Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2)C1C=CC=CC=1>CO.[C].[Pd]>[ClH:1].[OH:21][C:18]1[CH:19]=[CH:20][C:12]([CH2:11][CH2:10][NH2:9])=[C:13]2[C:17]=1[NH:16][N:15]=[CH:14]2
Reactant: Oc1ccc(CCNCc2ccccc2)c2cn[nH]c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCc1ccc(O)c2[nH]ncc12
Yield: 92.3 %

Procedure:
In the presence of 1.0 g of palladiumcarbon, 870 mg of N-benzyl-N-[2-(7-hydroxy-1H-indazol-4-yl)ethyl]amine, hydrochloride, is hydrogenated in 50 ml of methanol. The product is recrystallized from ethanol/diethyl ether, thus obtaining 565 mg of N-[2-(7-hydroxy-1H-indazol-4-yl)ethyl]amine, hydrochloride, mp 257°-260° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[N:3]=[CH:2]1.[N+:14]([O-])([O-:16])=[O:15].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:14]([C:7]1[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]2[N:3]=[CH:2][NH:1][C:5]=2[CH:6]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cccc2[nH]cnc12
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])cc2[nH]cnc12
Yield: 84.5 %

Procedure:
Methyl 1H-benzimidazole-4-carboxylate (315 mg) was dissolved in conc. sulfuric acid (3 mL), and the solution was stirred on ice bath. A small amount of potassium nitrate (199 mg) was added portion-wise, and the solution was stirred at room temperature for 4 hours. The reaction mixture was poured into ice, alkalified with 3N aqueous sodium hydroxide solution under stirring on ice bath, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. The titled compound (334 mg) was obtained as colorless powder after distilling off the solvent under reduced pressure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][C:12](=O)[C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1C(=O)N[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Temperature: 100 °C
Yield: 44 %

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one, from Example 101, Part A, (830 mg, 2.84 mmol) in 20 mL of THF was added lithium aluminum hydride (3.4 mL of a 1 M solution in THF, 3.4 mmol). The reaction was heated in a microwave oven at 100° C. for 1.5 h. The reaction was cooled, filtered through a pad of silica gel with 10% methanol/methylene chloride, and concentrated in vacuo. The residue was purified (ISCO, elution with 0-12% methanol/methylene chloride) to afford 345 mg (44%) of the title compound as a solid. 1H NMR (CDCl3): δ 7.40-7.25 (m, 5H), 7.08-6.98 (m, 2H), 6.80 (d, 1H), 4.12 (ABq, 2H), 3.87 (ABq, 2H), 3.42-3.37 (m, 1H), 3.15-3.06 (m, 2H), 2.98-2.90 (m, 1H), 2.80-2.71 (m, 2H), 2.17 (s, 3H). LRMS (ESI): 279.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:14][NH2:15])[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1)=[O:5])C>Cl>[NH2:15][CH2:14][C:6]1([C:4]([OH:5])=[O:3])[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1
Reactant: CCOC(=O)C1(CN)CC12CCCCC2
Agent: Cl
Product: NCC1(C(=O)O)CC12CCCCC2
Yield: 3.9 %

Procedure:
To 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid ethyl ester (5.0 g, 23.7 mmol) was added 50 mL 3N HCl (aq), and the mixture was refluxed for 72 hours. The crude 1H NMR indicated the hydrolysis had proceeded to 50% completion. The solution was concentrated, and the residue washed exhaustively with Et2O to remove the starting material, until a fine white solid was obtained. The combined solids were washed again with Et2O (3×15 mL) to give a chalky solid. A small portion of the batch was recrystallized from MeOH/EtOAc to furnish 0.17 g (3.3%) of 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid as a colorless solid, mp>250° C. (dec): 1H NMR (D2O) δ 3.37 (d, J=13.4 Hz, 1H), 2.83 (d, J=13.4 Hz, 1H), 1.21–1.33 (m, 10H), 0.99 (d, J=5.1 Hz, 1H), 0.47 (d, J=5.1 Hz, 1H). Anal. Calcd for C10H17NO2.HCl: C, 54.67; H, 8.26; N, 6.37. Found: C, 54.77; H, 8.41; N, 6.31. A second crop was also obtained (0.34 g, 6.6%). Anal. Calcd for C10H17NO2.HCl: C, 54.67; H, 8.26; N, 6.37. Found: C, 54.71; H, 8.42; N, 6.22. The Et2O washings were concentrated to provide 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid ethyl ester hydrochloride as a colorless solid, mp 118–120° C.: 1H NMR (CDCl3) δ 8.39 (br s, 3H), 4.23 (m, 2H), 3.66 (m, 1H), 3.31 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H), 1.42–1.54 (m, 9H), 1.28 (t, J=7.1 Hz, 3H), 1.03 (d, J=5.4 Hz, 1H). Anal. Calcd for C12H21NO2.HCl: C, 58.17; H, 8.95; N, 5.65. Found: C, 58.31; H, 8.87; N, 5.51.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/[OH:63])[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[CH2:3]([C:4]1[O:63][N:62]=[C:61]([NH:60][C:55]2[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]3[C:43](=[O:65])[N:42]([CH3:41])[C:51]4[C:46]([CH:45]=3)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=4)[CH:54]=2)[N:64]=1)[CH:2]([CH3:7])[CH3:1]
Reactant: CC(C)CC(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(CC(C)C)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Methylbutanoic acid (13 mg, 0.12 mmol), HATU (50 mg, 0.12 mmol), and DIPEA (0.023 mL, 0.12 mmol) were stirred in dry DMF (3 mL) for 1 h before 17 (40 mg, 0.118 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-isobutyl-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A68) as a solid. 1H NMR (400 MHz, d4-MeOH) δ 8.92 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.33 (d, J=1 Hz, 1H), 7.24 (dd, J=8, 4 Hz, 1H), 7.14 (d, J=4 Hz, 1H), 3.72 (s, 3H), 2.72 (s, 3H), 2.60 (d, J=8 Hz, 2H), 2.10-2.01 (m, 1H), 2.06 (s, 3H), 0.92 (d, J=8 Hz, 6H). MS m/z 403.4, 404.5 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:30])[CH2:28][CH3:29]>>[CH2:27]([O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH2:28][CH3:29]
Reactant: CCCO
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate, and 3 ml of propanol was heated to reflux while stirring for six hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-(3-propoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 71”).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.[CH2:9]([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21](Cl)=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[N:24]2)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>CN(C)C=O>[CH2:9]([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:8][CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[N:24]2)=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Reaction time: 72 h
Yield: 85.6 %

Procedure:
1-tetrahydro-2H-pyran-4-ylmethanamine (40 g, 0.347 mol) was added to a stirred solution of 7-(benzyloxy)-4-chloro-3-nitroquinoline (55 g, 0.176 mol) and triethylamine (50.96 g, 0.503 mol) in N,N-dimethylformamide (DMF) (250 mL) at 0° C. After complete addition, the ice bath was removed. To consume the remaining starting material, additional (1-tetrahydro-2H-pyran-4-ylmethanamine (11 g, 95.50 mmol) was added. The reaction proceeded at ambient temp for 3 days, then was chilled in an ice-water bath. Water (250 mL) was added drop wise which caused a solid to precipitate out of solution. After stirring for 1 hour, the solid was collected by filtration, washed with diethyl ether (800 mL), and dried under reduced pressure to afford 7-(benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (59.3 g) as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=O)[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](OCC)C>C1COCC1.C[Li]>[CH3:14][C:2]1([CH3:1])[CH2:13][CH2:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:15])[S:7][CH:8]=[C:4]2[CH2:3]1
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1scc2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (1051 mg, 5.0 mmol) in diethyl ether (15 mL) and THF (8 mL), methyllithium (7 mL of a 1.6 M solution in diethyl ether) is added. The mixture is stirred at rt for 15 min before the reaction is quenched with ethanol. The mixture is diluted with 10% aq. citric acid and extracted with TBME. The organic extract is washed three times with sat. aq. NaHCO3, dried over Na2SO4 and evaporated to give crude 1-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.0 g) as a brownish oil; LC-MS: tR=1.03 min, [M+1]=209.07.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)[CH:6]=[O:7]
Reactant: c1cn[nH]c1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1-n1cccn1
Temperature: 120 °C
Yield: 57.9 %

Procedure:
A mixture of 4-fluoro-3-methoxybenzaldehyde (2.00 g, 12.98 mmol), pyrazole (1.32 g, 19.39 mmol), and powdered K2CO3 (2.68 g, 19.39 mmol) in DMF (20 mL) was heated to 120° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×200 mL), dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.52 g (58%) of the title compound as a yellow oil. MS 203 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:21][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: NC1CCCC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCNC2CCCC2)c1
Yield: 87.5 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and cyclopentylamine (1.34 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (443 mg, 87.4%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 207.5° C. MS m/z (relative intensity, 70 eV) 301 (M+, 2), 272 (7), 99 (24), 98 (bp), 70 (7).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:13](=[O:14])[CH:12]3[CH2:15][C:10]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)([CH2:11]3)[C:9]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC>COCCO.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]23[CH2:11][CH:12]([CH2:15]2)[C:13](=[O:14])[N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]3=[O:25])=[CH:21][CH:20]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1CC1CCCCC1
Agent: [Pd]
Solvent: CCOCC
Solvent: COCCO
Product: Nc1ccc(C23CC(C2)C(=O)N(CC2CCCCC2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-cyclohexylmethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 140°-146° (from ether). Rf (ether)=0.25.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Mg+2].[O-]S(C(F)(F)F)(=O)=O.[C:18]1([CH:24]2[C:27]3([CH2:29][O:28]3)[O:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>C1COCC1>[OH:28][CH2:29][C:27]1([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][O:26]1
Reactant: c1ccc(C2COC23CO3)cc1
Reactant: c1nc[nH]n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: C1CCOC1
Product: OCC1(n2cncn2)OCC1c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of magnesium triflate (0.40 g, 1.23 mmol) in dry THF (5 mL) was added to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.20 g, 1.23 mmol) in dry THF (2 mL). The temperature was then lowered to 0° C., and a solution of 1H-1,2,4-triazole (0.22 g, 1.48 mmol) in dry THF (10 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2.5 hours, warmed to room temperature and stirred for an additional 3 hours. Then, the mixture was concentrated to provide a yellow oil, which was purified by flash chromatography on silica gel (CH2Cl2/methanol 99.5:0.5 to 99:1). 2-Hydroxymethyl-3-phenyl-2-(1,2,4-triazol-1-yl)oxetane was isolated as an oil which was a 2:1 mixture of diastereomers (0.13 g, 45%): IR (film) 3403, 2903, 1499, 1279, 702 cm−1; Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.11 (s, 1H), 7.40 (m, 5H), 5.11 (m, 1H), 5.06 (m, 1H), 4.74 (dd, J=16.3, 8.4 Hz, 1H), 3.94 (d, J=12.8 Hz, 1H), 3.83 (d, J=12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 133.3, 129.0, 127.9, 127.7, 127.4, 127.4, 98.5, 68.9, 63.7, 48.7. Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.67 (s, 1H), 7.12 (m, 5H), 5.11 (m, 1H), 5.06 (m, 1H), 4.74 (dd, J=16.3, 8.4 Hz, 1H), 4.75 (d, J=12.8 Hz, 1H), 4.31 (d, J=12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 133.3, 129.0, 127.9, 127.7, 127.4, 127.4, 98.5, 70.6, 67.2, 45.8; MS (EI) m/z 167, 149 (100), 71; HRMS (FAB) calculated for C12H14N3O2 (M++H) m/z 232.1086. Found: 232.1101.
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]2[CH:14]=[N:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=3[O:28][CH3:29])=[N:17][C:6]1=2)[CH2:2][CH2:3][CH3:4].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]2[CH:14]=[N:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:63][CH:64]4[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]4)=[O:25])=[CH:21][C:20]=3[O:28][CH3:29])=[N:17][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CN1CCC(N)CC1
Reactant: CCCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)O)cc3OC)nc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Reaction time: 0.08 h
Yield: 64.6 %

Procedure:
A mixture of 0.08 g (0.0002 mole) of 4-(9-butyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-44a), 0.091 g (0.00024 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 mL (0.0003 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.034 g (0.0003 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.064 g of 4-(9-butyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-44) as a white solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:66]=[CH:67][CH:68]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47]O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:42]=1)=[O:38])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:69]>O1CCOCC1>[OH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:66]=[CH:67][CH:68]=1)[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:33]([CH3:36])=[N:34][N:35]=3)[C:27]=2[CH:26]=[C:25]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][Cl:69])[CH:42]=1)=[O:38]
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cccc(CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)c4)n3Cc3cccc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12
Reactant: Cl
Solvent: C1COCCO1
Product: Cc1nnc2ccc3c(cc(C(=O)OCc4cccc(CCl)c4)n3Cc3cccc(CO)c3)n12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
3-({[tert-Butyl(diphenyl)silyl]oxy}methyl)benzyl 6-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (0.890 g, 0.954 mmol, from Step 5) was dissolved in 1,4-dioxane (20 mL) and 4.0 M solution of HCl in dioxane (20 mL, 80 mmol) was added. The reaction was stirred for 1 h at 110° C. Three additional portions of 4.0 M HCl in dioxane (10 mL, 40 mmol) were added periodically over the course of 6.5 hours at 110° C. After the third addition, the reaction mixture was heated at 110° C. in a sealed vessel for 48 hours. When the reaction was complete, the dioxane was evaporated and the residue was neutralized by the addition of saturated NaHCO3 solution. The product was extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-10% MeOH/DCM was used to isolate 3-(chloromethyl)benzyl 6-[3-(hydroxymethyl)benzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate, which was used in the displacement reaction that follows.
Reaction SMILES: [CH:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=Cc1ncccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ncccc1F
Yield: 92.9 %

Procedure:
A solution of 2-formyl-3-fluoropyridine (4.0 g, 32 mmol) and sodium borohydride (309 mg, 8 mmol) in absolute ethanol (40 mL) was stirred at 0° C. for 15 minutes and at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and filtered through diatomaceous earth to remove solids. The filtrate was evaporated and the resultant white solid was dissolved in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (5×30 mL) and the combined extracts were dried over anhydrous sodium sulfate. Solvent removal provided 3.78 g (93%) of the titled product as a pale yellow oil:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][Cl:18])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1nnn(-c2ccc(F)cc2)c1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-fluorophenyl)-4-methyl-5-hydroxymethyl-1,2,3-triazole (871 mg; 4.20 mmol), prepared as described in example 6, and thionyl chloride (400 ml; 5.46 mmol) in benzene (14 ml) was heated under reflux for 4 hours. The reaction mixture was kept under stirring at room temperature overnight, thionyl chloride and benzene were evaporated and the resultant crude compound was collected several times with benzene. After evaporation of the solvent, the crude compound was purified by chromatography on silica gel (230-400 mesh), eluent methylene chloride:acetone=95:5, giving the title compound (m.p. 70°-71° C.).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[S:24][CH2:25][CH2:26][C:27]([NH:29][C@H:30]([C:63]([OH:65])=[O:64])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:62])[CH2:36][CH2:37][S:38][C@H:39]1[O:56][C@H:55]([CH2:57][O:58]C(=O)C)[C@@H:50]([O:51]C(=O)C)[C@H:45]([O:46]C(=O)C)[C@@H:40]1[O:41]C(=O)C)=[O:28])(=O)C>CO.O.CCN(CC)CC>[C@H:6]1([S:24][CH2:25][CH2:26][C:27]([NH:29][C@H:30]([C:63]([OH:65])=[O:64])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:62])[CH2:36][CH2:37][S:38][C@H:39]2[O:56][C@H:55]([CH2:57][OH:58])[C@@H:50]([OH:51])[C@H:45]([OH:46])[C@@H:40]2[OH:41])=[O:28])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@H](SCCC(=O)NCCC[C@H](NC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NCCC[C@H](NC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C(=O)O
Yield: 99.5 %

Procedure:
A solution of 36 (100 mg) in MeOH-H2O-Et3N 5:4:1 (v/v/v, 3 ml) is kept for 3 hours at room temperature, and evaporated to a residue which is put on a Sephadex G-25 column and eluted with water. The desired fractions are combined and lyophilized to give the title compound (65 mg, 100%): NMR (D2O)δ: 5.38 (d, J1,2 =15 Hz), 5.35 (d,J1,2 =1.5 Hz) (H-1), 2.70 (t), 2.63 (t) (SCH2CH2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CS(OC)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH3:10])[C:4](=[O:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(O)ncc1F
Agent: COS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(F)c(N)nc1=O
Temperature: 85 °C
Reaction time: 21 h
Yield: 37 %

Procedure:
A 25 mL screw-top vial was charged with 4-amino-5-fluoropyrimidin-2-ol (151.0 mg, 1.17 mmol), K2CO3 (289.2 mg, 2.09 mmol), 18C6 (278.6 mg, 0.901 mmol) and anhydrous DMF (10 mL). Methyl methanesulfonate (0.0814 mL, 0.961 mmol) was added, and the resulting mixture was agitated on a rotary shaker at 85° C. for 21 h. After cooling to room temperature, the crude material was concentrated in vacuo and purified by reverse phase column chromatography to afford 4-amino-5-fluoro-1-methylpyrimidin-2(1H)-one (61.9 mg, 37%) as a beige solid: mp 195° C. (dec.); 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=6.8 Hz, 1H), 7.52 (s, 1H), 7.32 (s, 1H), 3.18 (s, 3H); ESIMS m/z 144 ([M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([N:13]([CH3:14])[CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: CNC
Reactant: CS(=O)Nc1cnc(Cl)nc1
Product: CN(C)S(C)(=O)=Nc1cnc(Cl)nc1

Procedure:
The title compound is prepared from N-(2-chloropyrimidin-5-yl)methanesulfinamide and dimethylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.72 min; Mass spectrum (ESI+): m/z=235 [M+H]+.