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2)n1
Product: O=c1nc(-c2cccnc2)cc[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
2-Methanesulfonyl-4-pyridin-3-yl-pyrimidine (846 mg, 3.58 mmol) was dissolved in dioxane (36 ml) and then 2N NaOHaq (18 ml, 36 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was re-dissolved in DCM-MeOH—NH4OH (90-10-1) and evaporated. The residue was purified by flash chromatography with DCM-MeOH (9-1) to give 500 mg of the title compound. (80% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:21][CH:22]=[O:23])[CH:6]=[C:7]([CH2:19]Br)[CH2:8][CH2:9][O:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[P:25]([O:34]C(C)C)([O:30][CH:31]([CH3:33])[CH3:32])[O:26][CH:27]([CH3:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:21][CH:22]=[O:23])[CH:6]=[C:7]([CH2:19][P:25]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:34])[CH2:8][CH2:9][O:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CCOC(=O)c1ccccc1)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CCOC(=O)c1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
8.4 g (21 mmol) of 6-benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 23 ml (84 mmol) of triisopropyl phosphite (90%) are heated to 80° C. and stirred under a pressure of ~130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 6-benzoyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brown oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:22][Si:23]([CH2:26][CH2:27][O:28][CH2:29]Cl)([CH3:25])[CH3:24]>ClCCl>[CH3:12][C:5]1([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3][CH:2]([O:1][CH2:29][O:28][CH2:27][CH2:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)C1(C)CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C)CCC(OCOCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of methyl 4-hydroxy-1-methylcyclohexane-1-carboxylate (2.1 g, 12.19 mmol, 1.00 equiv) in 20 mL of dichloromethane was added DIEA (4.74 g, 36.68 mmol, 3.01 equiv) and SEMCl (4.08 g, 24.47 mmol, 2.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and quenched with water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/20) to give the desired methyl 1-methyl-4-[[2-(trimethylsilyl)ethoxy]methoxy]cyclohexane-1-carboxylate (3.6 g, 98%) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is dissolved in methylene chloride and pyridine, and the mixture is cooled in an ice bath. Methanesulfonyl chloride is added dropwise, and the reaction mixture is stirred at ice bath temperature, then allowed to warm to room temperature. The reaction mixture is quenched by addition of water and extracted with methylene chloride. The organic layer is washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-methanesulfonamide.