Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[NH:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[P:18](Cl)(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:20]([O:19][P:18]([N:7]1[CH:1]2[CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: O=C(OCc1ccccc1)N1CCC2NC2C1
Reactant: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reaction time: 24 h
Yield: 21 %

Procedure:
To a solution of benzyl 3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in DCM (0.26M) was added diethyl phosphorochloridate (1.3 equiv.) and triethyl amine (1.5 equiv.). The reaction was stirred for 24 h, then concentrated to dryness. Added water and ethyl acetate, the organics were extracted, dried with Na2SO4, and concentrated. The crude was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (50% to 100% ethyl acetate) to yield benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate as a clear oil in 21% yield. LCMS (m/z): 369.0 (MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:28][O:29][C:30]1[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37](C2C=CC=CC=2)[C:38](=O)[O-:39])[N:31]=1>O1CCOCC1>[CH:1]1([O:6][C:7]2[C:12]([S:13]([NH:16][C:38]([NH:37][C:32]3[N:31]=[C:30]([O:29][CH3:28])[N:35]=[C:34]([CH3:36])[N:33]=3)=[O:39])(=[O:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1cccnc1OC1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2OC2CCCC2)n1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a mixture of 4.84 g of 2-cyclopentyloxypyridin-3-ylsulfonamide and 3.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of absolute dioxan are added 5.46 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate at 20° to 25° C. The mixture is stirred for 1/2 hour, the precipitate is isolated and the filtrate is concentrated by evaporation. The residue is triturated with 10 ml of 2N hydrochloric acid and the crystals so obtained are isolated, washed with ether and water and dried, affording 7.79 g of N-(2-cyclopentyloxypyridin-3-ylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea with a melting point of 170°-172° C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 98b (1.1 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3nc(C)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate (200 mg, 0.69 mmol) and 1-(3,5-dimethoxyphenyl)piperazine (154 mg, 0.69 mmol) were dissolved in anhydrous tetrahydrofuran (25 ml) and thereto DBU (105 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][C@@H:8]([N:18]1[C:23](=[O:24])[CH2:22][NH:21][C:20]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[N:28][C:19]1=2)[CH2:9][O:10]CC1C=CC=CC=1)([CH3:4])[CH3:3]>[OH-].[OH-].[Pd+2].CCO.[Pd]>[CH3:4][C:2]([Si:5]([CH3:31])([CH3:32])[O:6][CH2:7][C@@H:8]([N:18]1[C:23](=[O:24])[CH2:22][NH:21][C:20]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[N:28][C:19]1=2)[CH2:9][OH:10])([CH3:1])[CH3:3]
Reactant: COc1ccc2c(n1)N([C@@H](COCc1ccccc1)CO[Si](C)(C)C(C)(C)C)C(=O)CN2
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(n1)N([C@@H](CO)CO[Si](C)(C)C(C)(C)C)C(=O)CN2
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 95.1 %

Procedure:
A mixture of 4-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (250.4 g, 0.547 mol), Pearlman's catalyst (25 g) and 10% Pd/C (25 g, 50% wet) in EtOH (5 L) was stirred at 50° C. under 5 bar of H2 for 3.5 h. The reaction mixture was filtered through celite and the filtrate was evaporated to give 4-[(1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-(hydroxymethyl)ethyl]-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (191.2 g, 95%) as a dark blue solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]1O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1=Cc2c(cccc2-c2ccccc2)C1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 72.1 %

Procedure:
A 300-ml four-necked round flask equipped with a stirring bar, a dropping funnel and a thermometer was charged with 9.78 g (41.3 mmol) of 2-ethyl-1-hydroxy-4-phenylindane, 17.2 ml (123.8 mmol) of triethylamine, 0.25 g (2.1 mmol) of 4-dimethylaminopyridine and 98 ml of methylene chloride. To the mixture was dropwise added a solution containing 6.4 ml (82.5 mmol) of methanesulfonyl chloride dissolved in 6.5 ml of methylene chloride under a nitrogen atmosphere at 0° C. After the addition was completed, the reaction mixture was stirred for 3.5 hours at this temperature. The reaction mixture was poured onto 250 ml of ice-water. Then, the organic phase was separated and the aqueous phase was further extracted with 50 ml of methylene chloride two times. The combined organic phase was washed with a saturated aqueous solution of NaHCo3, and then a saturated aqueous solution of sodium chloride, followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluting with hexane) to obtain 6.56 g of the desired product as a pale yellow liquid (mixture of two kinds of isomers) (yield: 73%).
Reaction SMILES: [CH:1]1([C:4]2([C:12]#[N:13])[CH:8]([CH2:9][CH3:10])[CH2:7][NH:6][C:5]2=[O:11])[CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:14][C:15]1[N:20]=[C:19]([N:6]2[CH2:7][CH:8]([CH2:9][CH3:10])[C:4]([CH:1]3[CH2:2][CH2:3]3)([C:12]#[N:13])[C:5]2=[O:11])[CH:18]=[CH:17][N:16]=1
Reactant: CCC1CNC(=O)C1(C#N)C1CC1
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCC1CN(c2ccnc(Cl)n2)C(=O)C1(C#N)C1CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a mixture of 3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (3.7 g) obtained in Step B of Example 376, 2,4-dichloropyrimidine (3.1 g), cesium carbonate (13 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.71 g) in tetrahydrofuran (55 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.38 g), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3SR,4RS)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) and (3SR,4SR)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g). (3SR,4RS)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (500 mg) having a shorter retention time and (3R,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (510 mg) having a longer retention time. (3SR,4SR)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (560 mg) having a shorter retention time and (3R,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (600 mg) having a longer retention time.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C([O:19][C@@H:20]1[C@H:24]([O:25]C(=O)C2C=CC=CC=2)[C@@H:23]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:22][C@H:21]1[N:44]1[CH:52]=[N:51][C:50]2[C:45]1=[N:46][C:47]([Cl:54])=[N:48][C:49]=2Cl)(=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.N>O1CCOCC1>[Cl:54][C:47]1[N:48]=[C:49]([NH:10][C@H:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:50]2[N:51]=[CH:52][N:44]([C:45]=2[N:46]=1)[C@@H:21]1[O:22][C@H:23]([CH2:34][OH:35])[C@@H:24]([OH:25])[C@H:20]1[OH:19]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)Cc1ccccc1
Agent: N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 20.6 %

Procedure:
The title compound was prepared by reacting L-amphetamine (0.49 g, 3.6 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.9 g, 3.0 mmol) in dioxan (25 ml) in the presence of diisopropylethylamine (0.58 g, 4.5 mmol) followed by deprotection of the purified product using methanolic ammonia. Evaporation of the reaction mixture provided a gummy residue which crystallized on addition of dichloromethane (10 ml), to provide the title compound (0.26 g, 38%) as a solid, m.p. 132.5°-135.5° C. A further sample of the title compound (0.26 g) was obtained by flash chromatography of the mother liquors. 1H NMR (DMSO-d6)δ 1.22 (3H, d, -- CH3), 2.67-2.79 & 2.92-3.03 (2H, 2m, -- CH2 --), 3.51-3.58 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b), 3.94 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.41-4.54 (2H, m, H-2' and CH3C H--), 5.06 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.82 (1H, d, H-1'), 7.10-7.33 (5H, m, Ar--H), 8.28-8.44 (2H, m, H-8 and N--H).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: Clc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]([CH3:11])[CH3:10])[CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:22][O:23][CH3:24].O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:22][O:23][CH3:24])=[C:4]([N:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CN(C)c1cc(Br)ccc1O
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(Br)cc1N(C)C
Yield: 98.7 %

Procedure:
To a stirring solution of 4-bromo-2-dimethylamino-phenol (3.7 g, 17.13 mmol) in CH2Cl2 (100 mL) at room temperature was added ethyl-diisopropyl-amine (4.47 mL, 25.7 mmol) and chloro-methoxy-methane (1.69 mL, 22.27 mmol). The mixture was refluxed for 16 hrs, added water. The organic layer was collected and dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude N-(5-bromo-2-methoxymethoxyphenyl)dimethylamine as a red oil (4.4 g, 99%): 1H NMR (200 MHz, DMSO-d6): 6.96 (m, 3 H), 5.17 (s, 2 H), 3.40 (s, 3 H), 2.72 (s, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=15% ethyl acetate in hexanes; Rf=0.59.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](SC)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:25][C:26]([F:38])([F:37])[C:27]1[NH:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:36][C:34]5[CH:33]=[CH:32][C:30]6[N:31]=[C:27]([C:26]([F:38])([F:37])[F:25])[NH:28][C:29]=6[CH:35]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)CC4CC4)c3)n2n1
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Product: O=S(=O)(CC1CC1)c1cccc(-c2ccc3cnc(Nc4ccc5nc(C(F)(F)F)[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 7-(3-cyclopropylmethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.20 mmol) was coupled with 2-trifluoromethyl-3H-benzimidazol-5-ylamine (68.3 mg, 0.340 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 25 mg (22%) of brown powder; LC/MS: 513 (M+H); HPLC: 97% pure, RT=3.43 min; 1H NMR: (DMSO, δ) 9.60 (s, 1H), 8.97 (s, 1H), 8.53 (d, J=7.9, 1H), 8.41 (s, 1H), 7.90 (s, 1H), 7.81 (d, J=7.9, 1H), 7.70 (m, 2H), 7.60 (d, J=8.8, 1H), 7.21 (d, J=4.8, 1H), 6.91 (d, J=4.8, 1H), 3.20 (d, J=7.2, 2H), 0.77 (m, 1H), 0.32 (m, 2H), −0.01 (m, 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:36])[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39](I)[CH3:40]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:36])[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH2:39][CH3:40])[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cn[nH]c4)[C@@H](Cc4ccccc4)C3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cnn(CC)c4)[C@@H](Cc4ccccc4)C3)ccc12
Temperature: 60 °C
Yield: 44.8 %

Procedure:
A solution of (S)-1-(2-benzyl-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)piperazin-1-yl)-2-(1H-pyrazol-4-yl)ethanone (101 mg, 0.21 mmol) in DMF (1 mL) was treated with sodium hydride (10 mg, 0.25 mmol) as a 60% dispersion in mineral oil. Once bubbling subsided, ethyl iodide (18 μL, 0.23 mmol) was added and the mixture was heated to 60° C. for 24 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (5 mL) followed by brine (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude residue was purified by silica gel chromatography eluting with a 0-10% MeOH in CH2Cl2 gradient to afford product as a colorless solid (48 mg, 44%). LC/MS 4.03 min, [M+1]+ 511.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH:7]1[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]1[CH2:9][CH2:10]2
Reactant: COc1ccc2c(c1)CCC=C2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1C2CCc3cc(OC)ccc3C21

Procedure:
7-Methoxy-1,2-dihydronaphthalene (8.8 g, 0.055 mol) was mixed with 1 ml of degassed absolute methylene chloride and 20 mg of rhodium acetate (appr. 0.1 mol %). The reaction mixture was bubbled with nitrogen and ethyl diazoacetate (2 eq, 50% solution in degassed abs. methylene chloride) was added slowly through the syringe (flow rate about 1 ml/hour) to the stirred solution at ambient temperature. Gas evolution started upon the addition. The reaction was monitored by GC. Additional amount of catalyst was added during the reaction (about 20 mg). GC-ratio of cis/trans isomers was 21:48.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]2=[C:11]([C:14](=[S:16])[NH2:15])[N:12]=[CH:13][N:3]12.Br[CH2:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=O.C(N(CC)CC)C>CC#N>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[C:19]1[N:15]=[C:14]([C:11]2[N:12]=[CH:13][N:3]3[C:2](=[O:1])[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]=23)[S:16][CH:18]=1
Reactant: C#CCn1nnc2c(C(N)=S)ncn2c1=O
Reactant: O=C(CBr)c1nccs1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCn1nnc2c(-c3nc(-c4nccs4)cs3)ncn2c1=O
Yield: 38 %

Procedure:
4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.43 mmol) and 2-bromo-1-(1,3-thiazol-2-yl)ethanone (0.43 mmol) were stirred in MeCN (2 mL) overnight at room temperature. The reaction mixture containing a newly formed precipitate was then treated with sufficient triethylamine to solubilise before evaporating to dryness and purifying by column chromatography, eluting with 10% MeCN/DCM, to give the title compound. Yield 38%. δH (DMSO-d6) 9.00 (1H, s) 8.44 (1H, s), 7.97 (1H, d, J=3.2), 7.85 (1H, d, J=2.8), 5.16 (2H, d, J=2.4), 3.55 (1H, t, J=2.4).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][C:3]=1[O:20][CH3:21].O.NN>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(CN)ccc1Cl
Yield: 96.1 %

Procedure:
To a solution of N-(4-chloro-3-methoxybenzyl)phthalimide (3.00 g) in ethanol (60 mL) was added hydrazine hydrate (2.62 mL), and the mixture was heated for an hour under reflux. The resulting precipitates were faltered off and the filtrate was evaporated in vacuo. The residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 4-chloro-3-methoxybenzylamine as a yellow oil (1.64 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:19]=1[CH3:27]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1nc2ccccn2c1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(C)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (522 mg, 3.7 mmol) was dissolved in anhydrous DMF (20 mL), then were added potassium carbonate (1.52 g, 11.0 mmol) and 3-(bromomethyl)-2-methylimidazo[1,2-a]pyridine (5.5 mmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. The solid was removed by filtration washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 4-12% DCM/MeOH to afford 6-methyl-2-[({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)sulfanyl]pyrimidin-4-ol (165 mg, 16% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.42 (s, 3H), 4.84 (s, 2H), 6.01 (s, 1H), 6.94 (dt, J=6.8 Hz, J=1.4 Hz, 1H), 7.21-7.26 (m, 1H), 7.47 (td, J=9.0 Hz, J=1.0 Hz, 1H), 8.43 (td, J=6.8 Hz, J=1.2 Hz, 1H); LRMS (ES) m/z 287 (80%, M+1).
Reaction SMILES: [CH3:1][C:2]1([CH:15]=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[CH3:1][C:2]1([CH:15]=[N:18][OH:19])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(C=O)OCCc2c1[nH]c1ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C=NO)OCCc2c1[nH]c1ccccc21
Reaction time: 16 h

Procedure:
A solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-carboxaldehyde (547 mg), described in Example 777, aqueous hydroxylamine hydrochloride (2.5 ml of 5N) and aqueous sodium acetate (2.5 ml of 5N) and methanol (5 ml) is heated at 50° - 60° C. for 5 min. and then kept at 4° C. for 16 hr. The precipitate is collected and recrystallized from ethanol water to afford 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde oxime, m.p. 176° - 178° C.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1
Reactant: c1cc2c(c(N3CCNCC3)c1)COC2
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4COC5)CC3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.278 g, 1.186 mmol, 1.1 eq) and 1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine (0.217 g, 1.064 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.469 g, 4.425 mmol, 3.73 eq). The slurry was allowed to stir overnight at room temperature (18 h). The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1 N HCl in ether provided the title compound (0.143 g, 26%). CHN Found: C, 64.37; H, 6.54; N, 12.13. This calculates out for C24H30N4O3×1.00 HCl.