Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:21][CH:5]2[CH:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7][C:8]3[CH:9]([CH2:10][O:11][N:12]=3)[CH:4]2[O:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C>[OH:3][CH:4]1[CH:9]2[CH2:10][O:11][N:12]=[C:8]2[CH2:7][CH:6]([O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16])[CH:5]1[OH:21]
Reactant: CC1(C)OC2C(O[Si](C)(C)C(C)(C)C)CC3=NOCC3C2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O)C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
4,5-(Dimethylmethylenedioxy)-6-(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (327 mg) was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 1N hydrochloric acid was added, followed by stirring the mixture at room temperature for 4 hours. The reaction mixture was diluted with diethyl ether, and neutralized with a sodium hydrogen carbonate aqueous solution. The organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 196 mg of 4,5-dihydroxy-6-(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 68%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]3[S:19][C:20]([CH2:22][OH:23])=[CH:21][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1.[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:23][CH2:22][C:20]2[S:19][C:16]3[C:17](=[O:18])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:24])[CH3:1])=[CH:7][CH:8]=4)[CH:13]=[N:14][C:15]=3[CH:21]=2)[CH2:27][CH2:26]1
Reactant: CN(C)CCOc1ccc(-n2cnc3cc(CO)sc3c2=O)cc1
Reactant: BrCC1CC1
Product: CN(C)CCOc1ccc(-n2cnc3cc(COCC4CC4)sc3c2=O)cc1

Procedure:
3-[4-(2-Dimethylaminoethoxy)phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one was reacted with cyclopropylmethyl bromide by method V. The product with the molecular weight of 399.52 (C21H25N3O3S) was obtained in this way; MS (ESI): 400 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:8]2[N:7]=1)(=O)C.O.[SH2:21].[Na]>CO>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([SH:21])[N:9]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:8]2[N:7]=1
Reactant: S
Reactant: COC(=O)c1nc2nc(COC(C)=O)cc(Cl)n2n1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc2nc(CO)cc(S)n2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
Methyl 5-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-2-carboxylate (380 mg) (1.33 mmol) are dissolved in 20 ml of methanol. After the addition of 296 mg (4 mmol) of sodium hydrogen sulphide monohydrate the mixture is stirred at 60° C. for 5 hours. The reaction mixture is concentrated and brought to pH 3 with dilute aqueous hydrochloric acid. The product is filtered off under suction, washed with water/methanol and crystallized from methanol. There are obtained 290 mg of methyl 5-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-2-carboxylate as a brown powder.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH3:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([NH:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=1)=[O:38].FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][N:41]=4)=[O:38])=[C:21]([CH3:20])[CH:26]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)Nc1cc(C(F)(F)F)ccn1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1cc(-c2c(C)c(CN3CCOCC3)n3ncnc(N)c23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccn1
Yield: 36 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using 5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAI (1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)-pyridin-2-yl]urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) 59 mg (36%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 10.19 (s, 1H), 9.52 (br s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.23 (s, 1H), 7.18 (dd, J=2.1, 8.7 Hz, 1H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.42-2.40 (m, 4H), 2.35 (s, 3H), 2.09 (s, 3H); MS [M+H]+=541.1; LCMS RT=2.49.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:5]=1[CH2:6][Cl:7])([CH3:3])[CH3:2].[Br:18]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:18][C:9]1[C:8]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][C:10]=1[CH:12]([CH3:14])[CH3:13])[CH2:6][Cl:7]
Reactant: CC(C)c1cc(C(C)C)c(CCl)c(C(C)C)c1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(C(C)C)c(CCl)c(C(C)C)c1Br

Procedure:
To a solution of 25 parts of 2,4,6-triisopropylbenzyl chloride (Organic Reactions, Vol. I, p. 68) in 150 parts of carbon tetrachloride is added 1 part of iron powder. The mixture is cooled and maintained at 15°-20°C, and then a solution of 16 parts bromine in 15 parts carbon tetrachloride is added dropwise during two hours. The resulting solution is washed with dilute sodium bicarbonate solution and water. It is dried with magnesium sulfate and stripped of solvent in vacuo giving 3-bromo-2,4,6-triisopropylbenzyl chloride, b.p. 111°C. (0.05 mm.)
Reaction SMILES: [CH3:1][S:2](OCC1C=CC=C(C2N=C(N3CCOCC3)C3=CC(CN(C)C)=CN3N=2)C=1)(=[O:4])=[O:3].[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]([C:40]2[N:45]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[C:43]3=[CH:52][C:53]([CH2:55][N:56]([CH3:58])[CH3:57])=[CH:54][N:42]3[N:41]=2)[CH:37]=[CH:38][CH:39]=1.ClCCl>CO>[CH3:57][N:56]([CH2:55][C:53]1[CH:52]=[C:43]2[N:42]([CH:54]=1)[N:41]=[C:40]([C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[N:45]=[C:44]2[N:46]1[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1)[CH3:58]
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(COS(C)(=O)=O)c3)nn2c1
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CN)c3)nn2c1
Solvent: CO
Solvent: ClCCl
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CNS(C)(=O)=O)c3)nn2c1
Yield: 26.7 %

Procedure:
Compound I-26 was prepared by the method which was identical with that for preparing compound 19, wherein compound 20 (37 mg, 0.1 mmol) was used as the starting material. Light yellow solid (12 mg, 26.7%) were obtained by a preparative plate (dichloromethane:methanol=8:1). m.p. 238-240° C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 8.19 (d, J=7.1 Hz, 1H), 7.60 (s, 1H), 7.47-7.38 (m, 2 H), 6.88 (s, 1H), 4.41 (s, 2H), 4.02 (br, s, 4H), 3.81 (t, J=4.4 Hz, 4H), 2.95 (s, 2H), 2.94 (s, 3H), 2.87 (s, 1H), 2.51 (s, 6H). MS (EI) m/e (%): 444 (M+, 16).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCCC1.C(O)(=O)C>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11])[C:12]([CH3:13])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1C

Procedure:
349.6g (2.3 moles) of 4-amino-3-methyl-nitrobenzene were dissolved in 500g of tetrahydrofuran, 500g of acetic acid were added thereto, and 500g (3.5 moles) of acetic anhydride were added dropwise while stirring and heating at 70° to 80° C, and, after the completion of the acetic acid addition, the entire reaction system was reacted for 1 hour under reflux and then was allowed to cool whereby crystals were formed. The crystals were separated, filtered out and then dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:14](=O)[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:35](C(OCC)=O)[C:36]([O:38]CC)=[O:37]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](=[O:8])[O:9][C:35]([C:36]([OH:38])=[O:37])=[C:14]2[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1
Reactant: COc1cc(C(=O)O)c(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5-dimethoxy-2-(3,4,5-trimethoxybenzoyl)benzoic acid (5 g) in dimethylformamide (50 ral) ard added potassium carbonate (3.72 g) and diethyl bromomalonate (2.48 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove dimethylformamide, and thereto is added chloroform and water. The chloroform layer is separated, and thereto are added dioxane (80 ml) and conc. hydrochloric acid (80 ml). The mixture is heated under reflux for three hours. The reaction mixture is cooled, and the precipitated crystals are collected by filtration washed with acetone, and dried to give 6,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)isocoumarin-3-carboxylic acid (2.85 g) as listed in Table 57.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].[NH2:27]/[C:28](/[CH3:37])=[CH:29]\[C:30]([O:32][CH2:33][CH2:34][C:35]#[N:36])=[O:31]>CC(O)C>[CH3:37][C:28]1[NH:27][C:1]([CH3:2])=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:29]=1[C:30]([O:32][CH2:33][CH2:34][C:35]#[N:36])=[O:31]
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)NCC=Cc1ccccc1
Solvent: CC(C)O
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
424 mg (1.21 mmol) of 2-acetyl-3-(4-nitrophenyl)-N-(3-phenyl-2-propene-1-yl)acrylamide and 187 mg (1.21 mmol) of 2-cyanoethyl 3-aminocrotonate were heated at 70° C. under stirring in 10 ml of 2-propanol for 2 days. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: CN(C)CCN.[Cl:7][C:8]1[S:12][C:11]([CH2:13][O:14][N:15]2C(=O)C3=CC=CC=C3C2=O)=[CH:10][CH:9]=1.C(O)(=O)C.[C:30]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])(=O)[CH3:31]>CCO>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])=[C:33]([C:30](=[N:15][O:14][CH2:13][C:11]2[S:12][C:8]([Cl:7])=[CH:9][CH:10]=2)[CH3:31])[CH:38]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(Cl)s1
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NOCc1ccc(Cl)s1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
N,N-Dimethylethylenediamine (178 μL, 1.54 mmol) was added to a solution of N-(5-chlorothiophen-2-ylmethoxy)phthalimide (220 mg, 0.75 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h Glacial acetic acid (1 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (211 mg, 0.70 mmol) in EtOH (2 mL), and the mixture stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-{4-chloro-2-[1-(5-chlorothiophen-2-ylmethoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 194 (280 mg, 90%), as white crystals. 1H n.m.r. (400 MHz, CDCl3) δ 11.37, br s, 1H, 7.63, d, J=8.8 Hz, 1H, 7.48, d, J=24 Hz, 1H, 7.33, dd, J=2.4 and 8.8 Hz, 1H, 6.94, d, J=3.8 Hz; 6.81, d, J=3.8 Hz; 5.24, s, 2H, 2.33, s, 3H. HRMS (M+) 445.9540. N-(5-Chlorothiophen-2-ylmethoxy)phthalimide was prepared using the procedure reported in U.S. Pat. No. 4,071,533.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-Bromophenylacetic acid (10.7 g, 50 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole. 2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (3.8 g, 10 m mol) was reacted with 4-nitro benzylbromide (2.5 g, 12 mmol) as described in general procedure B to give 2-(4-bromobenzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-benzyl)-1H-imidazole.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[NH2:32][C:28]1[CH:27]=[C:26]([NH:33][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cccc(N)c1
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a solution of N-Boc-β-alanine (1.00 g) in N,N-dimethylactamide (5 mL), carbonyldiimidazole (888 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 20 minutes. To the reaction mixture, a solution of 1,3-phenylenediamine (1.15 g) in N,N-dimethylactamide (5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl (3-((3-aminophenyl)amino)-3-oxopropyl)carbamate (B6, 978 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](O)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Yield: 80.2 %

Procedure:
4-Iodo-1H-pyrrole-2-carboxylic acid methyl ester 57d (25.1 g, 100 mmol) was dissolved in 150 mL of dichloromethane followed by addition of triethylamine (30.6 mL, 220 mmol), 4-dimethylaminopyridine (1.22 g, 10 mmol) and p-toluenesulfonic acid (21 g, 110 mmol). The reaction mixture was reacted at 20° C. overnight. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 30 mL of hydrochloric acid (1 N). The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated aqueous sodium carbonate and saturated brine successively, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (32.5 g, yield 80.2%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>C1COCC1.[Pd]>[F:20][C:19]([F:21])([F:22])[CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: FC(F)(F)CCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1ccc(OCCCC(F)(F)F)cc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
60 g (193 mmol) of 1-(benzyloxy)-4-(4,4,4-trifluorobutoxy)benzene, and 7.61 g of Pd/C are dissolved in 900 mL of THF. 5 mL of triethylamine are added to the suspension. The reaction is hydrogenated under atmospheric pressure for 2 hours. The suspension is filtrated of 400 g of hyflo. The organic phase is concentrated under reduced pressure. Filtration of the residue on 900 g silica gel using toluene:ethyl acetate 4:1 as eluent and concentration under reduced pressure yields 41 g of 4-(4,4,4-trifluorobutoxy)phenol as a reddish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:11]([F:22])([F:21])[F:10])[CH:17]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Oc1cc(Br)cc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(Oc2cc(Br)cc(Br)c2)c1
Reaction time: 168 h

Procedure:
3,5-Dibromophenol (4.1 g; 16.2 mmol), 3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol), Cu(II) acetate (2.9 g; 16.2 mmol), TEA (5.6 mL; 40.5 mmol) and dichloromethane (150 mL) and molecular sieves (2 ml) was added to a reaction flask the reaction mixture was stirred for 7 days. Further 3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) was added and the reaction mixture stirred for 1 day. Further 3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) and TEA (5.6 mL; 40.5 mmol) was added and the reaction mixture stirred for 1 day. 5% Aqueous citric acid (150 mL) was added and the two phases were separated. The aqueous phase was extracted with dichloromethane (50 mL×2) and the organic phases were pooled, dried and evaporated to dryness. The crude product purified by flash chromatography (heptane→ethyl acetate:heptane 1:9). Yield: 1.86 g; HPLC-MS: m/z: 397. (M+H)+; Rt: 2.78 min.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][C:8]1[C:9](=[N:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[NH:10][C:11](=[O:26])[N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.[OH-].[Na+]>O.Cl>[C:2]([N:10]1[C:9](=[N:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[C:8]([CH2:7][CH2:6][NH2:5])=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11]1=[O:26])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: COc1cc2c(cc1OC)-c1c(CCN)c(=Nc3ccccc3C)[nH]c(=O)n1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1c(CCN)c(=Nc3ccccc3C)n(C(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
Sodium cyanate (0.64 g, 9.8 mmol) in water (13 ml) was added dropwise to a stirred solution of amine 3 (2 g, 4.9 mmol) in water (63 ml) and 1M HCl (9.8 ml) at 80° C. After stirring for 3 h at 80° C. the mixture was cooled and basified with 2M NaOH. The mixture was extracted with CH2Cl2 until no more product remained in the organic phase. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography [dichloromethane/methanol (97:3)] and the product triturated with ether to afford the title compound (1.0 g, 45%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(Cl)cc4)cc23)CC1
Yield: 97.8 %

Procedure:
By a method similar to Example 31, using 4-chlorobenzenesulfonyl chloride (242 mg, 1.15 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (220 mg, 0.96 mmol), 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 380 mg of a white solid. The crude product was recrystallized from ethyl acetate/hexanes to give 300 mg (78%) of the title compound as an off white powder: mp=182-183.5° C.; MS(m/e): 404 (M+); Calculated for C20H21ClN2O3S: C, 59.33; H, 5.23; N, 6.92. Found: C, 59.24; H, 5.22; N, 6.90.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:17](=O)([O-])O.[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CCc1cccc(I)c1
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cccc(I)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of the mixture of 3-(3-iodophenyl)propionic acid (12.0 g) in methanol (200 ml) was added thionyl chloride (11.0 g, 92.5 mmol), and the mixture was stirred for 30 minutes at 40° C. To the mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with toluene:ethyl acetate (1:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was separated and purified with silica gel chromatography (hexane:ethyl acetate=5:1→4:1) to give the subject compound (9.66 g, 61%:total of 3 steps).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1>C1COCC1>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc3ccccc3c2)oc1C

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dimethylfuran, 2-(bromomethyl)naphthalene and 1.6M n-BuLi/hexanes in THF. 1H NMR (DMSO-d6) δ1.89 (s, 3H), 2.15 (s, 3H), 4.08 (s, 2H), 5.95 (s, 1H), 7.40 (d, 1H), 7.45-7.57 (m, 2H), 7.77 (s, 1H), 7.83-7.91 (m, 3H).