Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: OCCC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 2-(tetrahydro-2H-pyran-4-yl)ethanol (3,3 g) in dry dichloromethane (100 ml) at 0° C. and under nitrogen was added triethylamine (4.6 ml), followed by methanesulphonyl chloride (2.6 ml) dropwise over 5 minutes. The reaction was stirred until the ice in the bath melted and left overnight at room temperature. The reaction was washed with saturated aqueous sodium bicarbonate (40 ml). The organic layer was dried by passing through a hydrophobic frit and concentrated in vacuo to yield the title compound as a yellow oil (5.4 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:30])[N:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:31]([O:33]C)=[O:32])=[CH:7][C@@H:6]1[O:35][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:30])[N:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:31]([OH:33])=[O:32])=[CH:7][C@@H:6]1[OH:35])(=[O:3])[CH3:2]
Reactant: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)OC)=C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1NC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](O)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of (4S,5S,6R)-5-acetylamino-4-(tert-butyldiphenylsilanyloxy)-6-[(2-biphenyl-4-yl-ethyl)propylcarbamoyl]-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (1.58 g) in anhydrous tetrahydrofuran (15 ml) was added a solution of tetra-n-butylammonium fluoride in anhydrous tetrahydrofuran (2.42 ml of a 1N solution) and the reaction was stirred for 16 hours at 23° C. The solvent was then removed in vacuo and the residue was suspended in brine and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was chromatographed over silica (Merck 9385, 20 g) using medium pressure (ca 4 psi) and dichloromethane/methanol (95:5 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white solid (0.91 g). 1H NMR (250 MHz, D6 -DMSO rotamers) 8.05 (1H, d, J=8 Hz), 7.63 (4H, m), 7.45 (2H, m), 7.34 (3H, m), 5.92+5.89 (1H, 2×d, J=3 Hz), 5.32 (1H, d, J=6 Hz), 5.01+4.97 (1H, 2×d, J=8 Hz), 4.28 (1H, m), 3.94 (1H, m), 3.73+3.68 (3H, 2×s), 3.45 (1H, m), 3.24 (1H, m), 2.96 (1H, m), 2.76 (1H, m), 1.82+1.79 (3H, 2×s), 1.57 (1H, m), 1.46 (1H, m), 0.83 (0.83(3H, m), Mass analysis: C27H32N2O6. Required: C, 67.48; H, 6.71; N, 5.83. Found: C, 67.08; H, 6.61; N, 5.60.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](O)([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:27])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([F:27])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
1-Benzhydryl-3-hydroxyazetidine-3-carbonitrile (10.5 g, 39.7 mmol) was dissolved in DCM and cooled to −78° C. DAST (12.80 g, 79.45 mmol) was slowly added and the reaction mixture was allowed to warm to rt where it was further stirred for 5 h. Reaction mixture was cooled to 0° C. and transferred into 500 mL NaHCO3 solution and extracted with (100 mL×3) DCM. Combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 15.0 g of crude product, which was purified by chromatography to obtain 6.0 g of 1-benzhydryl-3-fluoroazetidine-3-carbonitrile. (57.14% yield). 1H NMR (400 MHz, CDCl3, ppm) δ=7.6-7.1 (m, 10H); 4.46 (s, 1H); 3.9-3.6 (m, 2H); 3.5-3.2 (m, 2H).
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH-].[Na+]>C(O)C>[C:1]12([NH:6][C:7]3[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:18][CH3:19])[N:8]=3)[CH2:4][CH:3]([CH2:2]1)[CH2:5]2
Reactant: CCOC(=O)c1cnc(SC)nc1NC12CC(C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylate (120 g, 0.43 mol) was dissolved in ethanol (1.5 L) followed by the addition of an aqueous sodium hydroxide solution (530 mL, 1.06 mol, 2M) and the resulting mixture was stirred overnight at room temperature. After that the solvent was evaporated under reduced pressure (<42° C. bath temperature). The mixture was diluted with 500 mL of water and washed with tert-butyl methyl ether (2×500 mL). The aqueous layer was treated with aqueous hydrochloric acid solution (2N) to pH 4.2-4.5. The resulting solids were collected by filtration followed by washing with water (500 mL) and hexanes (500 mL). The wet cake was dried under reduced pressure overnight at 45° C. to afford the desired compound (108 g, 0.43 mol, 100% yield) as an off-white solid (116 mg, 0.365 mmol, 54.7% yield); 1H NMR (400 MHz, CD3OD) δ ppm 8.52 (s, 1H), 2.55 (s, 3H), 2.52 (s, 1H), 2.24 (s, 6H)
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[O:16][CH3:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:15])[CH:14]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[O:16][CH3:17]
Reactant: O=Cc1ccccc1
Reactant: COCOc1ccc(C=CC(C)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(=O)C=Cc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.7 %

Procedure:
1-(4-Methoxymethyloxy-3-methoxyphenyl)-1-buten-3-one (35j, 1.00 g, 4.2 mmol) and benzaldehyde (1b, 0.46 ml, 4.5 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.30 g, 7.5 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 1.35 g (99%) of an oil which was used without purification. The oil (36j, 1.30 g, 4.0 mmol) was stirred in methanol (50 ml) for 15 min at 60° C. Concentrated hydrochloric acid (3 drops) was added and the solution stirred for 18 hr at 60° C. The methanol was evaporated and the resulting residue extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a semi-solid. The crude semi-solid was chromatographed on silica gel with ethyl acetate/hexane to give 0.41 g (36%) of a yellow oil; 1H NMR δ 3.92 (s, 3H), 6.08 (s, 1H), 6.91 (d, 1H, J=16.1 Hz), 6.93 (d, 1H, J=8.2 Hz), 7.07 (d, 1H, J=15.9 Hz), 7.10 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 7.38 (m, 3H), 7.59 (m, 2H), 7.67 (d, 1H, J=15.9 Hz), 7.71 (d, 1H, J=15.9 Hz); 13C NMR: δ 56.0, 109.8, 114.9, 123.4, 125.3, 127.3, 128.3, 128.8, 130.3, 134.9, 142.8, 143.5, 146.8, 148.3, 188.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[S:52](Cl)(=[O:55])(=[O:54])[NH2:53]>O1CCCC1>[F:8][C:6]1[CH:7]=[C:2]([NH:1][S:52]([NH2:53])(=[O:55])=[O:54])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(F)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(F)cc(NS(N)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-fluorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (40 mg, 0.06 mmol) was treated with pyridine (20 μL, 0.25 mmol) and sulfamoyl chloride (24 mg, 0.21 mmol) in tetrahydrofuran (0.5 ml) according to the method described in Preparation 175 but stirring at room temperature overnight. The title compound was obtained (46 mg, 93% yield) without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.O>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1ccc(F)cc1F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1cc(I)c(F)cc1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
2,4-Difluorobenzoic acid (100 g, 633 mmol) was dissolved in trifluoromethanesulfonic acid (400 ml) and N-iodosuccinimide (157 g, 696 mmol) was added by portions at not more than 5° C. After the completion of the addition, the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was poured into iced water, and the mixture was stirred for 1 hr. The precipitated solid was collected by filtration, washed successively with water and hexane, and vacuum dried to give 2,4-difluoro-5-iodobenzoic acid (179 g yield quantitative) as a white solid.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([NH:32][C:33]2[N:34]=[CH:35][C:36]([C:45](O)=[O:46])=[N:37][C:38]=2[O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:48][O:49][C:50](=[O:57])[C:51]([NH2:56])([CH2:54][CH3:55])[CH2:52][CH3:53]>>[CH3:48][O:49][C:50](=[O:57])[C:51]([NH:56][C:45]([C:36]1[CH:35]=[N:34][C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:38]([O:39][CH2:40][C:41]([F:43])([F:44])[F:42])[N:37]=1)=[O:46])([CH2:54][CH3:55])[CH2:52][CH3:53]
Reactant: O=C(O)c1cnc(NC2CCCCC2)c(OCC(F)(F)F)n1
Reactant: CCC(N)(CC)C(=O)OC
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(NC2CCCCC2)c(OCC(F)(F)F)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-cyclohexylamino-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 447.5 (M+H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C(Cl)Cl>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:15])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
A mixture of 640 mg of methyl glycolate, 0.60 mL of pyridine, and 10 mL of methylene chloride was added to 10 mL of a methylene chloride solution including 1.44 g of 4-nitrophenyl chloroformate at room temperature, followed by stirring for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and diethyl ether and water were added to the residue and an organic layer was separated. The organic layer was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (using chloroform only), thereby obtaining 320 mg of methyl {[(4-nitrophenoxy)carbonyl]oxy}acetate.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[N:8][C:7]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=1[F:23])=[O:5])C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[C:16]([F:23])[C:15]=1[CH:14]1[C:13](=[O:24])[NH:12][C:7]2[N:8]=[N:9][CH:10]=[CH:11][C:6]=2[C:4]1=[O:5]
Reactant: CCOC(=O)c1ccnnc1NC(=O)Cc1c(F)cc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1Nc2nnccc2C(=O)C1c1c(F)cc(F)cc1F
Temperature: 0 °C

Procedure:
The product from Step 2 (2.0 g) was dissolved in dry THF (50 ml), and sodium bis-trimethylsilylamide (17.7 ml of a 11.0M solution in THF) was added dropwise with stirring under nitrogen at 0° C. The reaction was stirred for 3 hours at 0° C. and a yellow precipitate was formed. The reaction was quenched with concentrated hydrochloric acid and then poured into ice water. The solid was filtered, washed with water and air dried to give 6-(2,4,6-trifluorophenyl)-8H-pyrido[2,3-c]pyridazine-5,7-dione as a yellow solid (1.9 2 g), m.p. >330° C., still containing some THF, which was used without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])(=O)=O)=CC=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:34])=[C:24]([CH:33]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:34])=[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:28][CH:27]=2)[CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COCCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 24 h
Yield: 92.2 %

Procedure:
2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (3 g, 10.7 mmol), 4-(5-bromo-2-chlorobenzyl)phenol (3.8 g, 12.8 mmol), and Cs2CO3 (8.7 g, 26.8 mmol) were suspended in DMF (8 mL) at 50° C. The mixture was stirred for 24 hours at this temperature. The mixture was diluted with water and the aqueous layer was extracted with PE two times. The combined organic layers were washed with brine, concentrated and purified by flash chromatography (PE/EtOAc=50:1) to obtain a yellow solid (4 g, yield 91.9%), which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[C:12]#[N:13].Cl>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 880 mg (22mmol) of 60% sodium hydride (NaH) and 12 ml of N,N-dimethylformamide. To the system were added 2.9 ml (4 g, 40 mmol) of 2,2,2-trifluoroethanol via syringe over a period of 15 minutes and the mixture was stirred at room temperature for 20 minutes. To the system were added 1.72 g (10 mmol) of 2,5-dichlorobenzonitrile, and the mixture was heated at 90° C. for three days. The mixture was cooled to room temperature, poured into 50 ml of 2M aqueous HCl and extracted with three portions of ether. The combinedorganic fractions were dried (Na2SO4) and concentrated to afford2.5 g of a solid. The crude material was purified by flash column chromatography using 1:49 ethyl acetate/hexanes as the eluant to obtain 1.4 g of 5-chloro-2-(2,2,2-trifluoroethoxy)benzonitrile as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]2[CH2:31][CH2:30][O:29]C2=O)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.C[Al](C)C>[OH-].[NH4+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[N:22]=[C:18]3[CH3:17])[CH2:31][CH2:30][OH:29])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)cn1C1CCOC1=O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: C[Al](C)C
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc(C(F)(F)F)cn1C(CCO)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 55 °C
Yield: 23.5 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-amine (0.070 g, 0.32 mmol), 3-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]tetrahydrofuran-2-one (0.070 g, 0.30 mmol) and AlMe3 (0.50 mL, 1.0 mmol, 2 M/toluene) was heated at 55° C. for 1.5 hrs. The mixture was then cooled to room temperature, diluted with aqueous ammonium hydroxide, and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0˜20% MeOH/CH2Cl2 gradient elution) to give 3-[[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]amino]-3-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propan-1-ol (0.030 g, 24%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To 1.0 q (3.4 mmole) of 2-(4 mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro [5H]pyrrolo[1,2-a]imidazole prepared as in Example 16 in 50ml methylene chloride at ° C. was added a solution of 0.3 q (3.7 mmole, 0.26 ml) trimethylacetyl chloride in 10 ml CH2Cl2 over a period of 10 minutes. The reaction was allowed to come to room temperature and was stirred for 30 minutes. The mixture was then diluted with methylene chloride and washed with N NaHCO3, saturated NaCl, treated with Na2SO4, stripped, then flash chromatographed on silica with methylene chloride containing 1% to 5% MeOH. The isolated material was recrystallized from ethyl acetate to give 0.43 g of the titled compound. 33.5% yield, mp 216-217.5 ° C. C22H23N3OS, Calculated, C: 70.00, H: 6.14, N: 1.13; Found, C: 70.01, H: 6.20, N: 10.99.
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.C[C:15]([O:17][CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O>C(OC)(=O)CCCCC(OC)=O>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][O:17][CH3:15])[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: COC(=O)CCCCC(=O)OC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
17.9 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 4) and 1.04 g of trimethyl borate were added to 20 ml of dimethyl adipate. The mixture was cooled to 15° C. and 2.74 g of 7-ACA were added thereto, followed by stirring at 15° C. for 1.5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.06 g (yield 84%) of the desired compound with a high purity.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[NH:17][C:18]([CH3:23])=[C:19]([Cl:22])[C:20]=2[Cl:21])=[O:15])[CH2:9][CH2:8]1)[S:5][CH3:6])#[N:2].SC[C:26]([O:28][CH3:29])=[O:27]>CO>[NH2:2][C:1]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]3[NH:17][C:18]([CH3:23])=[C:19]([Cl:22])[C:20]=3[Cl:21])=[O:15])[CH2:9][CH2:8]2)[S:5][C:6]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CSC(=NC#N)N1CCC(NC(=O)c2[nH]c(C)c(Cl)c2Cl)CC1
Reactant: COC(=O)CS
Solvent: CO
Product: COC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl N-cyano-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carbimidothioate (Intermediate 91, 1.78 g, 4.8 mmol) and methyl mercaptoacetate (0.43 ml, 4.8 mmol) with TEA (1.2 ml, 8.6 mmol) in MeOH was stirred at room temperature overnight. Reaction mixture was concentrated to 50% volume, the precipitate was filtered off and the solid was washed with MeOH and dried.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CC[C@H]([OH:53])[C@@H](C)C2)CC1>>[OH:53][C@H:5]1[CH2:6][CH2:7][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:2][C@@H:3]1[CH3:4]
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5ccoc5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (preparation see example 36) and amine 14.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13]>>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: CC(C)(CCC=O)[N+](=O)[O-]
Reactant: O=C1CNC(=O)N1
Product: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]

Procedure:
Then, 4-methyl-4-nitropentanal and hydantoin are reacted to give 5-(4-methyl-4-nitropentylidene)hydantoin (see JP-A-11-140076).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([N:10]([CH2:12][C:13]2[S:17][CH:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=3)[NH:23][CH:22]=[C:21]4[CH:30]3[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]3)[CH:14]=2)[CH3:11])[CH2:44][CH2:43][CH2:2][CH2:9]1
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C5CCCC5)c4)cc23)CC1
Yield: 7.78 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting cyclopentyl(methyl)amine (99 mg, 1.0 mmol) for N-methylethanamine to afford 5.0 mg of the title compound (7.78%).