Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=1.[C:17]([CH:20]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:21](OCC)=[O:22])(=O)[CH3:18]>CC1C=CC=CC=1C.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>[OH:22][C:21]1[N:13]2[N:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[CH:1]=3)[CH:15]=[C:14]2[N:16]=[C:17]([CH3:18])[C:20]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: CCOC(=O)C(CC(=O)OC)C(C)=O
Reactant: Nc1cc(-c2ccc3c(c2)CCCC3)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
A suspension of 3-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-amine (6 g, 28.1 mmol), 1-ethyl 4-methyl 2-acetylsuccinate (24.52 mL, 141 mmol) and Ts-OH.H2O (0.096 g, 0.506 mmol) in o-xylene (200 mL) was heated at 150° C. (oil bath temp) for 16 h. (Note: mixture became homogeneous and in about 15 min slowly yellow solid started crashing out of the reaction.) Then, the reaction mixture was cooled, diluted with hexanes (300 mL), filtered, washed with hexanes and dried to afford methyl 2-(7-hydroxy-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.4 g, 23.90 mmol, 85% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.78-7.62 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 3.64 (s, 3H), 3.58 (s, 2H), 2.82-2.77 (m, 4H), 2.33 (s, 3H), 1.78 (t, J=3.0 Hz, 4H). LCMS (M+H)=352.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.C([Cu])#N.C(OC([N:40]1[C:44]2=[N:45][CH:46]=[C:47]([C:49]#[N:50])[CH:48]=[C:43]2[C:42]([CH2:51]Cl)=[CH:41]1)=O)(C)(C)C.N>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH2:51][C:42]2[C:43]3[C:44](=[N:45][CH:46]=[C:47]([C:49]#[N:50])[CH:48]=3)[NH:40][CH:41]=2)=[C:18]([F:23])[N:17]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Br)c(F)n1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(C#N)cnc21
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cncc(F)c1)c1ccc(Cc2c[nH]c3ncc(C#N)cc23)c(F)n1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (631, 0.600 g, 1.50 mmol, prepared as described in Example 60) in tetrahydrofuran (10.0 mL) at −25° C. under an atmosphere of nitrogen, was added a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.730 mL). The reaction was allowed to warm to 5° C. over 1 hour. The reaction was cooled to −35° C., followed by addition of a solution of CuCN.2LiCl (0.65 M in tetrahydrofuran, 2.4 mL). After 5 minutes, 3-chloromethyl-5-cyano-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (635, 0.086 g, 0.29 mmol) in tetrahydrofuran (4.0 mL) was added to the reaction. The reaction was allowed to warm to room temperature over 1 hour, then poured into a diluted ammonia solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (636, 0.13 g, 92%). MS (ESI) [M+H+]+=477.4.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:32](=[O:33])[CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)CCc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3-phenylpropionyl chloride (11 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:12][CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: OCCc1cc2cc(Br)ccc2o1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3o2)cc1
Temperature: 50 °C
Yield: 48.1 %

Procedure:
The product from Example 4A (1.21 g, 5.0 mmol), 4-dimethylaminopyridine (0.06 g, 0.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) were combined in dichloromethane (20 mL) stirred briefly and treated with para-toluenesulfonyl chloride (1.91 g, 10.0 mmol) in dichloromethane (2 mL) over about 5 minutes. After stirring at about 22° C. for 3 hours, the mixture was then washed with saturated NaHCO3 solution (20 mL, 2×), brine (20 mL), dried over Na2SO4, and distilled to dryness. The residue in acetonitrile (˜5 mL) was heated at 50° C. to effect dissolution, allowed to cool to room temperature slowly, and then cooled to about 0° C. The slurry was filtered and the obtained solid dried under reduced pressure at 40° C. to provide the title compound (0.95 g, 48% yield). MS-DCI (M+NH4)+ observed m/z at 412, 414; 1H NMR (CDCl3 at 400 MHz) δ 2.38 (s, 3H), 3.11 (m, 2H), 4.35 (m, 2H), 6.35 (m, 1H), 7.1-7.18 (m, 3H), 7.27 (dd, 1H), 7.56 (d, 1H), 7.64-7.67 (m, 2H); 13C NMR (CDCl3 at 100 MHz) δ 21.9, 28.8, 67.1, 103.7, 112.0, 115.5, 122.9, 126.3, 127.4, 129.4, 130.1, 132.3, 144.4, 153.0, 154.2 with 2 peaks overlapping.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:11]1([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:19][C:18]([CH3:21])([C:17]([O:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:22])[CH3:20]
Reactant: CC(C)(N)C(=O)OC1CCCC1
Reactant: O=Cc1cccc(CBr)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(NCc1cccc(CBr)c1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
To a solution of 3-(bromomethyl)-benzaldehyde (0.503 g, 2.52 mmol) in dichloroethane (20 mL) was added α,α-dimethylglycine cyclopentyl ester (0.893 g, 5.2 mmol) and sodium triacetoxyborohydride (1.47 g, 6.9 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (3 times 50 mL). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, 7:3 heptane:ethyl acetate) to yield the desired product (0.350 g, 39% yield). LC/MS: m/z 354/356 [M+H]+
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])[N:34]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Oc3ccccc3)c2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc(Oc4ccccc4)c3)cc2=O)n1
Yield: 48 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(3-phenoxy-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 49) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(3-phenoxy-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (0.63 g, 48%); ES+-HRMS m/e calcd for C31H35N5O5 [M+H+] 558.2711 found 558.2706. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.24-0-1.77 (m, 8H), 1.91 (m, 1H), 2.27 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.46 (dd, J=4.4, J=11.0 Hz, 1H), 5.89 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.4 Hz, 1 Hr), 6.94 (m, 1H), 6.96 (d, Jm=1.5 Hz, 1H), 7.05 (m, 1H), 7.11 (dd, Jo=7.8 Hz, 2H), 7.19 (t, Jo=7.4 Hz, 1H), 7.38-7.55 (m, 4H), 8.10 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]([OH:38])[CH:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=3)[N:21]=[CH:20][C:19]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[OH:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:40](OCC)(=[O:42])C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][CH:15]2[CH:16]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=4)[N:21]=[CH:20][C:19]=3[O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:17][C:40](=[O:42])[O:38]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: COc1ccc2ncc(OCc3ccccc3)c(C(O)C(O)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(OCc3ccccc3)c(C3OC(=O)OC3C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N,N′-Carbonyldiimidazole (2.56 g, 15.83 mmol, 5.0 eq) is added at room temperature to a stirred solution of {trans-4-[3-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-2,3-dihydroxy-propyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.70 g, 3.16 mmol, 1.0 eq) in toluene (150 mL). After 2 hours stirring at 70° C., solvent is removed and the crude is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford {trans-4-[5-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-2-oxo-[1,3]dioxolan-4-ylmethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.70 g, 96% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:36]([F:39])([F:38])[F:37])[N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:49][O:50][CH2:51][CH2:52][CH2:53][NH2:54]>CC(O)C>[CH3:49][O:50][CH2:51][CH2:52][CH2:53][NH:54][C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:18])[CH2:14][NH:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([C:36]([F:38])([F:37])[F:39])[N:3]=1
Reactant: CC(C)CN(C(=O)c1ccc(C(F)(F)F)nc1Cl)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCN
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1nc(C(F)(F)F)ccc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[2-chloro-6-(trifluoromethyl)pyridin-3-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (40 mg) and diisopropylethylamine (37 μl) in 2-propanol (3 ml) was added 3-methoxypropylamine (23 μl) and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 ml), 4 M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to reversed-phase preparative HPLC. Aqueous sodium hydrogen carbonate was added to the object fraction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (8.8 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].O[C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([NH:16][C:17](=[O:18])[C:12]=12)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][O:1][N:16]1[C:17](=[O:18])[C:12]2[C:13](=[CH:19][CH:20]=[CH:21][CH:11]=2)[C:14]1=[O:15]
Reactant: O=C1NC(=O)c2c(O)cccc21
Reactant: COC(=O)C(C)(C)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 33.6 %

Procedure:
To methyl hydroxypivalate (1.31 g, 9.89 mmol) were added tetrahydrofuran (40 ml), hydroxyphthalimide (3.23 g, 19.78 mmol) and triphenylphosphine (6.48 g, 24.73 mmol). After this solution was cooled to 0° C., diisopropyl azodicarboxylate (4.87 ml, 24.73 mmol) was added dropwise to the solution. While being allowed to warm gradually, the reaction mixture was stirred for 12 hours, and concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography to give the title compound (922 mg).
Reaction SMILES: Cl[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Se-2:13].[Na+].[Na+].Cl>C(O)C>[SeH:13][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: [Se-2]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C([SeH])C(=O)OCC

Procedure:
15 mmol of ClCH(COOC2H5)2 and 10 mmol of sodium selenide were heated in 50 ml of ethanol under reflux for 2 hours. After completion of the reaction, the reaction solution was slightly acidified with 1N HCl. Then, after insoluble material was removed from the solution, the reaction solvent was distilled off to obtain HSeCH(COOC2H5)2. The thus obtained HSeCH(COOC2H5)2 was put in aqueous ammonia and the reaction was allowed to proceed at 50° C. for 6 hours. After completion of the reaction, the solvent was distilled off to obtain HSeCH(CONH2)2. To the thus obtained HSeCH(CONH2)2 were added 50 ml of tetrahydrofuran and then 2 mmol of lithium aluminum hydride. The resulting mixture was heated under reflux for 10 hours to reduce the amide. After completion of the reaction, the insoluble portion was removed and the solvent was distilled off under reduced pressure. Then, the residue was purified by using cation exchange resin to obtain 2 mmol of 2-seleno-1,3-diaminopropane HSeCH(CH2NH2)2. To the thus obtained HSeCH(CH2NH2)2 was added 20 ml of an aqueous solution containing 2 mmol of potassium tetrachloroplatinate (II) and the resulting mixture was allowed to stand at room temperature for 4 days, so that a precipitate was formed. The precipitate was separated by filtration and dried to obtain 1.1 mmol of HSeCH(CH2NH2)2PtCl2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][N:28]1[CH2:35][CH:34]2[CH:30]([CH2:31][CH2:32][CH2:33]2)[CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:27][N:28]3[CH2:35][CH:34]4[CH2:33][CH2:32][CH2:31][CH:30]4[CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NN1CC2CCCC2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2cc(NN3CC4CCCC4C3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[Br:8].[N:23]1[CH:28]=[CH:27][N:26]=[C:25]2[S:29][C:30]([C:32](Cl)=[O:33])=[CH:31][C:24]=12>O1CCOCC1.O>[Br:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:18])[CH3:19])[CH:12]=2)=[CH:3][C:2]=1[NH:1][C:32]([C:30]1[S:29][C:25]2=[N:26][CH:27]=[CH:28][N:23]=[C:24]2[CH:31]=1)=[O:33]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(N)c2)c1
Reactant: O=C(Cl)c1cc2nccnc2s1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(NC(=O)c3cc4nccnc4s3)c2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of N-(3-amino-4-bromophenyl)-3-(2-cyanopropan-2-yl) 62 (215 mg, 0.600 mmol) and thieno[2,3-b]pyrazine-6-carbonyl chloride 63 (238 mg, 1.2 mmol) in dioxane (1 mL) was stirred for 2 h in microwave at 100° C. The reaction mixture was poured out in water, precipitate filtered off and washed with water and dried. Crystallization with acetonitrile gave crude compound 64 (340 mg, 109%). A sample of compound 64 was purified by HPLC to give the title compound N-(2-bromo-5-(3-(2-cyanopropan-2-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 64. NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.62 (t, d=7.8 Hz, 1H), 7.72-7.80 (m, 3H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (m, 2H), 8.57 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 10.55 (s, 1H), 10.76 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH2:11][CH2:12][OH:13])[O:7][C:6]1=[O:21])[CH3:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:13][CH2:12][CH2:11][C@@:8]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:7][C:6](=[O:21])[N:5]([C@H:3]([C:2]([CH3:22])([CH3:1])[CH3:23])[CH3:4])[CH2:10][CH2:9]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Yield: 102.6 %

Procedure:
To a solution of (S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (220 mg, 0.68 mmol) and triethylamine (206 mg, 2.04 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (233 mg, 2.04 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude 2-((S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (280 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:5])=[O:4].[CH2:12](Br)[C:13]#[CH:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:14][C:13]#[CH:12])([O-:5])=[O:4]
Reactant: C#CCBr
Reactant: O=[N+]([O-])C=C1NCCN1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1CCNC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
An ice-cooled mixture of 50 milliliters of dry dimethylformamide and 1.77 grams of a 57% by weight dispersion of sodium hydride in mineral oil, maintained under nitrogen atmosphere, was treated with 5.16 grams of 2-(nitromethylene)imidazolidine. After stirring for 1 hour, 7.97 grams of propargyl bromide was added. The mixture was stirred at 10° for an additional hour, allowed to warm to room temperature, and poured into 400 milliliters of saturated aqueous sodium sulfate. The product was extracted with three 300-milliliter portions of methylene chloride. The combined extract was dried with magnesium sulfate and the solvent was evaporated. Addition of ether to the residual oil gave a solid which was recrystallized from chloroform (charcoal) to give 3.1 grams of 3, as tan crystals, melting point: 146°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][CH:23]=O)[N:20]=[C:15]2[CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:23]=[N:22][CH:21]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC=O)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (0.10 g, 0.22 mmol) in 1,4-dioxane (4 mL) was treated with Lawesson's Reagent (0.053 g, 0.13 mmol) and heated to about 80° C. in an oil bath for about 15 min. The mixture was cooled and mercuric acetate (0.073 g, 0.23 mmol, Fluka) was added. The mixture was stirred for about 30 min at ambient temperature and another portion of mercuric acetate (0.073 g, 0.228 mmol, Fluka) was added and stirring was continued for about 2 h at ambient temperature. The mixture was diluted with EtOAc (20 mL) and filtered. The solvent was evaporated under reduced pressure then the material was purified by silica gel chromatography eluting with DCM/MeOH (95:5). The material obtained after concentration of the product-containing fractions was further purified by silica gel chromatography eluting with EtOAc to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 49%): LC/MS (Table 2, Method a) Rt=3.16 min; MS m/z: 448 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])=[NH:10].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22]N>CO>[CH3:19][O:20][C:21](=[O:24])[CH2:22]/[N:10]=[C:9](/[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH2:1])\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]
Reactant: COC(=O)CN
Reactant: N=C(c1cc(F)ccc1N)c1ccccc1Br
Agent: Cl
Solvent: CO
Product: COC(=O)C/N=C(/c1cc(F)ccc1N)c1ccccc1Br

Procedure:
A solution of 139.5 g (0.446 moles) of (2-amino-5-fluorophenyl)(2-bromophenyl)methanimine, 69.9 g (0.557 moles) of glycine methyl ester hydrochloride and 1.68 L of methanol was stirred at reflux for 5 hours under nitrogen. The solvent was then removed by evaporation under vacuum and the yellow, residual solid was partitioned between 1.4 L of methylene chloride and 1.4 L of saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with 0.5 L of methylene chloride. The combined organic extracts were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was redissolved in 0.5L of methylene chloride and concentrated to a dark yellow semi-solid (156.6 g). This solid was recrystallized from 400 mL of 1:3 EtOAc/Hexane to give 72.8 of (Z)-N-[(2-Amino-5-fluorophenyl)(2-bromophenyl)methylene]glycine methyl ester).