Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([CH2:23][CH3:24])[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:23]([C:21]1[N:22]=[C:15]2[NH:14][C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[NH:4][N:5]=[CH:6]4)=[CH:18][C:17](=[O:19])[N:16]2[N:20]=1)[CH3:24]
Reactant: CCc1nc2[nH]c(-c3ccc4c(cnn4C(C)=O)c3)cc(=O)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1nc2[nH]c(-c3ccc4[nH]ncc4c3)cc(=O)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-acetyl-1H-indazol-5-yl)-2-ethyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one (130 mg, crude) in methanol (5 ml) was added potassium carbonate (20 mg, 0.14 mmol) and water (1 ml), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and diluted with water (10 ml). The product was collected by filtration and washed with ethanol (10 ml) to afford 2-ethyl-5-(1H-indazol-5-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid (66 mg, 18% 2 steps).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1CC2C3C=CC=CC=3C(C=O)=CC=2C1=O.C[O:25]C(C1C=CC2C(=CC=CC=2)C=1O)=O>>[NH2:8][C@H:3]1[CH2:4][CH2:5][O:25][CH2:7][C@@H:2]1[OH:1].[NH2:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[OH:1]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: O=Cc1cc2c(c3ccccc13)CN([C@H]1CCCC[C@@H]1O)C2=O
Product: N[C@H]1CCCC[C@@H]1O
Product: N[C@H]1CCOC[C@@H]1O

Procedure:
5-Bromo-8-[(1S,2S)-2-hydrocyclohexyl]-3,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one was prepared employing the procedures described for the construction of 2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[e]isoindole-5-carbaldehyde in Example 1, substituting methyl 8-hydroxyquinoline-7-carboxylate for 1-hydroxy-2-naphthoic acid methyl ester, and substituting provide (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>CO.C(O)C>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:11][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:10]=2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(S)nc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1ccc(CSc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Yield: 40.8 %

Procedure:
A mixture of 5-nitro-1H-benzoimidazol-2-thiol (1.95 g, 0.01 mol), 4-bromomethyl-benzoic acid methyl ester (2.29 g, 0.01 mol), triethylamine (2 mL), and ethanol (100 mL) was heated at reflux for a period of 4.5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was evaporated. The residue was crystallized from ethyl acetate/hexane. The solid obtained was dissolved in methanol and the solution was saturated with hydrogen chloride. The methanol was evaporated. The residue was treated with ethyl acetate. The solid was collected to give the title compound (1.4 g, 41%) as a mono-hydrochloride, white solid, m.p. 228°-230° (dec.). Anal. Calcd. for C16H13N3O4S.HCl: C, 50.60; H, 3.72; N, 11.06. Found: C, 50.82; H, 3.68; N, 10.92. Mass spectrum (+FAB; [M+H]+) 344. 1H-NMR (DMSO-d6 ; 400 MHz) δ 8.32 (s, 1H), 8.06 (d, 1H), 7.88 (d, 2H), 7.62 (m, 3H), 5.0-7.4 f(br s, 4H), 4.67 (s, 2H), and 3.81 ppm (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: Cc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-bromo-1-methyl-2-nitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]2[CH2:16][CH2:17][C:12]1([C:18]([OH:20])=O)[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>O1CCCC1>[Cl:29][C:18]([C:12]12[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:20]
Reactant: O=C(OCc1ccccc1)N1C2CCC1(C(=O)O)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1C2CCC1(C(=O)Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 7-[(benzyloxy)carbonyl]-7-azabicyclo[2.2.1]heptane-1-carboxylic acid (550 mg) produced above, N,N-dimethylformamide (0.02 mL) and tetrahydrofuran (10 mL) was added dropwise ethanedioyl dichloride (0.80 mL) at room temperature. The mixture was stirred at room temperature for 30 min, and the reaction system was concentrated under reduced pressure. To the residue was added a small amount of tetrahydrofuran, and the mixture was concentrated again under reduced pressure to give a crude product (2.0 mmol) of the title compound. The obtained crude product of the title compound was used for the next reaction without further purification.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[C:8](Cl)[CH:7]=[C:6]([Cl:11])[N:5]=1.O>C(O)(C)C>[NH:5]1[CH2:6][CH2:7][CH:8]([OH:1])[CH2:9][CH2:4]1.[Cl:3][C:4]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:8]([OH:1])[CH2:9][CH2:4]2)[CH:7]=[C:6]([Cl:11])[N:5]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OC1CCN(c2cc(Cl)nc(Cl)c2)CC1
Product: OC1CCNCC1
Temperature: 60 °C
Yield: 37 %

Procedure:
A solution of piperdine-4-ol (1.2 g, 12.0 mmol) in isopropylalcohol (30 mL) was prepared and 1N NaOH (8 mL) was added with stirring. After stirring 15 min at room temperature, 2,4,6-trichloropyridine (2.0 g, 10.0 mmol) was added, and the resulting reaction mixture was heated at 60° C. for 10 hours. After this time, water was added to the reaction mixture (100 mL), and the product was extracted with ethyl acetate (200 mL×3). The organic extract was washed with brine solution followed by water, after which the organic layer was dried over using sodium sulphate and concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel, eluted with 30:70 ethyl acetate:petroleum ether, to afford the desired compound as light yellow solid (1 g, yield 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C(#N)C.CO>[NH2:34][CH:35]1[CH2:38][N:37]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:28])[CH2:36]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: NC1CNC1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 111.4 %

Procedure:
2.05 g of (2S, 4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidine carboxylic acid were dissolved in 20 ml of dry acetonitrile, and 0.78 g of N,N'-carbonyldiimidazole was added to the resulting solution, after which the mixture was stirred at 40° C. for 1 hour. The resulting mixture was then added dropwise to a solution of 1.00 g of 3-aminoazetidine dihydrochloride and 2.40 ml of diisopropylethylamine in 10 ml of methanol, whilst ice-cooling, and the mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 60 9385, manufactured by Merck, 100 g) to give 2.56 g of the title compound, in the form of an amorphous powder, from the fraction obtained by elution with a 65:35 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[O:15][CH:16]=[CH:17][N:18]=1)[C:8]([CH3:19])=[CH:7]2.[Br:20]N1C(=O)CCC1=O.C(OCC)C.C(OCC)(=O)C>CN(C)C=O>[Br:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[C:10](=[O:12])[N:9]([CH2:13][C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[C:8]=1[CH3:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cccc(F)c2c(=O)n1Cc1ncco1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(Br)c2cccc(F)c2c(=O)n1Cc1ncco1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of 8-fluoro-3-methyl-2-oxazol-2-ylmethyl-2H-isoquinolin-1-one (271 mg, 1.05 mmol) and N-bromosuccinimide (192 mg, 1.08 mmol) in N,N-dimethylformamide (4.8 mL) was stirred at 50° C. for 60 minutes. The reaction mixture was poured into diethyl ether (50 mL) and ethyl acetate (20 mL). A white solid precipitated, which was removed by filtration. The filtrate was washed with diluted brine (water:sat. NaCl(aq.)=1:1; 4×20 mL), dried over MgSO4 and evaporated to give a 321 mg of a solid (yield 90%), which was used in the next step without further purification. LC-MS (m/z) 337.3&339.4 (MH+), tR=1.1. 1H NMR (CDCl3, 500 MHz, TMS=0 ppm): 2.75 (s, 3H, Me), 5.52 (s, 2H, CH2), 7.07 (s (unres. d, J<1 Hz), 1H, oxazol), 7.16 (dd, J=8.1 Hz, J=11.1 Hz, 1H, C7-H), 7.62 (s (unres. d, J<1 Hz), 1H, oxazole), 7.66 (dt, J(t)=8.1 Hz, J(HF)=4.9 Hz, 1H, C6-H), 7.78 (d, J=8.2 Hz, 1H, C5-H).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3](=[O:24])[NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[NH:16]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:16][C:6]1[CH:7]=[CH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:10][C:5]=1[NH:4][C:3](=[O:24])[N:2]([CH3:1])[CH3:25]
Reactant: CN(C)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl (2-(3,3-dimethylureido)-4-(thiophen-2-yl)phenyl)carbamate (115 mg, 0.32 mmol) in dichloromethane (5 mL) was added TFA (2 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was concentrated. The crude residue was diluted with ethyl acetate (30 mL) and washed with a saturated aqueous solution of sodium bicarbonate, then water (20 mL), dried over sodium sulfate, filtered and concentrated. The obtained residue was washed with hexane (2 mL) to afford 3-(2-amino-5-(thiophen-2-yl)phenyl)-1,1-dimethylurea (65 mg, 83% yield). ESI+ MS: m/z 262 ([M]+). 1H NMR (500 MHz, d6-DMSO): δ7.68 (s, 1H), 7.34 (d, J=5.0, 1H), 7.29 (d, J=2.0, 1H), 7.19 (dd, J=4.5, 2.0, 2H), 7.04 (m, 1H), 6.73 (d, J=8.5, 1H), 5.00 (s, 2H), 2.93 (s, 6H).
Reaction SMILES: Br[C:2]1([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH:5]=[C:4](Br)[S:3]1.[Cu](C#N)[C:14]#[N:15].Cl.[CH3:19][N:20](C=O)C>>[C:14]([C:2]1([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH:5]=[C:4]([C:19]#[N:20])[S:3]1)#[N:15]
Reactant: N#C[Cu]C#N
Reactant: BrC1=CCC(Br)(c2cccs2)S1
Reactant: CN(C)C=O
Agent: Cl
Product: N#CC1=CCC(C#N)(c2cccs2)S1

Procedure:
The compound (1) prepared in Preparative Example 1 and 11.8 g (0.13 mmol) of copper cyanide (CuCN) were added to a reactor containing 150 mL of DMF. The mixture was refluxed for 4 hours. After the reaction was completed, a mixture of ferric chloride (FeCl3), concentrated hydrochloric acid and distilled water (48 g: 12 mL: 72 mL) was added to the reactor and heated at 60–70° C. for 30 minutes to crush the complex compound (RCN-Cu complex). The hot solution was extracted with toluene, and the obtained organic layer was washed with 50% hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to prepare 1.67 g of the title compound as a solid.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][OH:12])[CH3:7].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH3:14])[CH2:6][CH3:7])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: CCN(CC)CCCO
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
MsCl (6.0 mmol) was added dropwise at 0° C. to a stirred solution of 3-diethylamino-1-propanol (6.0 mmol), TEA (6.0 mmol) in anhydrous DCM (6 mL), and the mixture was stirred at the same temperature for 10 min, and at room temperature for additional 1 h. After the removal of the solvent in vacuo, the solid residue was mixed with 4-chloro-3-nitrophenol (5.0 mmol), and K2CO3 (10 mmol) in anhydrous DMF (10 mL), following the general procedure III (Step A). The crude product is purified using silica gel column chromatography 5% MeOH/DCM as eluent to yield 2-chloro-5-(3-diethylamino-1-propoxy)nitrobenzene (1.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([N:18]=[C:19](SC)SC)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:26][CH2:27][C@@:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]3[O:36][C@:28]4([CH2:27][N:26]=3)[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]4)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2ccc(OCc3ccccc3)nc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3nc(NC4=NC[C@@]5(CN6CCC5CC6)O4)sc3n2)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of dimethyl 5-(benzyloxy)thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (500 mg, 1.38 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (317 mg, 1.38 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in DMF (7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-20% [9:1 methanol:ammonium hydroxide]-chloroform) to afford (R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (390 mg, 67% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.18 (br. s., 1H) 7.76 (d, J=8.85 Hz, 1H) 7.50 (d, J=7.32 Hz, 2H) 7.41 (t, J=7.32 Hz, 2H) 7.32-7.37 (m, 1H) 5.42 (s, 2H) 4.02 (d, J=9.46 Hz, 1H) 3.68 (d, J=9.46 Hz, 1H) 3.37-3.44 (m, 1H) 2.75-3.06 (m, 5H) 2.13-2.25 (m, 2H) 1.73-1.82 (m, 1H) 1.49-1.70 (m, 3H). MS (LC/MS) R.T.=1.69; [M+H]+=421.98.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([C:30](=[N:32]O)[NH2:31])[CH:29]=1.CCN(C(C)C)C(C)C>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([C:30]2[N:32]=[C:18]([C:17]3[CH:21]=[C:22]([CH3:1])[C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[N:15][CH:16]=3)[O:20][N:31]=2)[CH:29]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: CC1CCCCN1c1ccc(C(=O)O)cn1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2cnc(N3CCCCC3C)c(C)c2)n1

Procedure:
Oxalyl chloride (130 μL; 1.54 mmol; 3 eq.), Intermediate 38 (120 mg; 0.51 mmol; 1 eq.), Intermediate 23 (94 mg; 0.51 mmol, 1 eq.) and DIEA (260 μL; 1.54 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 50/50) afforded the title compound as a white solid.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH:11]=[CH:10]1.[Cl-].[NH4+].C(OCC)C>C1COCC1>[C:1]1([C:10]2[CH2:11][CH2:12][CH2:13][C:9]=2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CCC1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1=C(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 160 ml (120 mmol) of a THF solution of phenylmagnesium chloride, a solution of 8.38 ml (100 mmol) of-2-cyclopentenone in 70 ml of THF was dropwise added with ice cooling. The mixture was stirred at 0° C. for 1 hour and then further stirred at room temperature for 1 hour. Then, 200 ml of an ammonium chloride saturated aqueous solution was added. To the reaction solution, diethyl ether was added to perform extraction. The resulting ether solution was dried over magnesium sulfate, and the solvent was distilled off to obtain of a crude product of phenylcyclopentenol as a gold liquid (17.5 g). In a glass tube oven, 6 g of the crude product was placed, and the product was heated at 180 to 190° C. for 1 hour at atmospheric pressure, then cooled to room temperature and slowly heated (finally) to 195° C. under reduced pressure (1 to 4 mmHg). As a result, 2.5 g of a white crystal was sublimed (51.3%).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>COCCOC.O>[CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][O:4][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1
Reactant: CCC(C)CO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCC(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To 2-methyl-1-butanol (0.855 mL) in DME (4 mL) was added sodium tert-butoxide (760 mg). The mixture was stirred at room temperature until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) was added followed by DME (4 mL). The reaction was heated at 110° C. overnight. The mixture was cooled and concentrated in vacuo to give a yellow residue. The residue was taken up in water (30 mL) and extracted with EtOAc (2×30 mL). The organics were separated and washed with brine (30 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow/brown residue. This material was taken on to the next step without further purification.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]C1C=C(C(=O)C)C=CC=1>CCOC(C)=O>[CH3:14][C:5]1[CH:6]=[C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])[CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)c1cccc(C)c1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1cccc(C)c1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.72 mL of 3′-methylacetophenone and 3.95 mL of EtOAc to yield 2.94 grams of Intermediate 21 as an oil: 1H NMR (400 MHz, CDCl3enol form) δ7.70 (m, 2H), 7.34 (m, 2H), 6.17 (s, 1H), 2.41 (s, 3H), 2.20 (s, 3H); low resolution MS (ES)m/e 177.1 (MH+).
Reaction SMILES: C([C:4]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]1[C:5]2=[C:6]2[CH2:19][CH:13]1[CH:12]1[CH:7]2[CH:8]2[CH2:20][CH:11]1[CH2:10][CH2:9]2)(O)=O.O1C=CCCC1>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>[CH2:16]=[CH:17][CH2:4][CH2:18][CH2:15][CH2:14][CH2:5][CH2:6][CH2:19][CH2:13][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:20]
Reactant: O=C(O)C12CCC(C1)C1C2=C2CC1C1C3CCC(C3)C21
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCCCCCCCCCCCCCC
Reaction time: 2 h

Procedure:
Subsequently, carboxyhexacyclo[6.6.1.13,6.110,13.02,7.09,14 ]heptadecen of 2.1 grams and 3,4-dihydro-2H-pyran of 1.71 grams were dissolved in tetrahydrofuran of 50 milli-litter, and p-toluen sulfonic acid of 0.03 gram was added to the solution. The reaction was continued at room temperature for 2 hours. The resultant material was diluted in ether of 100 milli-litter, and was washed in 3% solution of Na2CO3, saturated water of salt and water in this order, and the organic layer was dried with MgSO4. When ether and residual 3,4-dihydro-2H-pyran were removed in vacuum by using an evaporator, we obtained viscous-liquid of 12-tetrahydropyranyloxycarbonilhexacyclo[6.6.1.13,6.110,13.02,7.09,14 ]heptadecen of 2 grams.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC(C)(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 3,3-dimethylbutylamine (0.272 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.421 g, 45.9%): TOF MS ES+ 359.2 (M+H)+, HRMS calcd for C19H27N4O3 359.2083 (M+H)+. found 359.2093, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.0 min, 98.0% purity.