Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([Sn:13](Cl)(Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CCOCC>[C:14]1([SnH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Sn](Cl)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: c1ccc([SnH2]c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled suspension of 0.76 g of lithium aluminum hydride in 15 ml of dry ether, was added 6.88 g of diphenyltin dichloride dissolved in 20 ml of dry ether. After stirring for 30 minutes, 20 ml of water was added to the resulted reaction mixture, and the ether layer was washed with icy water and dried over calcium chloride. The subsequent concentration under reduced pressure gave diphenyltin hydride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (2.00 g, 9.99 mmol), 2-chloropyrimidine (3.43 g, 30.0 mmol), and K2CO3 (6.90 g, 49.9 mmol) in 1,4-dioxane (57 mL) was refluxed for 2 days. After cooled to room temperature, the mixture was filtered and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (Hexane:EtOAC=3:1) to give tert-butyl 1-(pyrimidine-2-yl)piperidin-4-ylcarbamate (2.78 g, quant.) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.23-1.44 (2H, m), 1.45 (9H, s), 1.95-2.08 (2H, m), 2.99-3.10 (2H, m), 3.72 (1H, brs), 4.39-4.53 (1H, m), 4.59-4.69 (2H, m), 6.47 (1H, t, J=4.8 Hz), 8.29 (2H, d, J=4.8 Hz). m/z=278.87 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1CCNC1
Product: Nc1ncnn2c(-c3ccc(CN4CCCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 8 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and pyrrolidine as starting materials, 17 mg (8%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.70 (m, 2 H), 3.40 (s, 2 H), 2.60 (m, 2 H), 1.70 (m, 4 H); ES-MS m/z 500.03 [M+H]+, HPLC RT (min) 2.30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:18])[CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cc(F)cc(F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cc(F)cc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3,5-difluorophenoxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:9]=[C:8]([CH2:10][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])[CH3:12])[N:7]([CH2:22][CH2:23][O:24][CH3:25])[N:6]=1)#[N:4].C([O-])(=O)C.[K+].S(=O)(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:9]1[C:5]([C:3]#[N:4])=[N:6][N:7]([CH2:22][CH2:23][O:24][CH3:25])[C:8]=1[CH2:10][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:13])[CH3:12]
Reactant: BrBr
Reactant: COCCn1nc(C#N)cc1CC(C)(C)NC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: COCCn1nc(C#N)c(Br)c1CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 9 h
Yield: 91.8 %

Procedure:
Bromine (19.5 g, 122 mmol) was added in a single portion to a solution of tert-butyl 2-[3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate (28.07 g, 87.1 mmol) and potassium acetate (12.8 g, 131 mmol) in acetic acid (174.2 mL). After 16 hours saturated aqueous sodium bisulfate was added until the reaction mixture was colorless. The acetic acid was removed under reduced pressure at about 30° C. The residue was made basic with 2 M sodium carbonate and then extracted with tert-butyl methyl ether (×3). The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. Analysis by HPLC indicated that the BOC group had been partially removed. The material was dissolved in dichloromethane (50 mL), combined with di-tert-butyl dicarbonate, and stirred for 9 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by IFC (65+M cartridge eluting with a gradient of 40 to 50% tert-butyl methyl ether in hexanes) to provide 32.1 g of tert-butyl 2-[4-bromo-3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate as a colorless, viscous resin.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1CCOC1
Product: OCc1c(Cl)cc(Cl)cc1Cl

Procedure:
To a stirred solution of 2,4,6-trichlorobenzoic acid (451 mg, 2.0 mmol) in THF (15 mL) was added BH3 (3 mL of a 1M solution in THF). After the addition, the solution was refluxed overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure to give (2,4,6-trichlorophenyl)-methanol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH:22](OC)O)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[C:27](=[O:34])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:28].C([SiH](CC)CC)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH2:22][NH:28][C:27](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:6][CH:7]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]
Reactant: CC(C)(C)OC(N)=O
Reactant: COC(O)C[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred mixture of 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol (Example 5a, 36 mg, 0.1 mmol), tert-butyl carbamate (35 mg, 0.3 mmol), triethylsilane (0.1 mL), and acetonitrile (0.5 mL) was added trifluoroacetic acid (0.03 mL). The mixture was stirred at RT for 40 hr. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave tert-butyl 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)ethylcarbamate as a trifluoroacetic acid salt (23 mg, 0.043 mmol, 43% yield). MS found: (M+H)+=426.3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][S:6][C:7](=O)[CH3:8].CO.[CH3:18][O:19][C:20]([C:22]1C(CBr)=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:21].C(OC(=O)C)C.C1CCCCC1>O>[CH3:18][O:19][C:20]([C:22]1[C:8]([CH2:7][S:6][CH2:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]([F:15])([F:14])[F:1])=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:21]
Reactant: COC(=O)c1ncccc1CBr
Reactant: CC(=O)SCc1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1ncccc1CSCc1ccccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of thioacetic acid S-(2-trifluoromethyl-benzyl)ester (10.2 g, 37.5 mmol) in methanol (130 ml) potassium carbonate (5.18 g, 37.5 mmol) was added at room temperature and it was stirred for 30 min. 3-Bromomethyl-pyridine-2-carboxylic acid methyl ester (4.40 g, 18.7 mmol) was added and after refluxing for 150 min the solution was diluted with water, extracted with ethylacetate, the organic phase dried with sodium sulfate and concentrated. Chromatography over silica with ethylacetate/cyclohexane gave 7.82 g colorless crystals (18.7 mmol).
Reaction SMILES: ClC1C=CC=CC=1.[F:8][C:9]([F:25])([F:24])[C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.Br[CH:27]([CH3:35])[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CC)CCC.O>[F:8][C:9]([F:24])([F:25])[C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:27]([CH3:35])[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)C=CC(C)Br
Agent: CCCC[N+](CC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Clc1ccccc1
Solvent: O
Product: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 6 h
Yield: 96 %

Procedure:
In a reactor, 100 ml of chlorobenzene and 100 ml of water were charged and then, 95.3 g (0.375 mole) of 4-(4-trifluoromethylphenoxy)phenol, 85.4 g (0.412 mole) of ethyl 4-bromo-2-pentenoate, 39.0 g (0.281 mole) of potassium carbonate and 1.1 g (0.00375 mole) of tributylethyl ammonium bromide were added. The mixture was refluxed with stirring for 6 hours to react them, and the water phase was removed and the organic phase was washed with 5% hydrochloric acid and with water and then, chlorobenzene, ethyl 4-bromo-2-pentenoate and low boiling by-products were distilled off at 100° C. under a reduced pressure of 0.02 to 0.05 mmHg to obtain 137.0 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoate. The yield was 96.0%.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>O1CCCC1>[NH2:33][C:19]1[N:20]=[C:21]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([C:2]([NH:1][CH:4]4[CH2:8][CH2:7][CH2:6][CH2:5]4)=[O:3])[CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)[N:18]=1
Reactant: O=C=NC1CCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCCC3)CC4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
Isocyanatocyclopentane (0.030 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (16 μL, 0.12 mmol) in tetrahydrofuran (0.3 mL). After 30 minutes, the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=436.5.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10](=[O:21])[CH2:9]3.[OH-].[Na+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl.C(OC(C)C)(C)C>CO>[O:30]1[CH2:29][CH:28]1[CH2:26][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[C:10](=[O:21])[CH2:9][CH:8]3[C:13]([C:4]4[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=4[CH2:6][CH2:7]3)=[N:12]2)=[CH:15][CH:16]=1
Reactant: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: O=C1CC2CCc3ccc(F)cc3C2=NN1c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To 50 ml of methanol is added 9 g of 9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, and 1.7 g of sodium hydroxide dissolved in 70 ml of methanol is added to the mixture under stirring at room temperature. Thereto is added 13 g of epichlorohydrin, and the mixture is heated under reflux for 2 hours. After the reaction mixture is filtered, the filtrate is concentrated under reduced pressure and the residue is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent is distilled off to give 12.5 g of a brown oily substance. This oily substance is subjected to column chromatography. Isopropyl ether is added to the resulting crystals, and the crystals are collected by filtration to give 4 g of 2-[4-(2,3-epoxypropoxy)phenyl]-9-fluoro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one as white crystals, m.p. 128°-130° C.
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][N:5]([CH:25]2[CH2:26][O:23][CH2:24]2)[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3COC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 341C (72 mg) in tetrahydrofuran (1.5 mL) and acetic acid (0.5 mL) was added oxetan-3-one (14 mg) and MP-cyanoborohydride (2.38 mmol/g, 162 mg). The mixture was stirred at room temperature overnight. The reaction was then filtered and the filtrate was concentrated under vacuum. The residue was slurried in ether and the product was collected by filtration.
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=[O:8].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 102.2 %

Procedure:
Methyl iodide (55.2 g, 389.2 mmol) was added dropwise to a stirred mixture of 3-hydroxy-4-nitrobenzaldehyde (50 g, 288.4 mmol) and potassium carbonate (53.8 g, 389.2 mmol) in DMF (250 ml). The reaction mixture was stirred overnight, poured into ice-cold water, and the precipitated solid was collected by filtration. The resulting solid was dried on a high vacuum overnight to obtain 53.4 g of 3-methoxy-4-nitrobenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:25]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([I:25])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: II
Reactant: Cc1ccc(C)n1-c1ccn(-c2ccccc2F)n1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2F)n1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Under nitrogen atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-1H-pyrazole (1.19 g) in tetrahydrofuran (10 ml) was cooled to −78° C., n-butyllithium (3.5 ml, 1.6M solution in n-hexane) was added dropwise thereto, and the mixture was stirred for 30 minutes. To this reaction solution was added dropwise a solution of iodine (1.42 g) in tetrahydrofuran (5 ml), and the mixture was stirred for 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium sulfite and a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting residue was added a mixed solvent of n-hexane/ethyl acetate (=6/1), the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (1.23 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[N:22]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[N:22]1[C:23]2[C:28](=[N:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:17][CH2:18]3)[C:8]2=[O:19])[CH2:4]1
Reactant: Clc1ccc2ncccc2n1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2ccc3ncccc3n2)C1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.133 g, 0.472 mmol), 2-chloro-1,5-naphthyridine (0.100 g, 0.608 mmol) and DMSO (2 mL). N,N-Diisopropylethylamine (0.250 mL, 1.437 mmol) was added and the reaction mixture was sealed under argon and heated at 100° C. for 59 h. The reaction was cooled to room temperature and partitioned between water/DCM. The aqueous layer was extracted with DCM (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (25 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:19) to give 67 mg (34%) of a white crystalline solid. ESI-MS 374.0 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (dd, J=4.30, 1.56 Hz, 1 H), 8.00 (d, J=3.33 Hz, 1 H), 7.97 (d, J=3.33 Hz, 1 H), 7.93 (d, J=9.19 Hz, 1 H), 7.81-7.89 (m, 2 H), 7.46 (dd, J=8.41, 4.11 Hz, 1 H), 7.02 (d, J=9.19 Hz, 1 H), 5.21 (m, 1 H), 4.64-4.76 (m, 1 H), 3.25-3.38 (m, 2 H), 2.91-3.02 (m, 1 H), 2.34-2.45 (m, 2 H), 0.94-1.11 (m, 4 H)
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3F)=[N+:2]=[N-:3].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:34]2[N:1]([C@H:4]3[CH2:24][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:35]=2)([OH:36])[CH3:33])=[CH:30][CH:31]=1
Reactant: C#CC(C)(O)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Product: CC(O)(c1ccc(F)cc1)c1cnnn1[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 2-(4-fluorophenyl)but-3-yn-2-ol. Separation of the resulting diastereoisomers was performed at the ester stage by flash chromatography using a gradient of 10-100% EA/Hex afforded 2 esters. The faster eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD column eluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. Retention times=6.9 and 8.4 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.1 and 31.2 respectively. The slower eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD eluting with 20% iPrOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm. Retention times=8.7 and 11.6 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.3 and 31.4 respectively. MS (+ESI) m/z: 453.1.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17](=[O:27])[N:18]([CH3:26])[CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:26][N:18]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:17]([CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH2:9]1)=[O:27]
Reactant: CN1CCC(N(C)C(=O)C2CN(C(=O)OC(C)(C)C)c3ccccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(N(C)C(=O)C2CNc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 3-[Methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (C) (3.93 g, 10.53 mmol) in dichloromethane (20 cm3) was cooled to 0° C. in an ice/water bath and trifluoroacetic acid (10 cm3) added. The solution was stirred at 0° C. for 1 hr before warming to room temperature. The solution was made basic with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×100 cm3). The organic layer was then dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford the title compound (D) (2.79 g, 10.2 mmol, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1

Procedure:
tert-Butyl 4-(3-(5-methylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (1.24 g, 3.26 mmol) from Step 4 was dissolved in CH2Cl2 (10 mL) and treated with HCl in dioxane (3.26 mL, 4.0 M, 13 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (1.48 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrBr
Reactant: CCOCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOCCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
6-Amino-9-benzyl-2-(3-ethoxypropoxy)purine (354 mg, 1.08 mmol) and bromine (1.0 ml) were dissolved in methylene chloride (50 ml). The solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (289 mg, yield 66%).