Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(N(CC)CC)C.Cl[CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]([O:21][C:22](=[O:25])[CH2:23]Cl)([CH3:20])[CH3:19])=[O:14].[C:26]([O:29]CC)(=[O:28])C>>[CH:1]([O:3][CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]([O:21][C:22](=[O:25])[CH2:23][O:29][CH:26]=[O:28])([CH3:20])[CH3:19])=[O:14])=[O:2]
Reactant: CC(C)(CCOC(=O)CCl)OC(=O)CCl
Reactant: CCOC(C)=O
Reactant: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(CCOC(=O)COC=O)OC(=O)COC=O
Reaction time: 0.5 h

Procedure:
Formic acid (67) (0.921 g, 20 mmol) and triethylamine (2.226 g, 22 mmol) were combined and stirred for 30 minutes. Compound (101) (0.454 g, 1.8 mmol) was then added and stirred for three days. The solution was dissolved in 10 mL of ethyl acetate and the precipitate was filtered and washed with 10 mL, diethylether. The combined filtrate was then washed with brine and dried with sodium sulfate. The solvent was evaporated to get dark brown viscous oil.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[CH2:1]([C:4]1[N:5]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:21][N:20]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCCc1cc2c(C#N)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(C#N)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 2-propyl-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.6 Hz, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.90-7.80 (m, 2H), 7.70 (d, J=8.4 Hz, 1H), 5.95 (s, 2H), 3.06 (t, 2H), 1.79-1.67 (m, 2H), 0.95 (t, J=7.2 Hz, 3H); MS (ES) m/z 436 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](=O)[C:31](O)=[O:32])[CH:24]=1>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:15]2[C:31](=[O:32])[C:30]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[N:22][C:21]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]2=3)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: COC(=O)c1cc(NC(C)=O)cc(Nc2ncccc2N)c1
Solvent: CO
Product: COC(=O)c1cc(NC(C)=O)cc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Yield: 70.6 %

Procedure:
A mixture of 2-[3-acetylamino-5-methoxycarbonylphenylamino]-3-aminopyridine (1.07 g) and 3-(3-pyridyl)pyruvic acid (0.65 g) in methanol (15 ml) was stirred under reflux for 5 hours. The precipitate was collected and washed with methanol to give 4-(3-acetylamino-5-methoxycarbonylphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.08 g).
Reaction SMILES: C([NH:4][C:5]1[CH:25]=[CH:24][C:8]([S:9]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][N:16]([CH:20]3[CH2:22][CH2:21]3)[C:15](=[O:23])[N:14]=2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O.S(N)(=O)(C1C=CC(N)=CC=1)=O>C(O)(=O)C>[CH:20]1([N:16]2[CH:17]=[C:18]([CH3:19])[C:13]([NH:12][S:9](=[O:10])([C:8]3[CH:24]=[CH:25][C:5]([NH2:4])=[CH:6][CH:7]=3)=[O:11])=[N:14][C:15]2=[O:23])[CH2:21][CH2:22]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(=O)n(C3CC3)cc2C)cc1
Agent: Nc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cn(C2CC2)c(=O)nc1NS(=O)(=O)c1ccc(N)cc1

Procedure:
A mixture of 500 mg. of N4 -acetyl-N1 -(1-cyclopropyl-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)sulfanilamide and 5 ml. of 10% aqueous sodium hydroxide was heated on the steam bath for 1 hour, diluted with 10 ml. of water, cooled and acidified by gradual addition of 1ml. of acetic acid. The initial oily precipitate quickly solidified and filtration gave 332 mg. of product melting at 128°-133°. Recrystallization from 7 ml. of ethanol gave 120 mg. of N1 -cyclopropyl-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)sulfanilamide, melting at 134°-136°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29][O:30][CH2:31]Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:29][O:30][CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(CCO)c1)Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1CN(Cc1cccc(CCO)c1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
A solution of (2-hydroxy-benzyl)-[3-(2-hydroxy-ethyl)-benzyl]-carbamic acid tert-butyl ester (250 mg) in anhydrous N,N-dimethylformamide (2 mL) was treated with sodium hydride (29 mg of 60% grade reagent) and the mixture stirred under nitrogen for 10 minutes. A solution of chloromethyl methyl ether (62 mg) in anhydrous N,N-dimethylformamide (0.5 mL) was added dropwise followed by stirring at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous brine, the organic layer was washed twice with aqueous brine, separated, dried and the solvent evaporated under reduced pressure. The residue was purified on silica eluting with 30% ethyl acetate in isohexane to yield the sub-titled compound (145 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:21][CH2:20][NH:19][CH2:18][C:12]=3[N:13]=[C:14]([S:16][CH3:17])[N:15]=2)=[CH:5][CH:4]=1.Cl[C:25]1[C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CC(N(C)C)=O>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:21][CH2:20][N:19]([C:25]4[C:30]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:18][C:12]=3[N:13]=[C:14]([S:16][CH3:17])[N:15]=2)=[CH:5][CH:4]=1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Reactant: CS(=O)(=O)c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Temperature: 150 °C
Yield: 52.2 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (320 mg, 0.00089 mol) and 2-chloro-3-(methylsulfonyl)pyridine (200.0 mg, 0.0009915 mol) were dissolved in dioxane (5 mL) and DMA (0.5 mL), N,N-diisopropylethylamine (0.17 g, 0.0013 mol) was added and the mixture was heated in a sealed tube via microwave at 150° C. for 30 min. Solvent was removed and the residue was purified by flash chromatography over silica gel to obtain the product as a white solid (230 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(F)c2F)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(F)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (195 mg, 0.402 mmol), DMAP (25.8 mg, 0.201 mmol) and Et3N (0.18 mL) in dry CH2Cl2 at 0° C. was added methyl chloroformate (189 mg, 2.013 mmol), the mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give the crude product (R)-tert-butyl 3-((R)-(2,3-difluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (168 mg, 98%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.21 (m, 3H), 4.57 (m, 1H), 4.44 (d, 1H), 4.08 (m, 1H), 3.82 (m, 1H), 3.53 (s, 3H), 3.29 (d, 2H), 2.93 (m, 2H), 1.79 (m, 1H), 1.63 (m, 1H), 1.43 (s, 9H), 1.34 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[C:8]([O:17]CC2C=CC=CC=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[C:8]([OH:17])=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1O
Yield: 80.6 %

Procedure:
Methyl 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoate (343 mg, 0.7360 mmol) was dissolved in methanol (10 ml), added to a methanolic suspension (40 ml) of 10% palladium-carbon (100 mg) and stirred for 16 hours at room temperature in a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (223 mg, 0.5930 mmol, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[O:23])[CH2:20][CH2:21]1)(=[O:15])[CH3:14]
Reactant: Nc1cccc2cccnc12
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(C(=O)Nc2cccc3cccnc23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of 8-aminoquinoline (48.50 g) in dimethylformamide (300 ml) was stirred at 80° C., under nitrogen, as a mixture of 1-acetylpiperidine-4-carbonyl chloride hydrochloride (106.30 g) and potassium carbonate (93.0 g) was added in portions. The slurry was stirred at 80° C. overnight, quenched with water (1200 ml) and extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified first by high performance liquid chromatography (silica; 25:1 dichloromethane-methanol), followed by flash chromatography (silica; 50:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated to give 58.5 g (58.6%) of product, as an oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=C)=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+].O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[CH:18]=[CH:19][C:20]([CH:25]=[O:35])=[CH:21][C:22]=5[O:23][CH2:24][C:13]=34)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc2c(c1)OCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
To a mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4H-chromeno[4,3-c]isoxazole (Preparation 62G, 0.060 g, 0.146 mmol) and a 50% aqueous solution of NMO (0.030 mL, 0.146 mmol) at room temperature was added a 4% aqueous solution of osmium tetroxide (0.046 mL, 5.85 μmol). The reaction mixture was stirred at room temperature for 5 h. The intermediate diol had an HPLC ret. time=3.09 min and an LCMS M+1=445.0. Sodium periodate (0.047 g, 0.219 mmol) was added to the homogeneous mixture followed by water (0.10 mL), and the reaction was stirred for 60 min. at room temperature. Concentration under reduced pressure afforded a tan solid residue that was then diluted with ethyl acetate (40 mL), washed with the water (10 mL), and washed with brine (10 mL). The organic layer was collected, and the aqueous layer was washed with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole-7-carbaldehyde (0.057 g, 0.138 mmol, 95% yield) as a pale yellow solid. The product had an HPLC ret. time=3.49 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [CH2:1]([Mg]I)[CH:2]([CH3:4])[CH3:3].[C:7]1([P:13](Cl)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[CH2:1]([P:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[Mg]I
Reactant: Br[Mg]c1ccccc1
Reactant: ClP(Cl)c1ccccc1
Solvent: CCOCC
Product: CC(C)CP(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
265 ml of a 1.8 Molar titrated solution of 477 mmoles of isobutylmagnesium iodide in ether was added dropwise to a stirred solution of 85.35 g (476.8 mmoles) of phenyldichlorophosphine in 750 ml of anhydrous ether, maintained at -25° C. under an inert atmosphere. After stirring for 15 minutes at a temperature of -25° C., the reaction mixture was allowed to gradually warm to a temperature of 0° C. 308 ml of a 2.01 Molar solution of 620 mmoles of phenylmagnesium bromide in ether was added dropwise at a temperature of between 0° C. and +10° C., then the solution was warmed to reflux for one-half hour. The mixture was then hydrolyzed. Distillation yielded an impure isobutyldiphenylphosphine. 31P-NMR δ=-20.66 ppm (relative intensity 999.96), δ=-5.88 ppm (relative intensity 26.64 probably triphenylphosphine), δ=-34.23 ppm (relative intensity 74.75, probably diisobutylphenylphosphine), and δ=-60.57 ppm (relative intensity 123.65, probably (phenyl)(i-butyl)PH), BP=97°-101° C. at 0.15 torr.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C@@H:21]23)[CH:26]=1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][NH:33][CH2:34][C@@H:21]23)[CH:26]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: FC(F)(F)c1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(F)(F)F)c1

Procedure:
Using 2,4-bis(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 129. LRMS (ES)+: 472.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a clean, dry 100 mL round bottom flask is added methyl 3-hydroxy-5-nitrobenzoate (240a, 0.4 g, 2 mmole, 1 eq), orthofluorobenzyl bromide (0.57 g, 3 mmole, 1.5 eq), potassium carbonate (0.56 g, 4 mmole, 2 eq), and DMF (3 mL). The reaction mixture was stirred at room temperature for 18 h and quenched with water and ethyl acetate. The product was extracted into the organic layer, dried over magnesium sulfate, filtered and evaporated. A white solid was obtained (0.49 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.59 (dt, 1H, J=1.8, 8.0 Hz), 7.42 (m, 1H), 7.24 (dt, 1H, J=1.0, 8.0 Hz), 7.22 (dt, 1H, J=1.3, 8.0 Hz), 5.33 (s, 2H), 3.98 (s, 3H). Calc'd for C15H12FNO5; m/z (M+H+)=306; found 306.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH3:27])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: CCCO
Product: CCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 75 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-propanol (6.0 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 75% yield (17.6 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (t, J=7.45 Hz, 3 H) 1.68-1.77 (m, 2 H) 2.44 (s, 3 H) 4.23 (t, J=6.65 Hz, 2 H) 6.90 (s, 1 H) 7.36 (dd, J=8.05, 7.70 Hz, 1 H) 7.42 (ddd, J=8.05, 2.34, 1.22 Hz, 1 H) 7.44 (dd, J=8.73, 1.95 Hz, 1H) 7.71 (dd, J=8.73, 0.60 Hz, 1 H) 7.71 (dd, J=1.95, 0.60 Hz, 1 H) 7.71 (dd, J=2.34, 1.53 Hz, 1 H) 7.84 (ddd, J=7.70, 1.53, 1.22 Hz, 1 H). MS (ESI+) m/z 424 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=3)[C:31]#[N:32])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=[O:36].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([S:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=3)[C:31]([NH2:32])=[O:36])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(F)c(C#N)c2)n1-c1ccc(F)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(F)c(C(N)=O)c2)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-2-fluorobenzonitrile (270 mg, 0.527 mmol) in TFA/H2SO4 (6 mL, 4:1, v/v) was heated at 65° C. for 8 h. The reaction mixture was cooled to room temperature, and the residue was partitioned into DCM and water. The separated organic layer was washed with satd NaHCO3, dried over MgSO4, filtered through Celite™, and concentrated. Purification by flash chromatography (DCM/EtOAc, 1:1) gave the title product (217 mg, 77%) as a white foam. 1H NMR (CDCl3, 400 MHz): δ 1.47 (s, 6H) 4.13 (s, 2H), 6.04 (br s, 1H), 6.36 (m, 2H), 6.65 (br s, 1H), 6.81 (m, 3H), 6.96 (s, 1H), 7.06 (m, 1H), 7.27 (m, 2H), 7.40 (m, 1H), 7.91 (m, 1H); MS (EI) m/z 532 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([NH:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH3:45].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=[C:5]([C:7]([N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:42][CH2:43][CH2:44][CH3:45])=[O:9])[N:6]=1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1Br
Reactant: CCCCNCCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred solution of 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (2.4 g, 7.47 mmol) in dry DMF (40 mL) was added HATU (4.26 g, 11.2 mmol), dibutylamine (1.15 g, 8.9 mmol) and diisopropyl ethylamine (2.84 g, 22.4 mmol) successively at 0° C. The reaction mixture was allowed to warm to room temperature over 30 minutes and stirring was continued for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude compound. The crude material was purified by flash chromatography (gradient from 20 to 30% EtOAc/hexanes) to provide the title compound (2.81 g, 87%). 1H NMR (CDCl3) δ 7.68 (s, 1H), 5.28 (s, 2H), 3.89 (t, J=8.0 Hz, 2H), 3.56 (t, J=8.0 Hz, 2H), 3.44 (t, J=8.0 Hz, 2H), 1.57-1.65 (m, 4H), 1.25-1.45 (m, 4H), 0.91-0.95 (m, 8H), 0.01 (s, 9H); MS(ESI+) m/z 434.2 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:12]([S:13](Cl)(=[O:15])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].[OH-:20].[Na+]>>[CH3:1][NH:2][S:13]([C:12]1[C:4]([O:20][C:4]2[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=2)=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])(=[O:15])=[O:14]
Reactant: [OH-]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Reactant: CN
Agent: [Na+]
Product: CNS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1

Procedure:
To a mixture of 1N sodium hydroxide (60 ml) and aqueous methylamine (3.43 g containing 1.2 g of methylamine) 4-chloro-5-chlorosulphonyl-3-nitro-benzoic acid (9.3 g) was added in portions, while stirring and keeping the mixture at 0°-3°C. Then the reaction mixture was left standing until it reached room temperature, after which the 4-chloro-5-methylsulphamyl-3-nitro-benzoic acid was precipitated by slow acidification with 4N hydrochloric acid. The precipitate was collected by suction and recrystallized from aqueous ethanol. The melting point was 228°-229°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:26][O:27][C:28](N1C=CC(Cl)=CN1)=[O:29].[CH2:37]1[N:42]2CC[N:39]([CH2:40][CH2:41]2)[CH2:38]1>CN(C=O)C>[CH3:26][O:27][C:28]([C:40]1[CH:41]=[N:42][C:37]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]3[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:12]([F:15])([F:13])[F:14])=[C:2]([Cl:1])[C:7]=2[Cl:8])=[CH:38][N:39]=1)=[O:29]
Reactant: C1CN2CCN1CC2
Reactant: COC(=O)N1C=CC(Cl)=CN1
Reactant: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2Cl)cn1
Yield: 646.3 %

Procedure:
In analogy to Example 163, 5-[2-(2,3-dichloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 197, step 5; 150 mg, 0.38 mmol) was reacted with methyl-5-chloro-2-pyridazinecarboxylate (67 mg, 0.38 mmol), 0.069 ml TEA and 6 mg DABCO in 2 ml DMF for 4 h at rt to give 184 mg of the title compound as an off-white solid. MS (M+H+)=532.1