Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C@@H:10]([CH2:21][NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:11]CC2C=CC(OC)=CC=2)[O:7][C@H:6]1[N:40]1[CH:45]=[CH:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])(=[O:3])[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C@@H:10]([CH2:21][NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:11])[O:7][C@H:6]1[N:40]1[CH:45]=[CH:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCC(=O)NC[C@@H](OCc1ccc(OC)cc1)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2ccc(=O)[nH]c2=O)O1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NC[C@@H](O)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2ccc(=O)[nH]c2=O)O1
Reaction time: 1 h
Yield: 24 %

Procedure:
240 mg of the product of Stage A dissolved in 2 ml of methylene chloride is added to 7.5 ml of a mixture of methylene chloride/trifluoroacetic acid (9/1) under a nitrogen atmosphere. The solution obtained is agitated for 1 hour followed by evaporating and drying. A product is obtained which is taken up in ether then in pentane followed by evaporation again. The product obtained is chromatographed and 47 mg of sought product is obtained.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][C@H:23]1[CH2:34][OH:35])=[O:21])([CH3:18])([CH3:17])[CH3:16].O[C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][C@H:23]1[CH2:34][O:35][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Yield: 149 %

Procedure:
DIAD (0.64 ml, 3.25 mmol) was added dropwise while stirring a mixture of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (1.16 g, 3.25 mmol), methyl 4-hydoxybenzoate (494 mg, 3.25 mmol) and triphenylphosphine (852 mg, 3.25 mmol) in THF (30 ml) at room temperature in a nitrogen gas stream. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 20 minutes and at 80° C. for 8 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (silica gel: 200 g), whereby from chloroform/acetone (20/1) eluate fractions, the title compound (2.07 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]>C(OCC)(=O)C.CCCCCC>[CH3:32][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]
Reactant: CCOC(=O)/C=C/c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 84 %

Procedure:
Using ethyl (2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate obtained in Example 178, the title compound was synthesized in the same manner as in Example 180. Yield: 84%. Melting point: 103-105° C. (ethyl acetate-hexane).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CS(C)=O.[OH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@H:26]1[O:28][CH2:27]1)(=O)=O>CC(C)=O.O>[O:28]1[CH2:27][C@H:26]1[CH2:25][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)=O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
Powdered K2CO3 (40 grams, 289 mmol, 300 mesh) was added to dimethyl sulfoxide (DMSO) (200 mL) containing H2O (4 mL) under N2 at room temperature and the mixture was stirred for 30 minutes. 4-Hydroxyindole (25.2 grams, 189 mmol) was added to the mixture (slight exotherm to 27° C.) and the mixture was stirred for 10 minutes. (S)-Glycidyl nosylate (50.0 grams, 193 mmol, 98.5% ee) was added (slight endotherm). The slurry was stirred for 30 minutes at 20-25° C. and for 23 hours at 25-27° C. until the reaction was complete. The mixture was diluted with acetone (400 mL) and filtered. The cake was washed with acetone (400 mL) and the combined filtrates were concentrated to a volume of ca. 250 mL under vacuum while maintaining the temperature below 35° C. This concentrate was added dropwise, over ca. 2 hours, to deionized H2O (650 mL) held at a temperature of 15-20° C. with an ice/water bath. The product slurry was stirred for 1 hour at this temperature and for 30 minutes at 5-10° C. The solid was isolated by filtration and washed with cold deionized H2O (150 mL). The solid was dried under vacuum at 35° C. to yield 30.3 grams of product.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]1[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[CH2:34][CH2:35]1)[CH2:18]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1CCN(c3ccccn3)CC1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.20 g), 1-(2-pyridyl)piperazine (823 mg), and potassium carbonate (1.04 g) in DMF (12 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (1.16 g) as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:3]1.[CH:26]1([CH2:29][NH:30][C:31](=[O:42])[NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:26]1([CH2:29][NH:30][C:31]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([N:7]3[C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]4[CH:11]=[CH:12][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=4)[CH2:3][C@@H:2]3[CH3:1])=[O:38])=[CH:40][CH:41]=2)=[O:42])[CH2:28][CH2:27]1
Reactant: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
2-(4-((-3,5-cis-Dimethylpiperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (0.27 mmol, 0.1 g), 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.27 mmol, 0.063 g) and triethylamine (0.81 mmol, 0.113 mL, 0.082 g) were combined in dichloromethane and stirred at room temperature. 1-Propanephosphonic acid cyclic anhydride (0.405 mmol, 0.241 mL, 0.258 g; 50% solution in ethyl acetate) was added and the reaction allowed to stir for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by acidic preparative HPLC to afford the desired compound (3 mg). MS (ESI) m/z 587.3 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[CH:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>CC(CC(C)=O)C>[CH:6]1([NH:11][CH2:2][C:3]([NH2:5])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC1CCCC1
Reactant: NC(=O)CCl
Solvent: CC(=O)CC(C)C
Product: NC(=O)CNC1CCCC1

Procedure:
To a solution of spiro[isobenzofuran-1(3H),4'-piperidine](14 g) in dichloromethane (160 ml) triethylamine (11 ml) was added. After cooling to 10° C. a solution of chloroacetylchloride (8 ml) in dichloromethane (10 ml) was added dropwise during 20 minutes. The reaction mixture was finally allowed to reach room temperature. the mixture was subsequently filtered through silica gel (eluted with ethyl acetate/n-heptane 60:40) affording 12 g of the α-chloroacetamide derivative. A mixture of the thus obtained α-chloroacetamide derivative (1.4 g) and cyclopentylamine in MIBK (25 ml) was refluxed for 2 h. The solvent was evaporated in vacuo and the cyclopentylamino derivative was extracted from an alkaline (pH>9) aqueous solution with ethyl acetate. The organic phase was worked up as above yielding 2.0 g of the α-(cyclopentylamino)acetamide derivative as a visceous oil. To a solution of the α-(cyclopentylamino)acetamide derivative (2 g) in MIBK 1'-chloracetyl-spiro[isobenzofuran-1(3H),4'-piperidine] (1.4 g) and potassium carbonate (1 g) were added. The mixture was refluxed for 3 h. After cooling to room-temperature the mixture was filtered through silica gel (eluted with 4 % triethylamine in ethyl acetate. Evaporation of the solvents afforded 2.4 g of the diamide which was reduced with LiAlH4 as described in example 1. The title compound 3a crystallized from a mixture of ethanol and acetone (1:4). Yield 1.3 g, mp 258°-260° C. 1H NMR (DMSO-d6)δ1.50-2.45 (m,16 H), 3.25-3.80 (m,17 H), 5.05 (s,4 H), 7.10-7.40 (m,8 H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([O:48][CH3:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:59])=[C:36]([O:48][CH3:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.55 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.26 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate and the solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.44 g) as colorless amorphous.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:32]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:32])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]2=[N:10]1
Reactant: COc1ccc2nn(-c3cc(C)ccc3O)nc2c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-methoxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 5.693 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-methoxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnet stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-methoxybenzotriazole was 6.3 g (84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.C[Si]([CH:22]=[N+:23]=[N-:24])(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH:22]=[N+:23]=[N-:24])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)c1ccc(Cl)c(Br)c1
Temperature: -5 °C

Procedure:
To a mixture of 3-bromo-4-chlorobenzoic acid (1.51 g, 6.4 mmol, 1.00 eq.) in DCM (25 mL) cooled at −5° C., oxalylchlorid (0.8 mL, 9.6 mmol, 1.50 eq.) and 4 drops of DMF were added. The reaction mixture was warmed to r.t. over 20 hours. The mixture was concentrated in vacuo. The resulting oil was dissolved in THF (50 mL) and cooled to −5° C. (Trimethylsilyl)diazomethane solution (2.0 M in hexanes, 7.2 mL, 14.4 mmol, 2.25 eq.) was added and the mixture was allowed to warm to r.t. over 18 hours. The mixture was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 60 fractions of 45 mL, Heptane to Heptane+20% AcOEt) to yield 1-(3-bromo-4-chloro-phenyl)-2-diazo-ethanone as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C>C(O)C.[C].[Pd]>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (273 mg) was dissolved in ethanol (5 ml), then triethylamine (420 μl) and 10% palladium-carbon (27 mg) were added, the reaction mixture was subjected to hydrogenation at a room temperature under normal pressure for 3 hours, there was obtained 2-chloro-4-nitroimidazole (124 mg, yield: 84.1%) as colorless solid product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH:6]([CH3:13])[CH2:5]2.CC(CC1C=CC=CC=1)CC(O)=O>>[CH3:13][CH:6]1[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[C:8](=[O:12])[CH2:7]1
Reactant: CC1CC(=O)c2ccc(Br)cc2C1
Agent: CC(CC(=O)O)Cc1ccccc1
Product: CC1CC(=O)c2ccccc2C1

Procedure:
3-Methyl-3,4-dihydronaphthalen-1(2H)-one was prepared in a similar manner as 6-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one of Example 48, except using 3-methyl-4-phenylbutanoic acid. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=7.9 Hz, 1H), 7.47 (dd, J=7.4, 7.4 Hz, 1H), 7.31 (dd, J=7.4, 7.4 Hz, 1H), 7.24 (d, J=7.4 Hz, 1H), 3.01-2.95 (m, 1H), 2.76-2.66 (m, 2H), 2.37-2.27 (m, 2H), 1.15 (d, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]O)=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][Cl:14])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCc1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCCCCc1ccncc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of 4-(4-pyridinyl)-1-butanol (Mayer J. M and Testa, B., Helv. Chim. Acta 65, pages 1868-1884 (1982)) (4.20 g, 27.7 mmol) in 30 mL of chloroform is cooled to 0° C. and treated with thionyl chloride (6.60 g, 55.54 mmol) in 30 mL of chloroform. The reaction is allowed to warm to room temperature over 15 hours. The volatiles are removed in vacuo. The residue is cooled to 0° C. and treated with 50 mL of cold 10% sodium hydroxide solution and the mixture is extracted with three 100-mL portions of chloroform. The combined organic extracts are dried over sodium sulfate and the solvents are removed under reduced pressure to give 4.25 g of 4-(4-pyridinyl)-1-butylchloride as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)ccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)ccc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 52.55 g (0.31 mol) of 4-chloro-3-methyl-benzoic acid in CH2Cl2 (1.2 L) with DMF (1 mL) at 0° C. under N2 with an outlet sparging through 2.5 N sodium hydroxide was added 29.56 mL (0.339 mol) of oxalyl chloride. The mixture was allowed to warm to room temperature over a 3 h period. The reaction mixture was concentrated and taken forward crude.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
4-Chloro-2-fluoroaniline (23 g) was dissolved in conc. sulfuric acid (120 ml), and the resultant mixture was cooled to -20° C., followed by dropwise addition of fuming nitric acid (15 g). The reaction mixture was stirred at -20° to -15° C. for 1.5 hours, poured into ice-water and then extracted with ether. The ether extract was washed with water and a saturated sodium bicarbonate solution, dried and concentrated. The residue was crystallized from a mixture of toluene and hexane (2:1) to obtain 20 g of 4-chloro-2-fluoro-5-nitroaniline. m.p., 83°-84.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:19]=[C:20]([Cl:28])[N:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=34)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:19]=[C:20]([Cl:28])[N:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=34)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(Cl)n4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nc(Cl)n4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
In a round-bottomed flask, 2-(3-chloro-6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (36 mg, 0.068 mmol) was dissolved in dichloromethane (0.4 ml) and trifluoroacetic acid (0.22 ml, 2.86 mmol) was added. The reaction was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.4 ml) and ethylenediamine (0.3 ml, 4.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 21 mg (77%) of 2-(3-chloro-6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a yellow powder. MS: (M+H)+=403; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.01 (br. s, 1H), 9.03 (s, 1H), 8.58 (d, J=3.8 Hz, 1H), 8.49 (dd, J=10.0, 5.5 Hz, 1H), 8.40 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.18-7.29 (m, 1H), 4.39 (d, J=7.9 Hz, 1H), 3.50 (qd, J=9.9, 4.3 Hz, 2H), 3.30 (s, 3H), 1.31 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:10][OH:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:1]([C:4]1[C:5]([CH:10]=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccnc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)c1cccnc1C=O
Reaction time: 18 h
Yield: 61.7 %

Procedure:
To a vigorously stirred solution of (3-isopropyl-pyridin-2-yl)-methanol (26 g, 170 mmol) in CH2Cl2 (575 mL) was added manganese(IV) oxide (105 g, 1.20 mol) under N2. The mixture was stirred for 18 h then filtered through a celite pad and concentrated in vacuo. Purification by column chromatography on silica gel (EtOAc/hexanes, 1:3) afforded 3-isopropyl-pyridine-2-carbaldehyde (15.65 g, 61%) as an orange oil. 1H NMR (CDCl3) δ 1.26 (d, 6H, J=7.0 Hz), 4.17 (sep, 1H, J=6.6 Hz) 7.45 (dd, 1H, J=7.9, 4.4 Hz), 7.84 (d, 1H, J=7.9 Hz), 8.56 (dd, 1H, J=4.4, 1.3 Hz), 10.2 (s, 1H).