Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:31]=[O:32])[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH:31]=[O:32])[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1nc(-c2ccccc2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 4-phenyl-1-trityl-1H-imidazole-2-carbaldehyde (414 mg, 1 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). After stirring at room temperature for 30 minutes, the solvent was removed in vacuo. The resulting residue was diluted with DCM (50 mL) and saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to give 4-phenyl-1H-imidazole-2-carbaldehyde as a white solid (160 mg). MS (ESI): m/z 173 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[S:11][C:12]([SH:15])=[N:13][N:14]=2)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].Br[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CC(=O)CC>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][S:9][C:10]2[S:11][C:12]([S:15][CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[N:13][N:14]=2)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(S)s2)ccc(C(C)=O)c1O
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCc1c(CSc2nnc(SCc3ccc(C(=O)O)cc3)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
To a mixture of 0.49 g of 2-[(4-acetyl-3-hydroxy-2propylbenzyl)thio]-5-mercapto-1,3,4-thiadiazole, 0.36 g of p-(bromomethyl)benzoic acid, 0.48 g of anhydrous potassium carbonate and 12 ml of 2-butanone was added a catalytic amount of tetra-n-butylammonium bromide followed by stirring at 60° C. for 45 minutes. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The thus obtained solid was recrystallized from isopropyl alcohol to give 0.50 g of p-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thiomethyl]benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]([O:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29])(=[O:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[C:17]([CH2:18]3)=[N:16][N:15]([C:28](=[O:29])[C:27]([O:26][C:23](=[O:25])[CH3:24])([CH3:32])[CH3:31])[CH:14]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Product: CC(=O)OC(C)(C)C(=O)n1cc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by acylation of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene using 2-acetoxyisobutyryl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cnc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) in acetic acid (10 mL) was added iron (2.465 g, 44.1 mmol) in one portion. The mixture was stirred at 80° C. for 15 min. The mixture was filtered and concentrated and then washed with aq. NaOH and extracted with EA. The crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=8:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (1 g, 4.58 mmol, 51.9% yield): 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.86 (d, J=8.60 Hz, 1H), 7.53 (d, J=8.60 Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J=6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:15]=1>>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:16]1[N:15]=[C:14]([NH:11][S:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:12])[CH2:7][CH2:6]2)(=[O:9])=[O:10])[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCS(=O)(=O)CC1
Product: COc1cc(NS(=O)(=O)N2CCS(=O)(=O)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from 1,1-dioxothiomorpholine-4-sulfonamide (0.31 g, McManus, J. M. et al, J. Med. Chem (1965) 8 766-776) and 4-chloro-2-[[(2,3-difluorophenyl) methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (1:1) as eluent. Yield: 0.48 g
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[CH:5]=[CH:4]1.[CH3:14]I>CN(C)C=O>[CH3:14][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[CH:5]=[CH:4]1
Reactant: OCc1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(CO)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
NaH(8.2 mm) in N,N-dimethylformamide ("DMF") (20 mL) was cooled to 0° C., then treated with a solution of the known 1H-indole-6-methanol (1 g,6.8 mm) in DMF(8 mL). After stirring for 1 hour at 0° C., methyl iodide ("MeI") (0.51 mL, 8.2 mm) dissolved in DMF (2 mL) was added, and the mixture was stirred at 0° C. overnight, then poured into ice/H2O(250 ml) and extracted with EtOAc(50 mL×3). The organic fraction was dried over MgSO4, filtered, evaporated and purified by flash column chromatography to afford 1-methyl-1H-indole-6-methanol (0.82 g. 75%). This product (1-methyl-1H-indole-6-methanol, 1 g, 6.2 mm) was dissolved in a mixture of pyridine (5 mL) and acetic anhydride (Ac2O) (5 mL) and stirred at room temperature overnight. The solvent was evaporated, and the residue purified by flash column chromatography to afford 1.09 g of Acetic acid 1-methyl-1H-indol-6-yl methyl ester.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:26]=[CH:25][C:18]([CH2:19]OS(C)(=O)=O)=[CH:17][C:16]=1[N+:27]([O-:29])=[O:28]>CCOC(C)=O>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:19][C:18]2[CH:25]=[CH:26][C:15]([F:14])=[C:16]([N+:27]([O-:29])=[O:28])[CH:17]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.0 eq of methanesulfonic acid 4-fluoro-3-nitro-benzyl ester (2B) in DMF (about 0.6 M 2B in DMF) was added about 1.05 eq of TEA and about 1.0 eq of t-butyl piperazine-1-carboxylate. The mixture was stirred for 30 min at room temperature, diluted with EtOAc, washed with NH4Cl solution, dried (Na2SO4) and evaporated. Purification by flash chromatography over silica with 50% EtOAc/hexanes as the eluant afforded 4-(4-fluoro-3-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2C).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>O1CCCC1>[N:25]1[CH:26]=[CH:27][C:28]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:29][CH:30]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccncc1
Reaction time: 0.08 h

Procedure:
Methyl (triphenylphosphoranylidene)acetate (3.4 grams) and 4-pyridine-carboxaldehyde (10.00 grams) were refluxed in tetrahydrofuran under nitrogen overnight. The reaction was evaporated in vacuo, and the residue was suspended in hexane (400 mL), heated to boiling on a steam bath for 5 minutes, and filtered through a filter aide. The filter cake was rinsed with hot hexane (2×200 mL), and the rinses and filtrate were combined and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (1500 mL) using 3:7 ethyl acetate:methylene chloride. The resulting waxy solid was suspended in a minimum amount of cyclohexane to yield the product as a white crystalline solid. Yield: 7.06 grams (46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.C[C:10]1([CH3:17])[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([N:13]2[CH2:14][C:10]([CH3:15])([CH3:17])[CH2:11][C:12]2=[O:16])=[N:6][CH:7]=1
Reactant: Brc1cnc(I)cn1
Reactant: CC1(C)CCNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N(c2cnc(Br)cn2)C1
Yield: 53.2 %

Procedure:
To a well stirred suspension of 2-bromo-5-iodopyrazine (300 mg, 1.05 mmol), 4,4-dimethylpiperidin-2-one (155 mg, 1.37 mmol, 1.3 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (24.4 mg, 0.042 mmol, 0.04 equiv.) in 4 ml of toluene were added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), (19.3 mg, 0.021 mmol, 0.02 equiv.) and the mixture was stirred for 5 hours at 100° C. The crude mixture was adsorbed on silicagel and purified by flash chromatography over a 20 g silicagel column using a 2:1 heptane/ethyl acetate mixture as eluant. The title compound (151 mg, 53% yield) was obtained as a white solid, MS: m/e=270.1, 272.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:33][CH2:34][CH3:35])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([NH:31][CH3:32])=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(OC)(O[CH3:40])(=O)=O.[OH-].[K+].C1COCC1>C(OCC)(=O)C.CCCCCC.O>[CH3:40][O:1][C:2]1[C:3]([CH2:33][CH2:34][CH3:35])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([NH:31][CH3:32])=[O:30])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]([CH:20]=[CH:21][CH:22]=1)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COS(=O)(=O)OC
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(O)c2CCC)cccc1OCC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)cccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 44 (105 mg, 0.2153 mmol), dimethyl sulfate (40.7 mg, 0.3229 mmol) and potassium hydroxide (15 mg, 0.2583 mmol) were added to 2.0 ml of THF. The reaction mixture was stirred at room temperature overnight, and then 10 ml of water was added. The mixture was extracted three times with ethyl acetate , and the extracts were combined and dried over anhydrous magnesium sulfate then filtered, and the solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel with 50/50 ethyl acetate/hexane as eluant gave the product as a colorless gum.
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C.[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47](CCC(O)=O)=[CH:46]1>>[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:46]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2c[nH]c3ccccc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(1H-indol-3-yl)-propionic acid (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([CH2:33][O:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][N:41]([CH2:44][C:45](O)=[O:46])[C:40](=[O:48])[N:39]=2)=[O:36])=[CH:31][CH:30]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([O:34][CH2:33][C:32]3[CH:49]=[CH:50][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[O:36])=[N:39][C:40]2=[O:48])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ccn(CC(=O)N3CCN(S(=O)(=O)c4nc5ccccc5s4)C(=O)C3)c(=O)n2)cc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(4-methoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.70 (bs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.72 (m, 2H), 7.34 (d, 2H), 7.01 (t, 1H), 6.93 (d, 2H), 5.10 (s, 2H), 4.81 (s, 1.2H), 4.71 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.85 (t, 0.8H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][CH2:6][C:5]1=[O:22].CC(C)([O-])C.[K+].[N:29](OC(C)(C)C)=[O:30]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:7][C:6](=[N:29][OH:30])[C:5]1=[O:22]
Reactant: COCN1C(=O)CCN(c2ccccc2F)c2ccccc21
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCN1C(=O)C(=NO)CN(c2ccccc2F)c2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
Under argon atmosphere, 1-methoxymethyl-2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (5.26 g) was dissolved in toluene (50 ml), the mixture was cooled on ice, potassium tert-butoxide (9.8 g) was added thereto at internal temperature 10° C., and stirred for 30 minutes under ice-cooling. tert-Butyl nitrite (5.0 g) was added thereto, the mixture was allowed to room temperature, and stirred for one hour and 30 minutes. Saturated brine was added to the reaction mixture, extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel NH-DM1020, produced by Fujisilicia Co. Ltd., chloroform:methanol=20:1), to thereby obtain 2.35 g of the titled compound as pale brown amorphous.
Reaction SMILES: ClC1SC(S([N:10]([S:22]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:24])=[O:23])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([CH2:60]O)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+]>C1COCC1.O.C(Cl)Cl>[CH3:50][O:51][C:52]1[CH:53]=[C:54]([CH2:60][N:13]2[C:14]3[C:19](=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][CH:15]=3)[C:11]([NH:10][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:12]2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]
Reactant: COc1ccc(CO)cc1OC
Reactant: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)cc1OC
Temperature: 60 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 10) (150 mg, 0.286 mmol), triphenylphosphine (150 mg, 0.572 mmol) and [3,4-bis(methyloxy)phenyl]methanol (Aldrich) (96 mg, 0.57 mmol) in THF (3 mL) was added at room temperature di-iso-propyl azodicarboxylate (0.113 mL, 0.572 mmol). The resulting mixture was stirred at 60° C. for 3 hours. DCM (3 mL) and water (3 mL) were added and the organic phase was separated. The aqueous layer was further extracted with 3 mL of DCM. The combine organic solutions were dried over an hydrophobic frit and concentrated under a nitrogen stream in a blowdown unit. The residue was purified by chromatography on silica 50 g cartridge on Flashmaster II using a gradient of 0-100% EtOAc in DCM over 60 min. The appropriate fractions were combined and evaporated in vacuo and the residue was dissolved in methanol (5 mL) and treated with a solution of sodium hydroxide (2M, 1.43 mL, 2.86 mmol). The resulting mixture was stirred at 60° C. for 2 hours. The solvents were evaporated off under reduced pressure, and the residue was partitioned between 2 mL of DCM, 3 mL of water. A solution of dilute HCl solution was added until the pH of the aqueous layer was around 1. The organic phase was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit and concentrated under a stream of nitrogen in a blowdown unit. The residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents NB (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed from appropriate fractions under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (52.6 mg, 37%). LCMS (System A) RT=1.17 min, ES+ve m/z 494/496 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])#[N:2].[CH3:13]OC(OC)N(C)C>C(Cl)Cl>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: N#CCc1ccccc1C(=O)O
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: COC(=O)c1ccccc1CC#N
Reaction time: 38 h

Procedure:
With gentle heating, 175 g (1.08 mol) of 2-cyanomethyl-benzoic acid (for preparation see: Org. Synthesis, Coll, Vol. 3,174) are dissolved in 1.7 liters of CH2Cl2; 242 ml (=90%, 1.6 mol) of dimethylformamide dimethylacetal are added dropwise at room temperature, and stirring is carried out for 38 hours to complete the reaction. The reaction mixture is washed with 2×1.2 liters of saturated NaHCO3 solution and brine. The aqueous phases are extracted using 2 portions of CH2Cl2, and the organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; ethyl acetate/hexane 1:4, applied in ethyl acetate/hexane/CH2Cl2) yields the title compound: m.p. 49-50° C.; 1H NMR (DMSO-d6) 7.96 (d, 1H), 7.66 (t, 1H), 7.57 (d, 1H), 7.51 (t, 1H), 4.26 (s, 2H), 3.86 (s, 3H); Anal. calc. (C10H9NO2) C 68.56%, H 5.18%, N 8.00%; found C 68.5%, H 5.1%, N 7.9%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6]([CH3:9])=[CH:7][O:8][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(N(C(C)C)C(C)C)C>C(O)C>[CH3:9][C:6]1[C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([N:1]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: Cc1cc2c(C)coc2cc1N
Reactant: BrCCCCCBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(C)coc2cc1N1CCCCC1

Procedure:
A mixture of 8 g (49.6 mmole) of 6-amino-3,5-dimethylbenzofuran, 23 g (0.1 mole) of 1,5-dibromopentane, 12.9 g (0.1 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 18 hours. The residue obtained after concentration by evaporation in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is chromatographed with petroleum ether/methylene chloride over silica gel. Distillation of the pure fractions in a bulb tube (130°/10-1 torr) yields 3,5-dimethyl-6-piperidinobenzofuran having a melting point of 64°-66°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([C:13]1([C:20]([O:22][CH3:23])=[O:21])[C:15]([CH3:17])([CH3:16])[C:14]1([CH3:19])[CH3:18])=[O:12].C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([C:13]2([C:20]([O:22][CH3:23])=[O:21])[C:14]([CH3:18])([CH3:19])[C:15]2([CH3:16])[CH3:17])=[O:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: COC(=O)C1(C(=O)Cl)C(C)(C)C1(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)C1(C(=O)Nc2ccc(Br)cc2C)C(C)(C)C1(C)C
Yield: 60 %

Procedure:
4-Bromo-2-methylaniline (2.09 grams, 0.01 mole) and methyl 1-chlorocarbonyl-2,2,3,3-tetramethylcyclopropanecarboxylate (2.45 grams, 0.01 mole), prepared in Part B, were reacted in the presence of 1.13 grams (0.01 mole) of triethylamine in 70 milliliters of benzene solution in a manner similar to that described in Example I to give 2.13 grams (0.006 mole) of methyl 1-(4-bromo-2-methylphenylamino-carbonyl)-2,2,3,3-tetramethylcyclopropaneca rboxylate.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(OC(C)C)n2)n[nH]1
Reactant: C1CCNCC1
Product: Cc1cc(Nc2cc3cc(N4CCCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and piperidine to give 5 mg of (1-Isopropoxy-6-piperidin-1-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 366 (MH+).