Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=2[CH:22]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]([F:30])([F:31])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=2[CH:22]=1
Reactant: COC(=O)C1=Cc2cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2CCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To methyl 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (494 mg, 1.15 mmol) dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml) was added a 1N aqueous solution of sodium hydroxide (3.5 ml), and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was mixed with 1 N hydrochloric acid (3.5 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (475 mg, 1.10 mmol, 96%).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].[CH2:12](O)[CH3:13]>>[ClH:3].[NH2:5][CH:6]([CH2:10][CH3:11])[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCO
Reactant: CCC(N)C(=O)O
Product: CCOC(=O)C(N)CC
Product: Cl
Temperature: 27 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
Thionyl chloride (1.25 moles) was added to a solution of 2-aminobutyric acid (1 mole) in SD12A3 (95% ethanol/5% toluene) at a temperature of <5° C. When addition was complete, the mixture was stirred at 27° C. for 16 hours and the resulting precipitate filtered off and washed with methyl t-butyl ether to give the desired product as a white solid (97% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[C:22](O)(=O)C.Cl>C(O)C>[CH:11]([C:7]1[CH:8]=[C:9]([CH2:22][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH2:6])([CH3:13])[CH3:12]
Reactant: C1COCCN1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(CN2CCOCC2)cc(C(C)C)c1N
Yield: 172.1 %

Procedure:
A solution of 2,6-diisopropylaniline (35.45 g, 0.20 mol), 37% aqueous formaldehyde (16.2 mL, 0.20 mol), morpholine (17.42 g, 0.20 mol), acetic acid (6.00 g, 0.10 mol), and ethanol (25 mL) were reacted under conditions similar to Example 1. After concentration on the rotary evaporator, the residue was dissolved in diethyl ether and washed with aqueous sodium bicarbonate and water. After drying the ether solution, a solution of hydrogen chloride (0.20 mol) in ethanol was added. Filtration and drying gave the hydrochloride salt of the title compound (47.58 g, 76.0%). The salt (20.0 g, 0.6 mol) was dissolved in acetone and treated with solid potassium bicarbonate. Upon filtration and evaporation of solvent, the title compound was obtained (16.27 g, 92.2%).
Reaction SMILES: C([C:4]1[C:5](CC=C)=[C:6]([CH:8]=[CH:9][C:10]=1[C:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])[CH3:12])[OH:7])C=C>C1(C)C=CC=CC=1.O1CCCC1>[OH:7][C:6]1[CH:5]=[CH:4][C:10]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])=[CH:9][CH:8]=1
Reactant: C=CCc1c(O)ccc(C(C)(C)c2ccc(O)cc2)c1CC=C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 70 °C

Procedure:
A 0.05 mL portion of hydrosilylation catalyst (a solution of platinum-olefin complex in toluene) was added to a solution of R7T8OSi(Me2)H, (R=cyclohexyl) (11.0 g, 10.2 mmol, 1eq) and diallylbisphenol A (12.6 g, 41 mmol, 4eq) in tetrahydrofuran (110 mL) contained in a thick walled glass reaction vessel. The reaction mixture was heated to 70° C. for 72 h. After this time the tetrahydrofuran solvent was removed to give a viscous, semisolid residue. Extraction of the residue with acetonitrile gave a white solid which was collected by vacuum filtration and dried to provide 13.6 g (96% of theory) of the mono-POSS bisphenol A as a pale yellow solid. The product was mono-allyl, mono-dimethylsiloxypropyl hepatcyclohexyloctasilsesquioxane bisphenol A (or monoPOSS-monoallyl-bisphenol A) (or R37T8 (R2 -R4)1) or CH2 =CHCH2 (HO)C6H3C(CH3)2C6H3 (OH)(CH2)3Si(CH3)2OSi8O12 (c--C6H11)7. This is a new chemical compound and an example of formula 4 (#4).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:18]([O:20][CH3:21])=[O:19])[C:16](=[O:17])[CH:9]1[CH2:10][C:11]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:12]=12)C1C=CC=CC=1.[C:28]([OH:31])(=[O:30])[CH3:29].[H][H]>[Pd].C(O)CC>[C:18]([OH:20])(=[O:19])/[CH:13]=[CH:29]/[C:28]([OH:31])=[O:30].[C:18]([C:13]12[C:16](=[O:17])[CH:9]([CH2:10][C:11]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:12]=31)[N:8]([CH3:1])[CH2:15][CH2:14]2)([O:20][CH3:21])=[O:19]
Reactant: CC(=O)O
Reactant: [H][H]
Reactant: COC(=O)C12CCN(Cc3ccccc3)C(Cc3ccc(OC)cc31)C2=O
Agent: [Pd]
Solvent: CCCO
Product: COC(=O)C12CCN(C)C(Cc3ccc(OC)cc31)C2=O
Product: O=C(O)/C=C/C(=O)O

Procedure:
Material V (0.01 m) in 50 ml. acetic acid was hydrogenated at 40 psi using 300 mg 10% palladium on carbon as catalyst until hydrogen uptake stopped (~100% theoretical observed). The catalyst was removed by filtration and the filtrate concentrated. The residue was treated with dilute potassium carbonate and extracted with methylene chloride to give an oil which was converted to a hydrogen fumarate salt in 1-propanol; mp 168°-171° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>CCOC(C)=O>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccnc(Br)c1
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2cccc(F)c2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 144 %

Procedure:
A 100-mL recovery flask containing 2-bromo-4-methoxypyridine (1.446 g, 7.69 mmol, purchased from Combi-Blocks, Inc.), 3-fluorophenylboronic acid (2.152 g, 15.38 mmol, purchased from Oakwood Products, Inc.), and 1,1′-bis(diphenylphosphino)ferrocene palladium(11)dichloride dichloromethane adduct (0.314 g, 0.385 mmol) was flushed with N2 and subsequently charged with dioxane (29 mL) and 1.9 M Na2CO3 in H2O (10 mL). The black-red mixture was stirred at 85° C. overnight. The next morning, after cooling to rt, the dark red mixture was diluted with H2O and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a black oil. Column chromatography (50 g Snap Ultra column, 10-100% EtOAc/hept) afforded 2-(3-fluorophenyl)-4-methoxypyridine (2.25 g, >99% yield) as a viscous yellow oil. m/z (ESI) 204.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:8]1)[CH3:2].S(=O)(=O)(O)[OH:28].[OH-].[K+]>O>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:28])=[CH:13][CH:14]=2)[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[N:8]1)[CH3:26]
Reactant: O=S(=O)(O)O
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccc(O)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture consisting of 14.1 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)indazole and 4.3 g of 95% by weight sulfuric acid was stirred for 3 hours at 80° C. To the mixture was added 13 ml of water, and the pH of the mixture was adjusted to 14 with potassium hydroxide. After the mixture was washed twice with 20 ml of chloroform, water was removed under reduced pressure. To the residue were added 12.5 g of potassium hydroxide and 0.6 ml of water, and the mixture was stirred for 8 hours at 250° C. After cooling, to the mixture was added hydrochloric acid to separate crystals. The crystals were obtained by filtration and dried to give 6.28 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-5-hydroxyindazole having the following analytical values in a yield of 40%.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1([CH3:57])[CH2:56][O:55][CH2:54][CH2:53][NH:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][C:51]2([CH3:57])[CH3:50])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC1(C)COCCN1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCOCC2(C)C)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-dimethylmorpholine and isolated as colorless gum (12.5 mg, 64%). MS (m/e): 415.4 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4]3[CH2:5][N:6]([C:15](=[O:17])[CH3:16])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.Cl.Cl.[N:20]1([C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C)C=O>[N:20]1([CH:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:2]3[C:3]4[C:4]5[CH2:5][N:6]([C:15](=[O:17])[CH3:16])[CH2:7][CH2:8][C:9]=5[S:10][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:30][CH2:31]2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CC(=O)N1CCc2sc3ncnc(Cl)c3c2C1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of 1-[3-chloro-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-one (100 mg, 0.37 mmol, 1.00 equiv) and trans-4-(morpholin-4-yl)cyclohexan-1-amine dihydrochloride (412 mg, 1.61 mol, 4.32 equiv) in 10 mL of N,N-dimethylformamide was added TEA (200 mg, 1.98 mmol, 5.29 equiv) and the resulting solution was stirred for 12 h at 50° C. under nitrogen. After concentration in vacuo, the crude product was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 35% in 11 min, up to 95% in 1.5 min, down to 10% in 1.5 min); detector: UV 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure and lyophilized overnight to give 76.9 mg (50%) of 1-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl)ethan-1-one as a white solid. MS (ES): m/z 416 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 1.40-1.60 (m, 4H), 2.08 (d, 2H), 2.20-2.45 (m, 6H), 2.60-2.70 (m, 4H), 2.92, 3.02 (t, t, 2H), 3.70-3.80 (m, 4H), 3.89, 3.95 (t, t, 2H), 4.05-4.22 (m, 1H), 4.96, 5.00 (s, s, 2H), 8.29, 8.30 (s, s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([O:13][C:14]3[C:22]4[C:17](=[CH:18][C:19]([N+:23]([O-])=O)=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([O:13][C:8]3[C:7]4[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=4)[NH:10][N:9]=3)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2c(Oc3n[nH]c4cc([N+](=O)[O-])ccc34)n[nH]c2c1
Agent: [Pd]
Product: Nc1ccc2c(Oc3n[nH]c4cc(N)ccc34)n[nH]c2c1

Procedure:
Indazolyl ethers can be prepared by the process outlined in Scheme 29. 6-Nitro-1H-2-hydroindazol-3-one 126 is protected such as with Boc2O and DMAP in CH2Cl2 at a temperature of about RT, to give the protected 6-nitro-2-hydroindazol-3-one. The protected 6-nitro-2-hydroindazol-3-one is reacted with an alcohol (where Rx is an appropriate substitutent selected from the possible substitutents on R) and Ph3P in a solvent, such as THF, and DEAD, at a temperature of about RT, to give the protected 6-nitro(indazol-3-yl)ether. The nitro intermediate is hydrogenated, such as with an H2 atmosphere in the presence of a catalyst, such as Pd/C, to give the protected 6-amino (indazol-3-yl)ether 127. The amine 127 is coupled and 2-chloronicotinic acid in a solvent, such as an alcohol, preferably pentanol, at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 130° C. to give the coupled and deprotected compound 128.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: Cc1ccc2[nH]cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2[nH]cc(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(5-methyl-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.061 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(5-methyl-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.018 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[O:11].[OH-:20].[Na+]>C1COCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([CH2:4][CH:5]([CH2:10][CH2:9][CH2:8][SH:7])[C:6]([OH:11])=[O:20])[CH:12]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(Cl)c(CC2CCCSC2=O)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(CC(CCCS)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A solution of 3-(2-Chloro-5-methoxycarbonylbenzyl)-tetrahydrothiopyrane-2-one IV (9.26 g, 31.0 mmol) in THF (70 mL) was purged for 15 minutes with nitrogen. A degassed aqueous sodium hydroxide solution (2.2 M, 70 mL, 154 mmol) was added to the solution and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was washed with ether, acidified by 3N HCl at 0° C., and extracted with ether. The extract was dried over MgSO4 and concentrated to afford 5-carboxy-2-chloro-alpha-(3-mercaptopropyl)benzenepropanoic acid 10 (8.42 g, 27.8 mmol, 90%) as a white solid: 1H NMR (CD3OD) δ 1.50-1.80 (m, 4H), 2.35-2.50 (m, 2H), 2.65-2.75 (m, 1H), 2.91 (dd, J=6.2, 13.8 Hz, 1H), 2.96 (dd, J=8.8, 13.8 Hz, 1 H), 7.39 (d, J=8.3 Hz, 1H), 7.76 (dd, J=2.0, 8.3 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H); 13C NMR (CD3OD) δ 25.1, 32.5, 33.2, 37.4, 46.8, 130.8, 131.2, 134.0, 139.1, 140.5, 169.2, 178.9. Anal. Calcd for C13H15ClO4S: C, 51.57; H, 4.99; S, 10.59; Cl, 11.71. Found: C, 51.59; H, 4.94; S, 10.43; Cl, 11.80.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][C:14]=1[S:21]([CH3:24])(=[O:23])=[O:22].C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:10]2[CH:9]=[C:8]([Cl:11])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]2=[NH:1])=[CH:15][C:14]=1[S:21]([CH3:24])(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1cc(CBr)ccc1Br
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(Cn2cc(Cl)cc(C(N)=O)c2=N)ccc1Br
Product: Cl
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A solution of 2-amino-5-chloronicotinamide (373 mg) and 1-bromo-4-(bromomethyl)-2-(methylsulfonyl)benzene (1.07 g) in DMF (5 ml) was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 1N sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained yellow solid was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (310 mg).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[C:21]([F:29])[C:22]([F:28])=[C:23]([F:27])[C:24]=3[F:26])[NH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[F:26][C:24]1[C:23]([F:27])=[C:22]([F:28])[C:21]([F:29])=[C:20]2[C:25]=1[C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[CH:18][NH:19]2
Reactant: O=C(OCc1ccccc1)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1c(F)c(F)c2c(C3CCNCC3)c[nH]c2c1F
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of N-benzyloxycarbonyl-4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (20.0 g, 49.21 mmol) [prepared as described in Step 1 above] in argon deoxygenated 80% ethanol/tetrahydrofuran (800 ml) was added 10% Pd-C (5 g), and the resulting mixture was stirred under a hydrogen atmosphere (1 atm) for 3 h. The mixture was degassed under argon, filtered through Celite, and concentrated in vacuo. The solid residue was recrystallized from methylene chloride/hexane to afford 4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (90%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH2:8]([O:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([CH3:20])=[CH:18][N:17]=[C:16]([NH2:21])[C:15]=2[N:22]=1)[CH3:9]>>[NH2:21][C:16]1[C:15]2[N:22]=[C:12]([CH2:11][O:10][CH2:8][CH3:9])[N:13]([CH2:19][CH2:14][CH2:15][CH2:16][NH:17][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:14]=2[C:19]([CH3:20])=[CH:18][N:17]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)ncc(C)c2[nH]1
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(=O)(=O)N(C)C

Procedure:
Using the method of Examples 115-135, dimethylsulfamoyl chloride was reacted 4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to the desired product. The observed accurate mass was 385.2029.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:27](Cl)[C:28]([OH:30])=[O:29]>C(O)(C)C>[CH:4]1[C:3]2[C:8]3([CH2:10][CH2:9]3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH:27]([C:28]([OH:30])=[O:29])[O:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: Oc1ccccc1C1(c2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)C1Oc2ccccc2C2(CC2)c2ccccc2O1
Reaction time: 24 h

Procedure:
An 18.5 g (0.082 mole) sample of unpurified 1,1-bis(2-hydroxyphenyl)cyclopropane was combined with 44.0 g (0.32 mole) of potassium carbonate, 2.0 g (0.012 mole) of potassium iodide, 8.0 ml of dichloroacetic acid, and 400 ml of isopropyl alcohol. The mixture was heated at reflux with stirring for 24 hours. Another 8 0 ml of dichloroacetic acid was added and the mixture heated at reflux with stirring for another 48 hours. The volatiles were then removed by evaporation under reduced pressure. The solid that remained was dissolved in 300 ml of water. The resulting solution was extracted with 500 ml of ether, acidified with concentrated hydrochloric acid (carefully due to foaming), and then extracted with three 500 ml portions of ether. The latter ether extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound in crude form as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].N1C=CC=CC=1>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
3-(4-Benzyloxyphenyl) propionic acid prepared in Example S (30 g, 117 mmol) was taken up in 300 mL of thionyl chloride. The reaction was kept under reflux for 5 hours, then cooled and concentrated. The residue was dissolved in 300 mL of CH2Cl2 and treated with N,O-dimethylhydroxyamine hydrochloride (14.1 g, 146 mmol) and 60 mL of pyridine at 0° C. The reaction was stirred overnight. The reaction was quenched with dilute HCl and extracted into EtOAc, and the organic layer was washed with sodium bicarbonate solution and dilute HCl and dried. The organic layer was dried (MgSO4) and concentrated. The residue was used further as crude reaction mixture or purified by flash silica gel column chromatography, eluting with EtOAc:hexane (1:9, then switching to 2:3).
Reaction SMILES: CC(C)(C)C[O:4][S:5]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].C([O-])CC.[Na+].C(N(CC)CCS)C>O1CCOCC1>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([S:5]([OH:7])(=[O:6])=[O:4])[CH:9]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Agent: CCC[O-]
Agent: CCN(CC)CCS
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Yield: 72.6 %

Procedure:
A stirred mixture of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester (1.42 g, 2.39 mmol), 2M sodium propanolate solution (3 ml, 6 mmol), 2-(diethylamino)-ethanthiol (0.37 g, 2.75 mmol) and dioxane (15 ml) was heated under reflux conditions for 24 h and evaporated. Water (40 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 ml). The water layers were combined, acidified with 2N HCl and extracted with ethyl acetate (2×50 ml). The latter two organic layers were combined, washed with brine (50 ml), dried (MgSO4) and evaporated to yield the crude 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid as a brown solid (0.91 g, 51%). Thionyl chloride (20 ml) and DMF (4 drops) were added and the stirred mixture was heated under reflux conditions for 4 h, evaporated and purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield the title compound as a light brown solid (0.43 g, 33%). MS (ISP) 542.2 [(M)+]; mp 176° C.