Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[C:6]([NH:8][S:9]([CH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:11])=[O:10])=[O:7])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>>[CH3:25][O:24][C:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]=1[CH2:12][S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])=[O:23]
Reactant: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)N=C=O

Procedure:
A suspension of 8.4 g of the product from Example 5 and 0.1 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) in 75 ml xylenes was heated to reflux temperatures. To this stirred solution was added 2 ml of phosgene at a rate that maintained the temperature above 130°. When the addition was complete, the turbid solution was heated at reflux temperature for 15 minutes, allowed to cool, and then filtered under an atmosphere of nitrogen. Removal of the solvent from the filtrate afforded the product as a viscous brown oil which was dissolved in dry methylene chloride and carried on to the next step without purification. The infrared spectrum of this intermediate displayed a characteristic isocyanate absorption at 2215 cm-1 and a carbonyl stretching absorption at 1730 cm-1.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH2:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.C(O)C1C=CC=CC=1>[B:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:3][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:2][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)O
Reactant: OCc1ccccc1
Solvent: O
Product: c1ccc(COB(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 70 °C

Procedure:
A mixture of 186g of boric acid and 990g of benzyl alcohol was heated at 70° C. During the reaction 180ml of a water/benzyl alcohol azeotrope were distilled over. The residue was distilled under a pressure of 0.5-10mm Hg and in this manner 950g of the title compound were obtained as a clear liquid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH:3]=[CH:4]B(O)O.[CH3:10][C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([NH:15][C:16]1[C:24](C2C=NC=CC=2)=[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1)=[O:14]>>[CH3:1][C:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:24]1[C:16]([NH:15][C:13](=[O:14])[CH2:12][C:11]([CH3:31])([CH3:10])[CH3:32])=[N:17][N:18]2[CH:23]=[CH:22][CH:21]=[N:20][C:19]=12
Reactant: CC(C)(C)C=CB(O)O
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Product: CC(C)(C)/C=C/c1c(NC(=O)CC(C)(C)C)nn2cccnc12

Procedure:
3,3-Dimethyl-1-butenylboronic acid (Aalenchem) and the product from Example 110B were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.03-10.05 (bs, 1H), 9.00 (dd, J=6.9, 1.7 Hz, 1H), 8.57 (dd, J=4.1, 1.7 Hz, 1H), 7.03 (dd, J=6.9, 4.1 Hz, 1H), 6.75 (d, J=16.3 Hz, 1H), 6.23 (d, J=16.3 Hz, 1H), 2.26 (s, 2H), 1.09 (s, 9H), 1.07 (s, 9H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[NH2:21])[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40]([CH:42]=O)=[N:41][C:34]=2[NH:33]1.[BH4-].[Na+]>CCO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[NH:21][CH2:42][C:40]3[CH:39]=[CH:38][C:35]4[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=4[N:41]=3)[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N)[C@H]4C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](NCc5ccc6c(n5)NC(=O)CS6)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 35.4 %

Procedure:
To a solution of (±)-(1S,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azabicyclo[3.2.0]heptan-6-amine (31 mg, 0.098 mmol) in EtOH:DCM (1 mL, 1:1) were added Na2SO4 (21 mg, 0.15 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (19 mg, 0.097 mmol). After 12 h at 25° C., NaBH4 (6 mg, 0.15 mmol) was added. After an additional 1 hr, the reaction was concentrated and the residue was partitioned between DCM/H2O. The combined organic fractions were dried over MgSO4, concentrated and purified via column chromatography (silica, 0-3% MeOH in DCM (1% NH4OH)) yielding the title compound (17 mg, 35%) as a yellow oil: LC/MS (ES) m/e 495 (M+H)+; 1H NMR (CD3OD, 400 Hz) δ 8.62 (s, 1H), 8.20 (d, J=9.1 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.18 (d, J=9.1 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 4.92 (s, 3H), 3.66-3.7 (m, 2H), 3.50-3.58 (m, 4H), 2.88-3.09 (m, 5H), 2.79-2.88 (m, 1H), 2.6-2.63 (m, 1H), 2.19-2.24 (m, 2H), 1.88-1.94 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C@@H:5]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:19]2=[O:34])[CH2:4][CH2:3]1.[CH:35]([N:38](C(C)C)CC)(C)[CH3:36].BrCC#N>C(#N)C>[CH2:27]([O:26][C:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@H:5]2[CH2:4][CH2:3][C@@H:2]([NH:1][CH2:36][C:35]#[N:38])[CH2:7][C@H:6]2[NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:19]1=[O:34])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: N#CCBr
Solvent: CC#N
Product: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](NCC#N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 30 h

Procedure:
Example 1, Alternative Preparation, Step 3: A stirring solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-5-amino-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (400 mg, 0.82 mmol) in acetonitrile (3 mL) was charged sequentially with diisopropylethylamine (315.8 mg, 3 eq) and bromoacetonitrile (109.5 mg, 1.1 eq). The mixture was stirred at40° C. for 30 h. The solvent was removed under reduce pressure. The residue was purified by silica gel column chromatography, using 1.5% of methanol in dichloromethane as the eluant. The desired 2-(trimethylsilyl)ethyl(1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(cyanomethylamino)cyclohexylcarbamate was obtained as a white solid (400 mg, 93%). LC/MS found [M+H]+=530.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:26][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(Sc2ccccc2)c1C
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)c2ccccc2)c1C

Procedure:
Prepared from product of example 7 (6.0 g, 15.3 mmol) and MCPBA (3.11 g of an 85% mixture with MCBA, (ether/petroleum ether) afforded the product as a white solid (4.85 g).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]([F:17])([F:16])[S:8](N1C=CN=C1)(=[O:10])=[O:9].[Cl-].[CH2:19]([NH+:21]1[CH:25]=[CH:24][N:23]([CH3:26])[CH2:22]1)[CH3:20].O>C1COCC1>[CH2:19]([NH+:21]1[CH:25]=[CH:24][N:23]([CH3:26])[CH2:22]1)[CH3:20].[F:6][C:7]([F:17])([F:16])[S:8]([CH:2]([C:1]#[N:5])[C:3]#[N:4])(=[O:10])=[O:9]
Reactant: N#CCC#N
Reactant: O=S(=O)(n1ccnc1)C(F)(F)F
Agent: CC[NH+]1C=CN(C)C1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)S(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
To 6.61 g of malononitrile (100 mmoles) in solution in 50 ml of THF at −20° C., there is added, in portions, 795 mg of lithium hydride LiH. After 2 hours at −20° C., there is added 20.14 g (100 mmoles) of 1-(trifluoromethanesulfonyl)imidazole) (commercially available from Fluka). The reaction was continued during 4 hours at −20° C., and during 48 hours at room temperature. The solvent was then evaporated and the residue was reclaimed in 60 ml of water. There is then added 14.66 g (100 mmoles) of 1-ethyl-3-methyl-1H-imidazolium chloride (commercially available from Aldrich) to the aqueous solution. A dense phase which is denser than water was immediately formed. This phase was recovered by extraction with dichloromethane. After evaporation of dichloromethane and drying under vacuum at 40° C. of the liquid obtained, a molten salt of 1-ethyl-3-methyl-1H-imidazolium of trifluoromethanesulfonylmalononitrile was obtained, with a purity characterized by a proton, carbon and fluorine RMN higher than 98%.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([S:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O.[NH2:25][CH2:26][CH2:27][CH2:28][NH2:29]>>[NH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[C:6]2[CH:7]=[C:8]([S:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc3snc(Cl)c3c2)cc1
Reactant: NCCCN
Solvent: O
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCN)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of 3-chloro-N-(4-methoxybenzyl)benzo[d]isothiazole-5-sulfonamide (52 mg, 0.1 mmol) in 1,3-diaminopropane (1 mL) was allowed to stir at room temperature for 80 min. The dark brown reaction mixture was then poured over water (10 mL) and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3-(3-aminopropylamino)-N-(4-methoxybenzyl)benzo[d]isothiazole-5-sulfonamide (57 mg) as an orange oil. 1H NMR (300 MHz, CD3OD): 8.22 (dd,1H), 7.54 (dd, 1H), 7.29 (dd, 1H), 7.04 (d, 2H), 6.64 (d, 2H), 4.00 (s, 2H), 3.64 (s, 3H), 3.36 (t, 2H), 2.82 (d, 2H), 1.94-2.02 ppm (m, 2H). MW=406 confirmed by LC-MS, tr=7.95 min (Method Y) MH+=407.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@@H:33]3[CH2:37][CH2:36][C@H:35]([NH:38]C(=O)OC(C)(C)C)[CH2:34]3)[N:14]3[C:19]4[CH:20]=[CH:21][N:22]([S:23]([C:26]5[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:18]=4[N:17]=[CH:16][C:15]=23)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].O1CCOCC1.[ClH:52]>CCOCC>[NH2:38][C@H:35]1[CH2:36][CH2:37][C@@H:33]([C:13]2[N:14]3[C:19]4[CH:20]=[CH:21][N:22]([S:23]([C:26]5[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=5)(=[O:24])=[O:25])[C:18]=4[N:17]=[CH:16][C:15]3=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:10][CH:9]=3)[N:12]=2)[CH2:34]1.[ClH:52]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc([C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)n23)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc([C@@H]4CC[C@H](N)C4)n23)cc1
Temperature: 60 °C

Procedure:
To a flask was added tert-butyl (1S,3R)-3-(3-(4-(2-hydroxypropan-2-yl)phenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentylcarbamate (0.48 g, 0.76 mmol; prepared using J.1 from Example #2, Step B with (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid [PepTech], L.1 with mercury(II) trifluoroacetate, AB and D with Preparation #H.1), 1,4-dioxane (7.6 mL) and HCl (4.0 M in 1,4-dioxane, 1.9 mL, 7.6 mmol). The reaction mixture was heated to about 60° C. for about 30 min. The mixture was cooled to rt and diluted with Et2O (20 mL). The solid was collected by filtration, washed with Et2O (10 mL) and dried under reduced pressure at about 60° C. overnight to give 2-(4-(1-((1R,3S)-3-aminocyclopentyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol, hydrochloric acid (0.39 g, 91% yield): LC/MS (Table 2, Method a) Rt=3.06 min; MS m/z 574 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][S:6][CH2:5][C:4]1=O)#[N:2].[ClH:9].[NH2:10]O.CCOCC>C(#N)C>[ClH:9].[NH2:10][C:4]1[C:3]([C:1]#[N:2])=[CH:7][S:6][CH:5]=1
Reactant: NO
Reactant: N#CC1CSCC1=O
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1cscc1N

Procedure:
4-Cyano-3-oxotetrahydrothiophene (1.27 g) was dissolved in acetonitrile (15 ml) with heating and stirring. Hydroxylamine hydrochloride (0.69 g) was added to the refluxing solution and the mixture was refluxed for 11/2hour. After cooling, ether (25 ml) was added and the title compound was filtered off and air-dried. Yield 1.35 g (84%); mp 244°-246°. δ'H nmr (CDCl3 /DMSO-d6) 9.2(br s) 8.55 (d, J=4Hz) 7.85 (d, J=4Hz).
Reaction SMILES: [H-].[Na+].[ClH:3].Cl.[NH2:5][C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH2:15][NH:14][CH2:13][CH2:12][C:10]=2[N:11]=1.I[CH2:24][CH3:25]>CN(C)C=O>[ClH:22].[ClH:3].[NH2:5][C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH2:15][N:14]([CH2:24][CH3:25])[CH2:13][CH2:12][C:10]=2[N:11]=1
Reactant: Nc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2nc(N)nc(-c3ccc(Cl)cc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 158.3 %

Procedure:
A suspension of sodium hydride (12.7 g, 320 mmol), washed three times pentanes, in dimethylformamide (200 mL) was treated with 2-amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride (35.3 g, 110 mmol). The mixture was stirred at room temperature for 2 hours, and iodoethane (8.8 mL, 110 mmol) was added. The mixture was stirred at room temperature overnight, quenched with water and the resulting precipitate was collected by filtration to give 31.5 g (79%) of 2-amino-4-(4-chlorophenyl)-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride. m.p.>260° C. MS: 289 (MH+). IR(KBr): 3224, 2641, 2311, 1623 cm-1.
Reaction SMILES: CN(C)CC.[CH:6]1([C:10]([N:12]2[CH2:18][CH2:17][CH:16]3[CH2:19][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:21][CH2:22][N:15]3[C:14]3[N:31]=[CH:32][CH:33]=[CH:34][C:13]2=3)=O)[CH2:9][CH2:8][CH2:7]1>O1CCCC1>[CH:6]1([CH2:10][N:12]2[CH2:18][CH2:17][CH:16]3[CH2:19][N:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[CH2:21][CH2:22][N:15]3[C:14]3[N:31]=[CH:32][CH:33]=[CH:34][C:13]2=3)[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(C1CCC1)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Agent: CCN(C)C
Solvent: C1CCOC1
Product: Fc1ccc(CN2CCN3c4ncccc4N(CC4CCC4)CCC3C2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of alane-dimethylethylamine complex (0.5 M in toluene, 3.1 mL, 1.55 mmol) was added to a stirring solution of the product of Example 65A (122 mg, 0.31 mmol) in tetrahydrofuran (5.0 mL) at room temperature under nitrogen. The turbid solution was stirred at room temperature for 4 hours. The reaction was quenched by addition of methanol (1 mL), followed after 5 minutes by water (5 mL) and 25% NaOH (0.5 mL). The aqueous layer was separated and extracted with ethyl acetate (2×5 mL) and the combined organic phase was washed with brine (5 mL), dried (Na2SO4) and concentrated under vacuum to provide a residue that was purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30×75 mm), eluted with methanol:10 mM (NH4)2CO3 in water (50:50-95:5) to provide the title compound 1H NMR (300 MHz, CDCl3) δ ppm 1.62-1.94 (m, 6H), 1.97-2.12 (m, 2H), 2.13-2.26 (m, 1H), 2.30-2.49 (m, 1H), 2.51-2.69 (m, 2H), 2.72-2.87 (m, 1H), 2.91-3.03 (m, 1H), 3.02-3.15 (m, 2H), 3.17-3.70 (m, 6H), 6.74 (dd, J=7.8, 4.7 Hz, 1H), 6.92 (dd, J=7.8, 1.4 Hz, 1H), 7.01 (t, J=8.6 Hz, 2H), 7.27-7.39 (m, 2H), 7.79 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 381 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=O)C.[BH4-].[Na+].O1CCCC1.C(O)C>CO>[OH:3][CH2:4][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)COc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1ccc(-c2ccc(OCCO)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 4′-hydroxybiphenyl-4-carboxylate (2.262 g), ethyl bromoacetate (1.871 g) and potassium carbonate (1.940 g) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 1 hr. Diethylamine (6.820 g) was added to the reaction mixture. After being stirred at room temperature for 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate (3.06 g) as a crude product. A mixture of the crude ethyl 4′-ethoxycarbonylmethoxybiphenyl-4-carboxylate, sodium borohydride (0.706 g), tetrahydrofuran (40 mL) and ethanol (10 mL) was stirred at 60° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture, and stirred at room temperature for additional 30 minutes. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (3.000 g)
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[C:48]2[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:46](=[O:57])[N:45]([CH2:58][CH3:59])[C:44]=2[CH:43]=[CH:42][CH:41]=1>>[CH2:58]([N:45]1[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:39][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:3]3)[C:48]=2[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:46]1=[O:57])[CH3:59]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(CBr)cccc21
Product: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21

Procedure:
Analogously to Method D, 0.340 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.272 g of 4-bromomethyl-1-ethyl-3-(2-trimethylsilanylethoxymethyl)-1,3-dihydrobenzimidazol-2-one are reacted. The title compound is obtained as a dark yellow resin. Rf=0.50 (1:1 EtOAc-heptane); Rt=6.67.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[CH:25]1([C:28]([NH2:31])([CH3:30])[CH3:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:31][C:28]([CH:25]5[CH2:27][CH2:26]5)([CH3:30])[CH3:29])=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Reactant: CC(C)(N)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C4CC4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.4 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 2-cyclopropylpropan-2-amine hydrochloride (0.05 g, 0.37 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature for 5 hours. Then HATU (0.114 g, 0.3 mmol) was added, the final reaction mixture was stirred for additional 15 hour. The mixture was poured into 30 mL of water with stirring. After 30 minutes, the mixture was filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 65% acetonitrile/35% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(2-cyclopropylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.025 g, 28%) as a yellow solid. MS: (M+H)+=409; 1H NMR (300 MHz, DMSO): δ 12.81 (s, 1H), 9.04 (s, 1H), 8.41-8.38 (m, 2H), 7.95-7.87 (m, 2H), 7.21 (d, 1H, J=7.2 Hz), 4.15 (s, 3H), 1.53-1.20 (m, 7H), 0.42 (brs, 4H).
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([O:26]C)=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].[OH-].[Na+].Cl.O>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)O)n1
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
To a solution of methyl 6-[2-(butan-2-yl)-6-chloro-5-methoxyindol-1-ylmethyl]pyridine-2-carboxylate (200 mg) in tetrahydrofuran (3.08 mL) and methanol (1.32 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.775 mL) at room temperature, followed by stirring for 2.5 hours. To the reaction mixture was added 1 mol/L hydrochloric acid (1.55 mL). To the mixture were added water and ethyl acetate to separate the organic layer. The organic layer was washed with water twice, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (190 mg). 1H-NMR (DMSO-d6) δ ppm: 0.77 (3H, t, J=7.4 Hz), 1.17 (3H, d, J=6.9 Hz), 1.40-1.70 (2H, m), 2.80-2.95 (1H, m), 3.83 (3H, s), 5.45-5.65 (2H, m), 6.30 (1H, s), 6.70 (1H, d, J=7.3 Hz), 7.20 (1H, s), 7.55 (1H, s), 7.80-7.95 (2H, m), 13.00-13.50 (1H, br).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.F[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=1.[Cl-].[Na+]>C1C=CC=CC=1.CCCCCC.O1CCCC1.CCOCC>[F:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:15]2[CH:14]=[CH:13][C:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:17][CH:16]=2)[N:26]=1
Reactant: Fc1cccc(F)n1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(F)n3)cc2)CC1

Procedure:
12.48 g (40.40 mmol) of 4-(trans-4-pentylcyclohexyl)bromobenzene in 30 ml of benzene are stirred with 25.20 ml (40.40 mmol) of a 1.6-molar n-butyllithium solution in hexane at room temperature under argon for 18 hours. The reaction mixture is then slowly added dropwise at 0° C. under argon to a solution of 4.20 g (36.70 mmol) of 2,6-difluoropyridine in 30 ml of tetrahydrofuran. After a reaction time of one hour at 0° C., the mixture is distributed between ether and sodium chloride solution, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and freed from solvent. Purification of the residue by chromatography gives 0.94 g of 2-fluoro-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine. ##STR50##