Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:24])=[CH:26][CH:27]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise 4-heptylbenzoyl chloride (950 μL) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (1051 mg) was obtained as a white solid (90%) in 96.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br.[CH2:2]([C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([F:25])[CH:18]=2)=[CH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(O)=O>[CH2:2]([C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:25])[CH:18]=2)=[CH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnc(Cc3ccccc3)n(C)c2=O)cc1F
Agent: Br
Solvent: CC(=O)O
Product: Cn1c(Cc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Temperature: 130 °C
Reaction time: 3 h

Procedure:
HBr (40%, ACS reagent grade) was added to 2-benzyl-5-(3-fluoro-4-methoxyphenyl)-3-methyl-3H-pyrimidin-4-one (Step 4, 9 g, 26 mmol) in HOAc (90 mL). The reaction was heated to 130° C. and monitored by HPLC. After 3 h, the reaction was cooled to RT and the solid was collected by filtration. The solid was washed with H2O and Et2O and dried to afford the title compound as a yellow solid. MS (ESI pos. ion) m/z: 311.1. Calc'd for C18H15FN2O2: 310.11.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[Cl:32][CH2:33][C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)=[O:35]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(trifluoromethyl)benzamide (200 mg, 0.450 mmol) produced in Example C8(iv) in N,N-dimethylformamide (5 mL) was added chloroacetyl chloride (104 μL, 0.900 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with a mixed solution of ethyl acetate and hexane to give the title compound (218 mg, 93%) as a white powder. The powder was used for the next reaction without further purification operation.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]#[N:28])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27]#[N:28])[CH2:25][CH2:26]5)=[CH:20][CH:19]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Reactant: N#CC1(c2ccc(Cl)cc2)CC1
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C#N)CC5)cc4)nc23)cn1

Procedure:
Reaction of 8-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine with 1-(4-chlorophenyl)-1-cyclopropanecarbonitrile following general procedure 2 gives the title compound as a solid.
Reaction SMILES: [C:1](=[O:3])=[O:2].[OH-:4].[OH-].[Mg+2:6]>>[C:1](=[O:4])([OH:3])[O-:2].[Mg+2:6].[C:1](=[O:4])([OH:3])[O-:2]
Reactant: [OH-]
Reactant: O=C=O
Agent: [Mg+2]
Product: O=C([O-])O

Procedure:
The instant invention is based upon the discovery of a method for recovering extremely high purity magnesium carbonate from a magnesium hydroxide slurry. The magnesium hydroxide slurry can be produced in any conventional way, for example by adding lightly burned dolomite or lime, preferably the former, to sea water or the like to precipitate magnesium hydroxide, and then processing the precipitated hydroxide in a conventional way. The slurry can also be produced by suspending in water burned magnesite, burned dolomite or other natural or processed materials which will form magnesium hydroxide that can be carbonated. Materials which form slurries containing less than about 90 percent of magnesium oxide, on a dry solids basis, are comparatively undesirable because they usually contain substantial amounts of water-soluble impurities which contaminate the final product and, in addition, are expensive because they require large quantities of high purity carbon dioxide. The method of the invention involves carbonating a magnesium hydroxide slurry to produce magnesium bicarbonate, and then continuing the carbonation to convert a part of the magnesium bicarbonate to a crystalline magnesium carbonate so that the slurry contains both dissolved magnesium bicarbonate and a crystalline magnesium carbonate precipitate. Insoluble material is subsequently removed from the carbonated slurry by filtration, and the filtrate is decarbonated, for example by heating, vacuum, or both. Finally, hydrous magnesium carbonate of high purity, which is precipitated as a result of the decarbonation, is recovered, for example by filtration.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1>[CH3:31][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
A solution of the product of Example 44, step C (85 mg, 0.189 mmol), trimethylboraxine (0.026 mL, 0.189 mmol), potassium carbonate (78 mg, 0.567 mmol) and tetrakis-(triphenylphosphine)palladium (21.8 mg, 0.0189 mmol) in water/1,4-dioxane (1:10, 0.55 mL) was heated to 110° C. for 5 h and then stirred at ambient temperature for 15 h. The reaction mixture was then filtered through a celite bed and concentrated in vacuo to afford the crude product which was then purified by column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to provide tert-butyl 6-methyl-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (43 mg, 53%): 1H NMR (CDCl3, 300 MHz) δ 7.98-7.94 (m, 3H), 7.63 (s, 1H), 7.54-7.46 (m, 3H), 4.56 (s, 2H), 3.83 (br s, 2H), 2.86 (br s, 2H), 2.51 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.CN([CH:22]=[O:23])C1C=CC=CC=1.S(=O)(=O)(O)O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:22]=[O:23]
Reactant: Fc1cccc(F)c1
Reactant: CN(C=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1F
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
1,3-Difluorobenzene (25 g., 0.22 mole) was dissolved in 150 ml. of tetrahydrofuran and cooled to -50° C. Butyl lithium (99 ml. of 2.3 M in hexane, 0.228 mole) was added over 20 minutes, maintaining the temperature at -50° C. After 1.5 hours of stirring at the same temperature, N-methylformanilide (29.7 g., 0.22 mole) in 50 ml. of tetrahydrofuran was added over 20 minutes at -50° C. After an additional 1.5 hours of stirring at -50° C., the reaction mixture was poured slowly into 1 liter of cold 1 N sulfuric acid, and extracted with three portions of ether. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was distilled. Middle cuts were combined to yield 2,6-difluorobenzaldehyde (18.2 g., 58%; b.p. 72°-74°/12 mm.).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[N:19]=1)[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10]CC)=O)[CH2:2][CH3:3]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:29]1([CH3:30])[CH:28]=[C:27]([CH3:31])[CH:26]=[C:25]([CH3:32])[C:24]=1[C:20]1[N:19]2[C:18]([CH:23]=[CH:22][CH:21]=1)=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:10]
Reactant: CCCOC(C=C(C(=O)OCC)C(=O)OCC)c1cccc(-c2c(C)cc(C)cc2C)n1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCOc1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reaction time: 0.25 h
Yield: 7.1 %

Procedure:
Diethyl 2[2-propoxy-2-(6-mesitylpyridin-2-yl)-ethylidene]-malonate (0.189 g, 0.43 mmol) was dissolved in 4 mL of Dowtherm A (phenyl ether: biphenyl 2:1 ratio). The solution was placed in a pre-heated oil bath set at 220° C. The reaction stirred at this temperature for 15 minutes. The solution was cooled and flash chromatographed (20-50% ethyl acetate/hexanes) to give 0.012 g (7% yield) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[NH:27][CH2:26][CH2:25][CH2:24]3)=[O:16]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[N:27]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:26][CH2:25][CH2:24]3)=[O:16]
Reactant: COC(=O)c1cccc2c1[C@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 43 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 43% of theory; TLC: rf=0.30 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[NH:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=[C:12]3[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(Nc1ccc2c(c1)OCCO2)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of the compound from Step A and 4.0 g (48 mmol) of sodium bicarbonate in 50 mL of 1,4-dioxane was added 3.0 mL (24 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as yellow solid. LC/MS 369.1 (M+1).
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]1=[O:16])(=O)C.[NH3:17]>CO>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH2:17])=[O:12])[C:6]1=[O:16]
Reactant: N
Reactant: CCOC(=O)CN1CCC(OC(C)=O)C1=O
Solvent: CO
Product: NC(=O)CN1CCC(O)C1=O
Reaction time: 1 h

Procedure:
0.40 g of ethyl (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetate is treated with 45 ml of a saturated solution of ammonia in methanol. The mixture is left to stand at room temperature for 1 hour and then evaporated. The residue is treated four times with acetonitrile and in each case again evaporated. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which melts at 163°-164° after recrystallization from methanol/diethyl ether (1:3).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36]>CN(C=O)C>[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH:41][C:15](=[O:17])[CH2:14][CH2:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:10][CH:9]=1)=[O:18])[CH3:36]
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h
Yield: 449.2 %

Procedure:
An aliquot of 4-[[4-(aminoiminomethyl)phenyl]-amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (1.36 g) was added to dry DMF (50 ml) followed by N-methylmorpholine (0.6 mL) and isobutyl chloroformate (0.65 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred for 5 min, then 0.45 g β-alanine ethyl ester hydrochloride was added followed by 0.6 mL of N-methylmorpholine. After 4 hr, the solvent was removed under reduced pressure and the product was purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to give 4.4 g of white solid: 1H NMR (d6 -DMSO) δ 1.2 (t, 3H, J=7 Hz), 2.45 (m, 4H), 2.6 (m, 2H), 3.25 (m, 2H), 4.05 (q, 2H, J=7 Hz), 7.8 (s, 4H), 8.0 (m, 1H), 8.85 (bs, 2H), 9.18 (bs, 2H), 10.4 (s, 1H); MS (ES) m/z 335.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.[CH3:25][C:26]([CH3:28])=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH:26]([CH3:28])[CH3:25])[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.152 g, 0.4 mmol) in methanol-acetic acid (95:5) (5 mL) was treated with acetone (5 mL) and sodium cyanoborohydride (0.111 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 24 h, then it was diluted with 1 N NaOH until pH 13 and extracted with dichloromethane. The organic extracts were combined, dried with MgSO4, filtered and concentrated in vacuo to provide the title compound (0.158 g, 92%). The crude material was triturated in dichloromethane-hexanes, giving a white powder which was filtered and dried under vacuum at 60° C.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:46])[NH:36][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([CH3:39])[CH3:38])[CH:30]=2)=[CH:27][C:12]2[C:13]([C:23]([NH:25][CH3:26])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1>N1C=CC=CC=1>[CH:1]1([S:4]([NH:8][C:9]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:46])[NH:36][C:37]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([CH3:39])[CH3:38])[CH:30]=3)=[CH:27][C:12]3[C:13]([C:23]([NH:25][CH3:26])=[O:24])=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[O:15][C:11]=3[CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(=O)(=O)C3CC3)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Cyclopropanesulfonyl chloride (8 μL, 0.058 mmol) was added to a stirring solution of 6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (20 mg, 0.038 mmol) in Pyridine (0.5 mL) at rt. It was allowed to stir for 2 hours. The mixture was concentrated purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (17 mg, 70%). 1H NMR (500 MHz, CD3OD) δ ppm 8.41 (1H, br. s.), 7.91-8.01 (3H, m), 7.78-7.86 (2H, m), 7.61-7.71 (2H, m), 7.58 (1H, t, J=7.63 Hz), 7.41-7.49 (2H, m), 7.24-7.33 (4H, m), 7.18 (1H, t, J=6.87 Hz), 2.94 (3H, s), 2.34-2.43 (1H, m), 1.77 (6H, s), 0.80-1.03 (4H, m). LC-MS retention time: 1.53 min; m/z (MH+): 626. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.40 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=12.65 min, purity=99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9]([SH:12])=[N:10][N:11]=1.CCN(CC)CC.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35]Br>C(Cl)Cl>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35][S:12][C:9]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:11][N:10]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: COc1ccc(Cc2nnc(S)n2-c2ccc(F)cc2)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nnc(SCc3c(F)cccc3F)n2-c2ccc(F)cc2)cc1OC
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 5-(3,4-dimethoxybenzyl)-4-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol (119 mg, 0.345 mmol) and Et3N (53 μL, 0.379 mmol) in CH2Cl2 (1.8 mL) was added 2,6-difluorobenzyl bromide (88 mg, 0.414 mmol). After stirring 2 h, the reaction mixture was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to yield the title product (107 mg, 66%) as a white foam. 1H NMR (400 MHz, (CD3)2CO) δ 7.25 (m, 1H), 7.10 (m, 2H), 6.98 (m, 2H), 6.84 (m, 2H), 6.63 (d, J=8.2 Hz, 1H), 6.4 (d, J=2.0 Hz, 1H), 6.31 (m, 1H), 4.45 (s, 2H), 3.82 (s, 2H), 3.61 (s, 3H), 3.54 (s, 3H); MS (EI) m/z 472.3 (MH+).
Reaction SMILES: [C:1]1([Si:7](Cl)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:18])([F:17])[S:13]([OH:16])(=[O:15])=[O:14]>>[O:16]([Si:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])[S:13]([C:12]([F:18])([F:17])[F:11])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C[Si](C)(Cl)c1ccccc1
Product: C[Si](C)(OS(=O)(=O)C(F)(F)F)c1ccccc1
Reaction time: 6 h

Procedure:
Phenyldimethylsilyl triflate was prepared by cooling 5 ml of phenyldimethylsilyl chloride to a temperature between 0° and 5° C., and then adding 4.2 ml of trifluoromethanesulfonic acid in a dropwise fashion over a period of about 30 minutes. The resulting mixture was then stirred at a temperature of between 0° and 5° C. for about 6 hours, and subsequently left to stand, with cooling, overnight. The resulting preparation could be used without any further purification.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26](O)C.C=O>O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=3)[CH2:26]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)cc1C(F)(F)F
Reactant: CCO
Agent: C=O
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)cc1C(F)(F)F

Procedure:
2-Phenylamino-N-(3-trifluoromethyl-4-sulphamoylphenyl)-acetamide (11.2g) was added to ethanol (200 ml) and paraformaldehyde (1.3g) in water (400 ml) added thereto under reflux. The mixture was refluxed 11/2 hr, cooled and worked up as in Example 6(c) to yield 11,8 g, m.p. 235°-238°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]2[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:28][C:23]1[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:30][CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 86.1 %

Procedure:
Using the procedure described in Example 93, Part A, 3-nitrobenzoyl chloride (2.3 mmol) and N1-(4-methoxybenzoyl)-1,2-benzenediamine (2.1 mmol) yielded 708 mg (86%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC([N:33]1[CH:37]=[C:36]([CH2:38]O)[CH:35]=[N:34]1)=O)(C)(C)C>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:38][C:36]2[CH:37]=[N:33][NH:34][CH:35]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Product: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Yield: 57.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g) and 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (2.4 g) as starting materials, N-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-carboxamide (2.9 g) was obtained.