Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(-c2ccc(C(C)Br)nc2)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ccc(C(C)n3ccnc3)nc2)cc1
Temperature: 50 °C
Yield: 71.6 %

Procedure:
To a stirred solution of 1H-imidazole (0.069 g, 1.0 mmol) in DMF (7 mL) was added 2-(1-bromoethyl)-5-(4-methoxyphenyl)pyridine (0.150 g, 0.50 mmol) and K2CO3 (354 mg, 2.5 mmol). The reaction was heated at 50° C. for about 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 100-200μ) using 2% methanol in DCM eluent to afford 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-methoxyphenyl)pyridine as an off-white solid (0.1 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, 1H), 7.99 (dd, 1H), 7.80 (s, 1H), 7.63 (d, 2H), 7.26 (s, 1H), 7.03 (d, 1H), 7.21 (d, 2H), 6.89 (s, 1H), 5.64-5.59 (m, 1H), 3.78 (s, 3H), 1.81 (d, 3H), LC-MS m/z calcd for [M+H]+ 280.14. found 280.2.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:20])/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])(=O)=O.[I-:28].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[CH3:20]/[C:8](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:7]\[CH2:6][CH2:5][I:28]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOS(=O)(=O)c1ccc(C)cc1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCI
Yield: 76 %

Procedure:
The (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl tosylate obtained from previous step was dissolved in acetone (50 mL), then added sodium iodide (3.30 g, 22 mmol) and the resulting mixture was stirred at room temperature for 0.5 hours followed by heating at reflux for 3 hours. After cooling, the reaction mixture was poured into cold aqueous sodium thiosulfate solution and extracted with ether. The ethereal extract was washed with water, dried and filtered. Evaporation of the filtrate left a residue which was purified by flash chromatography on a silica gel column. Elution of the column with Hexane:ether (50:1, v:v) provided the title compound (1.85 g, 5.34 mmol, 76% for two steps) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.O.[C@@:24]12([CH2:34][S:35]([OH:38])(=[O:37])=[O:36])[C:31]([CH3:33])([CH3:32])[CH:28]([CH2:29][CH2:30]1)[CH2:27][C:25]2=[O:26].O>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.[CH3:32][C:31]1([CH3:33])[C:24]2([CH2:34][S:35]([OH:38])(=[O:37])=[O:36])[C:25]([CH2:27][CH:28]1[CH2:29][CH2:30]2)=[O:26]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Solvent: CCO
Solvent: O
Product: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Temperature: 35 °C
Reaction time: 3 h

Procedure:
(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (100 g), (1R)-(-)-10-camphorsulfonic acid monohydrate (85.3 g), and radiolite (1 g) in ethanol (1,000 ml) were heated under reflux. It was cooled to 35° C., and 0.2 g of seed crystals were added thereto, thereafter it was agitated at an interior temperature of 20~30° C. for 3 hr, and after ethanol (1,000 ml) was added therto, it was agitated overnight at 20~30° C. The following day, water (25 ml) was added thereto and it was agitated for 1 hr at 20~30° C., and after the temperature was raised to 33~37° C., it was agitated for 30 min. It was cooled to 20~30° C., thereafter the precipitated crystals were collected by filtration, washed with ethanol (100 ml), and dried overnight under vacuum to obtain (+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSA salt as colorless coarse crystals.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][C:16]=3[CH3:23])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH3:40][S:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:43])=[O:42].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]([CH3:23])=[CH:17][CH:18]=[C:19]([CH2:21][N:47]4[CH2:48][CH2:49][N:44]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:45][CH2:46]4)[N:20]=3)=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1ccc(CO)nc1-c1ccc2c(c1)N(C)S(=O)(=O)N2CC1CC1(F)F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(CN2CCN(S(C)(=O)=O)CC2)nc1-c1ccc2c(c1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
(6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-5-methylpyridin-2-yl)methanol (26-6) (25 mg, 0.06 mmol, 1 eq) was dissolved in NMP (0.5 mL) and triethylamine (0.03 mL, 0.18 mmol, 3.0 eq) was added followed by mesyl chloride (0.01 mL, 0.12 mmol, 2.0 eq). After 10 minutes, 1-(methylsulfonyl)piperazine (20.8 mg, 0.13 mmol, 2.0 eq) and DIPEA (0.033 mL, 0.19 mmol, 3.0 eq) were added. The resulting mixture stirred at 80° C. for 10 minutes. The mixture was cooled and purified by reverse phase chromatography (Waters Sunfire MSC18, 15-65% acetonitrile in water with 0.1% TFA modifier) to afford 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(3-methyl-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (26-7) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=7.6 Hz, 1 H); 7.48 (d, J=7.6 Hz, 1 H); 7.25 (dd, J=1.6, 8.4 Hz, 1 H); 7.19 (s, 1 H); 7.13 (d, J=8.0 Hz, 1 H); 4.53 (s, 2 H); 3.97 (d, J=7.2 Hz, 2 H); 3.56 (m, 4 H); 3.49 (m, 4 H); 3.33 (s, 3 H); 2.95 (s, 3 H); 2.43 (s, 3 H); 2.21 (m, 1 H); 1.64 (m, 1 H); 1.42 (m, 1H). HRMS m/z (M+H) 542.1693 found, 542.1702 required.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[OH:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc(OCc2ccccc2)c(Br)c1
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2cc(F)ccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 2.4 mL) was added dropwise to a solution of 1-benzyloxy-2-bromo-4-fluorobenzene (1.5 g, 5.33 mmol) in THF (60 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-methoxybenzaldehyde (0.6 g, 4.42 mmol) in THF (20 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (0.98 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23](O)=[O:24])[CH:17]=3)=[C:9]([CH3:26])[CH:8]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:48][O:49][C:50]1[CH:59]=[CH:58][C:53]([C:54]([NH:56][NH2:57])=[O:55])=[CH:52][CH:51]=1>C1COCC1>[CH3:48][O:49][C:50]1[CH:51]=[CH:52][C:53]([C:54]([NH:56][NH:57][C:23]([C:18]2[CH:17]=[C:16]3[C:21]([CH:22]=[C:14]([C:10]4[C:11]([CH3:13])=[CH:12][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:8][C:9]=4[CH3:26])[NH:15]3)=[CH:20][CH:19]=2)=[O:24])=[O:55])=[CH:58][CH:59]=1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Reactant: COc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)NNC(=O)c4ccc(OC)cc4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-[4-(2-methoxycarbonylethyl)-2,6-dimethylphenyl]-1H-indole-6-carboxylic acid (200 mg, 570 μmol) and HOBT (85 mg, 630 μmol) in THF (10 mL) was added EDCI (164 mg, 860 μmol) and the solution was stirred at RT for 10 min. Then a solution of 4-methoxybenzoic acid hydrazide (104 mg, 630 μmols) in THF (5 mL) was added and the mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure and the residual material was chromatographed using a 50-90% gradient of heptane/ethyl acetate to give the title compound.
Reaction SMILES: COC(=O)CC[S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7].C[O-].[Na+].C1C(=O)N([Cl:36])C(=O)C1>C1COCC1>[Cl:36][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: COC(=O)CCS(=O)(=O)c1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2ccc(S(=O)(=O)Cl)cc21
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 6-[(3-methoxy-3-oxopropyl)sulfonyl]-1H-indole-1-carboxylate (400 mg, 1.13 mmol) in THF (5.5 mL) was added sodium methoxide (2.26 mL, 0.5 M, 1.13 mmol). The reaction mixture was stirred for 20 minutes, then the solvents were removed under reduced pressure and the residue was stripped down from heptanes to generate a white foam. This foam was suspended in DCM (5.5 mL) at 0° C. and then NCS (151 mg, 1.13 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was quenched by the addition of brine (4 mL) and the phases were separated using a phase separator. The aqueous layer washed with DCM. The combined organics were concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(OC)cc2)c1C(=O)OC
Yield: 116.4 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol) in acetone (45 mL) and potassium carbonate (2.2 g, 15.7 mmol), was added 1-bromomethyl-4-methoxy-benzene (0.79 mL, 5.5 mmol). The mixture was refluxed for six hours. The solvent was evaporated in vacuo, and the residue was partitioned between water (50 mL) and ethyl acetate (80 mL). The organic layer was washed with water (2×50 mL), dried, concentrated in vacuo, and purified by flash column chromatography (Silica Gel, EtOAc/Hexane, 0% gradient to 100% 30 min) to give 3-(4-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.0 g, 115% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:36]([NH:40][C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1)=[O:28])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccccc4)CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccccc4)CC3)c2c1

Procedure:
A solution of 3.74 g of 3-[4-(4-phenylpiperazino)butyl]indole-5-carboxylic acid in 500 ml of DMF is treated with 1.01 g of N-methylmorpholine. A solution of one equivalent of tert-butylamine in 5 ml of DMF, 1.35 g of 1-hydroxybenzotriazole and a solution of 1.92 g of N-(3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride in 20 ml of DMF are added with stirring. The mixture is stirred for 16 hours at 20° and the filtrate is evaporated. After working up in a conventional manner, 3-[4-(4-phenylpiperazino)butyl]indole-5-carboxylic acid N-tert-butylamide is obtained.
Reaction SMILES: O=[O+][O-].[CH3:4][C:5]([S@:8]([N:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=1)=[O:9])([CH3:7])[CH3:6].ClCCl.[BH4-].[Na+].[CH3:29][OH:30]>>[OH:30][CH2:29][C@@H:11]([NH:10][S:8]([C:5]([CH3:4])([CH3:6])[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][N:13]=1
Reactant: CC(C)(C)[S@@](=O)N=Cc1ccc(OCC(F)(F)F)cn1
Reactant: CO
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)S(=O)N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Ozone was bubbled through a mixture of (R)-2-methyl-N-[(5-(2,2,2-trifluoroethoxy)pyridine-2-yl)methylene]propane-2-sulfinamide (8.10 g, 24.1 mmol) in a 1:1 mixture of dichloromethane and methanol (96 ml) at −78° C. until no starting material was observed by LC/MS. Nitrogen was bubbled through the reaction for fifteen minutes. To the solution was added in portions sodium borohydride (3.64 g, 96.0 mmol) over ten minutes. The reaction was allowed to warm to room temperature, stirred for 16 hours and then concentrated in vacuum. The resulting residue was washed with brine (2×60 ml) and extracted with ethyl acetate (2×75 ml). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give an oil. Purification by flash chromatography (SiO2, 50-100% ethyl acetate in hexanes, followed by 0-10% methanol in ethyl acetate, gradient) gave N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}-2-methylpropane-2-sulfinamide as a white solid (5.10 g, 61.6%); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.28 (dd, J=2.8 Hz and 8.4 Hz, 1H), 4.62-4.60 (m, 1H), 4.53-4.48 (m, 1H), 4.39 (q, J=8.0 Hz, 2H), 3.91-3.88 (m, 2H), 3.22 (m, 1H), 1.27 (s, 9H); MS (Electrospray): m/z 341.1 (M+H).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=CC=1)([O-])=O.[C:27]1([C:33]2([C:45]#[N:46])[CH2:38][CH2:37][CH:36]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCCCCC.CCOC(C)=O>C1COCC1>[F:25][C:20]1[CH:19]=[C:18]([CH:17]2[CH2:16][O:15][C:14](=[O:26])[N:13]2[C:11]([N:42]2[CH2:41][CH2:40][N:39]([CH:36]3[CH2:37][CH2:38][C:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:45]#[N:46])[CH2:34][CH2:35]3)[CH2:44][CH2:43]2)=[O:12])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: N#CC1(c2ccccc2)CCC(N2CCNCC2)CC1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC1(c2ccccc2)CCC(N2CCN(C(=O)N3C(=O)OCC3c3ccc(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
To a solution of 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (80 mg, 0.21 mmol) in 5 ml of THF was added 1-phenyl-4-piperazin-1-yl-cyclohexanecarbonitrile (80 mg, 0.29 mmol) in a portion and the resulting solution was stirred for 12 h at 25° C. Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography (50% Hexane/EtOAc) to provide 53 mg (51%) of the desired product as a colorless oil. The product obtained was converted to the HCl salt and recrystallized from EtOAc-Et2O to afford 43 mg of the product as white solid: mp 148°151° C.; Anal. Calc. For C27H28F2N4O3.1.0HCl requires C, 61.07; H, 5.50; N, 10.55. Found: C, 59.48; H, 5.41; N, 10.34.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH:18]1([C:24]2[N:32]3[C:27](C=NC=N3)=[C:26]([I:33])[N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[CH:18]1([C:24]2[N:32]3[C:27]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:26]([I:33])[N:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: c1nc[nH]n1
Reactant: Ic1nc(C2CCCCC2)n2ncncc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncnn2c(C3CCCCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1H-1,2,4-triazole (1 g, 0.02 mol) in acetonitrile (23 mL) was added dropwise phosphoryl chloride (0.6 mL, 0.007 mol) and triethylamine (3 mL, 0.02 mol) at 0° C. To this mixture was added 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H-one (77 mg, 0.224 mmol) and the resulting mixture refluxed overnight. The cooled mixture was then quenched with excess NH3 in iPrOH (pH 8) stirred at rt for 30 min. then filtered and the isolated solid washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography over silica gel eluting with 2% MeOH in DCM to afford the 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine. 1H NMR (400 MHz-DMSO-d6) δ 1.14-1.91 (m, 10H), 3.11-3.18 (m, 1H), 6.75 (br.s, 1H), 7.84 (s, 1H) 8.42 (bs, 1H); MS (ES+): m/z: 344.01 (100) [MH+]. HPLC: tR=3.10 min (OpenLynx: polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:28])=[C:7]([S:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=O)[CH:8]=2)[N:3]=1.[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35])[CH3:30].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:29]([O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][CH2:23][C:22]1[CH:21]=[C:20]([S:19][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[F:28])[N:3]=[C:2]([NH2:1])[C:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10]3)[CH:27]=[CH:26][CH:25]=1)[CH3:30]
Reactant: CCOc1ccccc1CN
Reactant: Nc1nc2cc(F)c(Sc3cccc(C=O)c3)cc2cc1CC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccccc1CNCc1cccc(Sc2cc3cc(CC4CCOCC4)c(N)nc3cc2F)c1

Procedure:
3-[2-Amino-7-fluoro-3-(tetrahydro-pyran-4-ylmethyl)-quinolin-6-ylsulfanyl]-benzaldehyde (40 mg, 0.1 mmol) was dissolved in methanol (1 mL), and then 2-ethoxybenzyl amine (60 μL, 0.38 mmol) was added. The resulting mixture was subjected to μW @ 300W, 130° C. for 12 min. NaBH4 (50 mg, 1.3 mmol) was then added portionwise over 1.5 h. The solvent was removed to yield a residue, to which was added 0.1 N NaOH (5 mL). The resulting mixture was extracted with chloroform (3×). The organic layers were combined and dried with MgSO4 and filtered. The solvent was removed to yield a second residue which was purified on silica gel (2-10% MeOH/dichloromethane) to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:14][CH:13]([CH2:15][OH:16])[CH:12]2[CH2:17][OH:18])=[C:4]([O:19]CC2C=CC=CC=2)[N:3]=1.C[O-].[Na+].Cl.CS(C)=O>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:14][CH:13]([CH2:15][OH:16])[CH:12]3[CH2:17][OH:18])[C:9]=2[N:10]=1
Reactant: Nc1nc(OCc2ccccc2)c2ncn(C3CC(CO)C3CO)c2n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: Nc1nc2c(ncn2C2CC(CO)C2CO)c(=O)[nH]1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of [1S-(1α, 2β, 3α)]-3-[2-amino -6-(phenylmethoxy)-9H-purin-9-yl]-1,2-cyclobutanedimethanol, dibenzoate ester (20.0 g.) in 550 ml. of methanol under argon was treated with 5 ml. of 25% sodium methoxide in methanol and heated at 40° C. for 2 hours. Aqueous hydrochloric acid (3N, 275 ml.) was then added to the reaction mixture, and heating was continued at 50° C. for 2 hours. This mixture was concentrated to 100 ml. and the solution was transferred to a separatory funnel, with addition of another 100 ml. of water. The solution was extracted with ether (3×100 ml.) and the pH of the aqueous layer was adjusted to 8.5 with the slow addition of 360 ml. of 2N potassium hydroxide. The resulting thick precipitate was filtered and the damp solid was recrystallized by dissolving in 200 ml. of hot water, filtering while hot, and chilling at 5° C. overnight. Drying in vacuo over phosphorus pentoxide gave 7.65 g. of an impure white solid. Chromatography on 750 ml. of CHP-20P resin with gradient elution using acetonitrile and water, concentration of the pertinent product fractions until turbid, and chilling this turbid solution for 1 hour at 0° C. gave crystals which were filtered. Drying in vacuo at room temperature over phosphorus pentoxide gave 6.3 g. of the title compound as a white crystalline solid, m. p. >270° C., [α]D =-27° (c=1.0, DMSO).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[CH2:30][C:29]5[C:28]([C:31]#[N:32])=[CH:27][CH:26]=[CH:25][C:24]=5[C:23]4=[O:33])=[CH:20][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].CO.[BH4-].[Na+]>C(Cl)Cl>[NH2:32][CH2:31][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH2:30][N:22]([C:21]1[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=4)[N:14]=3)[NH:19][CH:20]=1)[C:23]2=[O:33]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4c(C#N)cccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5c(CN)cccc5C4=O)c3n2)cc1
Reaction time: 2 h

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-1-oxo-isoindoline-4-carbonitrile (80 mg, 0.1143 mmol) dissolved in DCM (10 mL) and MeOH (5 mL) under N2. CoCl2 (29.68 mg, 0.2286 mmol) added and the reaction mixture cooled in an ice bath. NaBH4 (43 mg, 1.143 mmol) added in one portion. Ice bath removed and mixture stirred for 2 h then cooled in an ice bath and water (˜5 mL) added. Mixture diluted with DCM (˜20 mL) and stirred vigorously for 20 mins. Layers separated and aqueous phase extracted with DCM. Aqueous phase basified by addition of sat NaHCO3 solution and extracted with DCM (×2). Combined organics dried and concentrated to a brown foam. This material deprotected using Method E Step 2 to give the title compound after purification by hplc; 1H NMR (400 MHz, DMSO) δ 1.21 (6H, s), 3.50 (1H, sep), 4.03 (2H, s), 5.59 (2H, s), 7.56 (1H, t), 7.71 (2H, m), 8.01 (2H, d), 8.51 (1H, s), 8.54 (2H, d), 9.12 (1H, s) ppm; MS (ES+) 462.0.