Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9].[S-2:10].[Na+].[Na+].[CH3:13][C:14]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=1[CH2:16]Cl>O>[Cl:8][C:7]1[C:2]([S:10][CH2:16][C:15]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=2[CH3:13])=[N+:3]([O-:9])[CH:4]=[CH:5][CH:6]=1
Reactant: [O-][n+]1cccc(Cl)c1Cl
Reactant: Cc1ccc(C)c(CCl)c1
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C)c(CSc2c(Cl)ccc[n+]2[O-])c1
Temperature: 25 °C

Procedure:
2,3-Dichloropyridine N-oxide (4.3 g, 0.026 mole) (prepared according to U.S. Pat. No. 3,850,939) and sodium sulfide (3.4 g, 0.026 mole) were mixed with 25 mL of water and then heated to 70 degrees for two hours. The resulting mixture was cooled to room temperature and treated with 2,5-dimethylbenzyl chloride (4.3 g, 0.026 mole) drop wise. After the addition, the mixture was heated to 70 degrees for four hours, then cooled in an ice bath. The precipitated solid was filtered and washed with cold toluene leaving 3.5 g of product. Recrystallization from toluene afforded pure product having a melting point of 77-80° C. The compound was identified by its NMR spectrum. NMR data (CDCl3): 2.3 (s, 6H); 4.5 (s, 2H); 7.1-8.0 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)[CH3:20]
Reactant: CCOC(=O)CI
Reactant: OCCc1cccc(C(F)(F)F)c1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 78.1, 2-(3-trifluoromethyl-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(3-trifluoromethyl-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. MS: m/e=277.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1.Br[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[N:8]([CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]3)[C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1
Reactant: Cn1c(=O)[nH]c2c(OCC3CCC3)c(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Product: Cn1c(=O)n(CCC2CCN(C(=O)OC(C)(C)C)CC2)c2c(OCC3CCC3)c(Br)ccc21

Procedure:
This compound was synthesized according to the procedure of Example 44, Step 2, using 5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate as the starting materials. LCMS calculated for C20H29BrN3O2 ([M-Boc+H]+H)+: m/z=422.2, 424.2. found: 422.0, 424.0.
Reaction SMILES: [NH2:1]C1C=CC=CC=1.[C:8]12[C:17](=[O:18])O[C:14](=[O:15])[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13]2.O>C(O)(=O)C>[C:17]1(=[O:18])[NH:1][C:14](=[O:15])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]1=2
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C2=C1CCCC2

Procedure:
4.5 g (0.017 mole) of the above aniline and 2.7 g (0.018 mole) of cyclohexene-1,2-dicarboxylic anhydride in 70 ml of glacial acetic acid are stirred for 3 hours at 70° C. After the mixture has been cooled, 100 ml of water are added and the precipitate is filtered off, washed with water and dried. 3.5 g (52%) of N-[4-tetrahydropyran-4-ylmethyl)-3,3-dihydro-2H-1,4-benzoxazin -3-on-6-yl]-3,4,5,6-tetrahydrophthalimide (mp. 187-189° C.) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][C:20]#[N:21]>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[C:20]([NH2:21])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[N:4][CH:3]=2
Reactant: COc1ccccc1CCC#N
Reactant: Nc1cnccc1C=O
Product: COc1ccccc1Cc1cc2ccncc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 3-amino-4-pyridine carboxaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25](C)([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][N:9]=2)=[CH:6][CH:5]=[C:4]([CH3:29])[N:3]=1.C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)=[CH:10][N:9]=2)=[CH:6][CH:5]=[C:4]([CH3:29])[N:3]=1
Reactant: Cc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c(F)n1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)c(F)n1

Procedure:
The title compound (0.166 g, 96%) was prepared as a white solid from 1,1-dimethylethyl 4-{[(2′-fluoro-6′-methyl-2,3′-bipyridin-5-yl)oxy]methyl}-1-piperidinecarboxylate (0.18 g, 0.45 mmol) and TFA (0.35 mL) in CH2Cl2 (10 mL) then diisopropylethylamine (2.0 mL) and isopropyl chloroformate (1.0M in toluene, 0.54 mL, 0.54 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.45-8.35 (m, 2H), 7.82 (d, 1H, J=8.6 Hz), 7.30-7.25 (m, 1H), 7.20-7.10 (m, 1H), 4.91 (septet, 1H, J=6.3 Hz), 4.22 (bs, 2H), 3.89 (d, 2H, J=6.4 Hz), 2.85-2.70 (m, 2H), 2.53 (s, 3H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 388 (M+H).
Reaction SMILES: [Br-:1].ClC[CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:9])[CH3:8].[Br-].[Cl:23]CCCCCC[N+](CCCCCCCCCCCC)(C)C.C(N(C)C)CCCCCCCCCCC>>[Br-:1].[Cl:23][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:9])[CH3:8]
Reactant: CCCCCCCCCCCC[N+](C)(C)CCCCCCCl
Reactant: CCCCCCCCCCCC[N+](C)(C)CCCCCl
Agent: CCCCCCCCCCCCN(C)C
Agent: [Br-]
Product: CCCCCCCCCCCC[N+](C)(C)CCCCl

Procedure:
(4-Chlorobutyl)dodecyldimethylammonium bromide and (6-chlorohexyl)dodecyldimethylammonium bromide can be prepared by a similar process using the appropriate bromochloroalkane and dodecyldimethylamine.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[BH4-].[Na+].O.Cl>O1CCCC1>[Br:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]([CH3:11])[OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C)=O)c(O)c1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)c(O)c1Br
Reaction time: 2 h

Procedure:
64.3 g (0.262 mole) of 3'-bromo-2'-hydroxy-4'-methoxyacetophenone (prepared according to the method of T. M. CRESP et al., J. Chem. Soc. Perkin Trans., Part 1, (1973), 340-345) dissolved in 560 ml of tetrahydrofuran, are added dropwise in the course of 80 minutes and at a temperature of from 13° to 18° C. to a suspension of 13.89 g (0.367 mole) of sodium borohydride in 300 ml of tetrahydrofuran. Thereafter, stirring is continued for 2 hours at ambient temperature. The reaction mixture is decomposed by the addition of 140 ml of tetrahydrofuran containing 3 ml of water, then 60 ml of water are added again thereto. The mixture is acidified by the addition of 415 ml of a 1N aqueous solution of hydrochloric acid. The tetrahydrofuran is removed under reduced pressure and the aqueous phase is extracted 4 times with dichloromethane. The organic phases are dried over anhydrous sodium sulfate and then distilled. The residue obtained(70 g) is used as such in the following step.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]3[CH2:17][CH2:16][NH:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:25][C:24]1[C:19]([N:15]2[CH2:16][CH2:17][C:9]3[C:8]([NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:14]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Clc1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Clc1cccnc1N1CCc2c(ncnc2Nc2ccccc2)C1
Temperature: 150 °C
Yield: 25.6 %

Procedure:
5,6,7,8-Tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine (500 mg, 2.2 mmol) was dissoled in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (423 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (190 mg, 27%).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([NH2:25])[CH2:23][CH3:24].C(N(CC)CC)C.O>C(O)C>[CH2:22]([NH:25][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[CH2:23][CH3:24]
Reactant: CCCN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCNc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole (2.2 grams), propylamine (0.39 gram), and excess triethylamine were mixed in about 50 milliliters of ethanol. The reaction mixture was heated to reflux and refluxed over a weekend (about 60 hours). The reaction mixture was then poured into water and acidified. The desired 4-propylamino-7-nitro-2,5-bis(trifluoromethyl)benzimidazole product precipitated and was separated by filtration. After recrystallization from a mixture of ethanol and water, the compound melted at 129°-31°C. Analysis, Calc.: C, 40.4; H, 2.81; N, 15.73 Found: C, 40.5; H, 2.78; N, 15.51
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18]O)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2].[Cl:33]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O1CCCC1>[Cl:33][CH2:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)CN(c1cc(CO)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CN(c1cc(CCl)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1

Procedure:
The product of step (v) (0.5 g) in tetrahydrofuran (20 ml) was treated with triphosgene (0.114 g) then pyridine (0.183 g). After 16 hours the reaction was evaporated and purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 0.4 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.N12CCN(CC1)CC2.O>ClCCl>[CH3:1][C:2]1[N:3]([CH:18]([CH:20]([O:22][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(C)C(C)n2c(C)c(C(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a mixture of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (1.1 g, 3.6 mmol) in dichloromethane (4 mL) were added 4-methylbenzene-1-sulfonyl chloride (1.3 g, 7.2 mmol), and 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was added to water (30 mL). The aqueous layers was extracted with dichloromethane (10 mL×3). The combined organic layers was dried over sodium sulfate and concentrate to afford tert-butyl 2-methyl-1-(3-(tosyloxy)butan-2-yl)-1H-indole-3-carboxylate (1.6 g, yield: 96%) as a yellow oil. LRMS (M+H+) m/z: calcd 457.19. found 458.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)=[O:11])[N:9]=1)[CH3:3].[BH4-].[Na+].C(O)(C)C.[ClH:21]>O>[ClH:21].[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH3:1]
Reactant: CCOC(=O)c1csc(CN(C)C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CN(C)Cc1nc(CO)cs1

Procedure:
Alternatively, a mixture of 2.14 g of ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate and 0.38 g of sodium borohydride in 20 ml. of isopropanol was heated with stirring at reflux temperature for about 14 hours. The reaction mixture was cooled, and 2 ml. of water were added carefully followed by 4 ml. of 5N aqueous hydrochloric acid. The volatile constituents were removed by evaporation. Methanol (10 ml.) was added and the mixture heated to refluxing temperature for about one hour. Methanol was removed by evaporation and the residual solids digested in 10 ml. of isopropanol on the stream bath. The isopropanol solution was separated by decantation and the solids reextracted with 10 ml. of isopropanol. The isopropanol solutions and extracts were combined and the combined solution filtered while hot to remove insoluble material. The filtrate was chilled and a crystalline solid appeared which separated and was recovered by filtration. Recrystallization of the filter cake from isopropanol gave 1.73 g of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride melting at 153°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH:21]=NC=N3)[C:14]3=[C:22]([CH3:26])[N:23]=[C:24]([CH3:25])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)CN>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[CH2:21][NH:17][C:15]1[C:14]2=[C:22]([CH3:26])[N:23]=[C:24]([CH3:25])[N:13]2[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=1
Reactant: COc1ccc(-c2nc(-n3cncn3)c3c(C)nc(C)n3n2)cc1OC
Reactant: COc1cc(CN)cc(OC)c1
Product: COc1cc(CNc2nc(-c3ccc(OC)c(OC)c3)nn3c(C)nc(C)c23)cc(OC)c1

Procedure:
Prepared analogously to Example 1 from Example 37A (80 mg, 0.23 mmol) and 3,5-dimethoxybenzylamine (396 mg, 2.32 mmol). Purification is carried out by flash chromatography (eluent dichloromethane/methanol 80:1).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.C([O:41][C:42](=O)[CH:43]([CH:47]=O)[CH:44]([CH3:46])[CH3:45])C>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:42](=[O:41])[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:47][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C(C=O)C(C)C
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: CCO
Product: CC(C)c1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Yield: 22.5 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.48 g, 1.74 mmol) (prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol) in ethanol (16 mL) was added 2-formyl-3-methyl-butyric acid ethyl ester (0.33 g, 2.1 mmol). The reaction mixture was heated at reflux for 24 hours. It was then concentrated to remove solvent and loaded on silica gel column. Chromatography with (1-5%) 2-propanol/methylene chloride gave 0.144 g of the title compound. [α]D25 −15.80 (c 0.5, CHCl3).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[CH2:23][C@H:24]4[C@@H:29]([C:30]=3[CH:31]=2)[CH2:28][CH2:27][CH2:26][NH:25]4)[CH:16]=[N:15]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:29]4[C:30]5[CH:31]=[C:19]([C:17]6[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=6)[CH:20]=[CH:21][C:22]=5[CH2:23][C@H:24]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cn1cc(-c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)cn1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: Cn1cc(-c2ccc3c(c2)[C@H]2CCCN(C(=O)c4ccc5[nH]cnc5c4)[C@H]2C3)cn1
Yield: 78 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-(1-methyl-1H-pyrazol-4-yl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 78% of theory; LC (method 1): tR=2.35 min; Mass spectrum (ESI+): m/z=398 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[NH2:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2N)C1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2NC(=O)c2nc(Br)cnc2N)C1
Reaction time: 60 h

Procedure:
A solution containing 1 eq each of tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate, 3-amino-6-bromopyrazine-2-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo. After purification by silica gel chromatography (EtOAc eluant), tert-butyl 1-(3-(3-amino-6-bromopyrazine-2-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate was obtained (78%). LCMS (m/z): 492.2 (MH+); LC Rt=2.68 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22]C(=O)OC(C)(C)C)[CH2:17]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:38]>>[ClH:38].[NH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])[C:4]=23)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CO)c23)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CO)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.220 g, 0.470 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-50 CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide hydrochloride (0.045 g, 22% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.46 (s, 1H), 4.17 (s, 2H), 3.60-3.51 (m, 2H), 3.33-3.28 (m, 1H), 3.22-3.13 (m, 2H), 2.08-2.05 (m, 1H), 1.76-1.72 (m, 2H), 1.54-1.51 (m, 1H). LCMS (APCI+) m/z 368, 370 (M+H)+.
Reaction SMILES: C(O[C:5]([CH3:9])([CH3:8])[C:6]#[CH:7])(=O)C.[N:10]1([C:16]([O:18]C(C)(C)C)=O)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[OH-].[Na+].N>O1CCCC1.C(OCC)(=O)C>[CH3:6][C:5]([CH3:9])([CH3:8])[C:16]([N:10]1[CH2:11][CH2:12][N:13]([C:5]([CH3:8])([CH3:9])[C:6]#[CH:7])[CH2:14][CH2:15]1)=[O:18]
Reactant: C#CC(C)(C)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC(C)(C)N1CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 157 %

Procedure:
0.756 g (6 mmol) of 1,1-dimethylprop-2-yn-1-yl acetate (J. Org. Chem. 1994, 59, 2282-4) and 2.235 g (12 mmol) of 1,1-dimethylethyl piperazine-1-carboxylate are dissolved in 9 ml of tetrahydrofuran and then 0.059 g (0.6 mmol) of cuprous chloride is added. The mixture is heated at reflux for 3 hours. After cooling to ambient temperature, 100 ml of ethyl acetate, 10 ml of 1N aqueous sodium hydroxide and 2 ml of 30% ammonia are added. The organic phase is separated off and washed with 2 times 10 ml of water and then with 10 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated. The product is purified by chromatography on silica gel, eluting with an 85/15 then 75/25 and 65/35 mixture of cyclohexane and ethyl acetate, to give 1.19 g (4.71 mmol) of product in the form of a pale yellow solid.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3](O)[CH:2]=1.[OH-:9].[Na+].CS(C)=O.[CH3:15][CH:16]([CH2:24]Cl)[CH2:17][Si:18]([CH3:23])([O:21][CH3:22])[O:19][CH3:20]>C1(C)C=CC=CC=1>[NH2:7][C:6]1[CH:1]=[C:2]([CH:3]=[CH:4][CH:5]=1)[O:9][CH2:20][O:19][Si:18]([CH2:17][CH:16]([CH3:24])[CH3:15])([CH3:23])[O:21][CH3:22]
Reactant: Nc1ccc(O)cc1
Reactant: [OH-]
Reactant: CO[Si](C)(CC(C)CCl)OC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CO[Si](C)(CC(C)C)OCOc1cccc(N)c1
Temperature: 115 °C

Procedure:
Using the general procedure described in Example 1 a reactor is charged with 60 g (0.55 mole) of p-aminophenol, 43.28 g of a 50% by weight aqueous solution of sodium hydroxide (0.54 mole NaOH), 112 cc dimethylsulfoxide and 120 cc toluene. The resultant mixture is heated to the boiling point for six hours under a nitrogen atmosphere to remove all of the water present by azeotropic distillation. The reaction mixture is then allowed to cool to about 75° C., at which time 117 g (0.56 mole) of 2-methylchloropropyl methyldimethoxysilane are added dropwise while the reaction mixture is stirred. Following completion of the addition the reaction mixture is heated at 115° C. for about 16 hours, following which the mixture is allowed to cool and is filtered to remove any solid material. The solvents are then removed under a pressure of about 15 mm of mercury at a temperature of about 60° C. The pressure is then reduced to 2 mm of mercury and the material boiling at 165° C. is collected. Analysis by vapor phase chromatography indicates that the purity of the product, a pale yellow viscous liquid, was greater than 98%.