Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]1[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=1)=[CH:7]2.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:13][O:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:29]([C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)(=[O:31])=[O:30])[CH:7]=[C:8]1[C:14]1[S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:18]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cnc(-c2cc3cccc(N)c3n2COC)s1
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3n2COC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a mixture of ethyl 2-[7-amino-1-(methoxymethyl)-1H-indol-2-yl]-1,3-thiazole-5-carboxylate (2.18 g) and pyridine (25 mL) was added thiophene-2-sulfonyl chloride (1.50 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (2.19 g, yield 70%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 133-134° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=2)[CH:10]=1.[CH3:44][NH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.CC(C)=O>[CH3:44][N:45]([CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:28](=[O:37])[NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([C:8](=[O:38])[NH:7][CH2:6][C:5]3[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:30]=1)[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1
Reactant: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 54.6 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (2.5 mL), acetone (2.5 mL), tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (48 mg, 0.20 mmol, 1.20 equiv), potassium carbonate (68 mg, 0.49 mmol, 3.00 equiv), and potassium iodide (6 mg, 0.04 mmol, 0.20 equiv). The resulting solution was stirred for 2.5 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 75.5 mg (49%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.28 (s, 1H), 9.58-9.54 (m, 1H), 8.94-8.92 (d, J=5.1 Hz, 1H), 8.33-8.27 (m, 2H), 8.04 (s, 1H), 7.96-7.93 (d, J=7.8 Hz, 1H), 7.85-7.84 (d, J=4.2 Hz, 1H), 7.71-7.55 (m, 7H), 7.31-7.28 (d, J=8.1 Hz, 1H), 4.64-4.62 (d, J=5.7 Hz, 2H), 4.29 (s, 2H), 3.44-3.31 (m, 8H), 3.20 (s, 2H), 3.06 (s, 2H), 3.27-3.26 (m, 6H), 1.73 (s, 4H), 1.60 (s, 2H), 1.39 (s, 9H). MS (ES, m/z): 814 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH3:21][C:22]1([CH3:45])[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([CH2:32][CH2:33]C3C=C(C)C=CC=3S([O-])(=O)=O)[CH:30]=[CH:31][C:24]=2[O:23]1>O>[CH3:21][C:22]1([CH3:45])[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][O:1][C:2]3[CH:3]=[C:4]([NH:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=3)[CH:30]=[CH:31][C:24]=2[O:23]1
Reactant: CN(C)C(=O)Nc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCc2ccc3c(c2)CCC(C)(C)O3)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1cccc(OCCc2ccc3c(c2)CCC(C)(C)O3)c1
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
1.8 g of 1-(3-hydroxyphenyl)-3,3-dimethylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.4 g of 60% sodium hydride was added thereto. After the mixture was stirred for 15 minutes, 3.6 g of 3-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)ethyl]-p-toluene sulfonate was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into iced water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous sodium sulfate and ethyl acetate was distilled off. The residue was purified by silica gel column chromatography using n-hexane/ethyl acetate (1/1) as a developer to obtain 2.4 g of Compound No. 94 shown in Table 5.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8]#[N:9].Cl.[NH3:11]>CO>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8](=[NH:11])[NH2:9]
Reactant: N
Reactant: N#Cc1ncc[nH]c1=O
Agent: Cl
Solvent: CO
Product: N=C(N)c1ncc[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In 33 ml of methanol was dissolved 1.1 g of 3-oxo-3,4-dihydro-2-pyrazinecarbonitrile synthesized according to the description of J. Heterocycl. Chem., Vol. 19, Pages 1,397-1,402 (1982). While cooling the solution with ice, gaseous hydrogen chloride was introduced until saturation, after which the solution was stirred at the same temperature as above for 8 hours. The solvent was removed under reduced pressure, the residue thus obtained and dissolved in 55 ml of a 7 mol/L solution of ammonia in methanol at an ice-cooled temperature, and the solution thus obtained was stirred at the same temperature as above for 5 minutes. The solid product formed was collected by filtration to obtain 1.1 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide as a light yellow-colored solid product.
Reaction SMILES: [CH2:1]([N:21]=[N+]=[N-])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[F-].[Na+]>CCOCC>[CH2:1]([NH2:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN=[N+]=[N-]
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a magnetically stirred solution of 132 mg (0.43 mmol) of arachidonyl azide in 3 mL of Et2O, 4 mL of a 1.0 M LAH solution in THF (4.0 mmol) was added dropwise at room temperature. The reaction mixture was refluxed for 3 h and then it was cooled to ambient temperature. 210 mg (5 mmol) of NaF was added and the reaction was quenched with wet Et2O. The white mixture was filtered and the solvent was evaporated to dryness. Silica gel chromatography (eluents: CH2Cl2/MeOP-up to 50% MeOH), evaporation of solvent, followed by Millipore filtration of a CH2Cl2 solution of the product then gave 78.9 mg (0.28 mmol, 64% yield) of arachidonyl-amine as a colorless oil. TLC (EtOAc/CH2Cl2 (20:80)) Rf 0.33; 1H NMR (200 MHz, CDCl3) δ 5.38 (m, 8 H), 2.82 (m, 6 H), 2.70 (t, 2 H, J=6.6 Hz), 2.08 (m, 4 H), 1.40 (m, 4 H), 1.26 (m, 6 H), 0.89 (t, 3 H, J=6.4 Hz).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:7]2[CH2:8][C:9]([F:12])([F:11])[CH2:10][CH:6]2[O:5][N:4]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]>>[F:13][CH:2]([F:1])[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:7]2[CH2:8][C:9]([F:12])([F:11])[CH2:10][CH:6]2[O:5][NH:4]1
Reactant: FC(F)C1=NOC2CC(F)(F)CC12
Reactant: Fc1ccccc1Br
Product: Fc1ccccc1C1(C(F)F)NOC2CC(F)(F)CC21

Procedure:
Intermediate XXIX-1 was obtained following general procedure L: Starting from rac-(3aR,6aR)-3-difluoromethyl-5,5-difluoro-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole, the reaction with 1-bromo-2-fluoro-benzene yielded the product rac-(3S,3aR,6aR)-3-difluoromethyl-5,5-difluoro-3-(2-fluoro-phenyl)-hexahydro-cyclopenta[d]isoxazole as a light brown oil. MS: m/z=294.4 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52][CH:51]=1>CN(C=O)C>[N:50]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52][CH:51]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cncnc2)c1
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: COc1cccc2cc(C(=O)Nc3cccc(-c4cncnc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 61.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyrimidin-5-yl-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.015 g of product in 62% yield: LCMS (ESI) m/z 374 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CO.CC(O)=O.[Pd]>[NH2:1][C:2]1[C:3]([NH2:18])=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N2CCOCC2)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(N2CCOCC2)nc(N)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 2-amino-6-morpholino-3-nitroisonicotinate (4.8 g, 17 mmol) and 10% Pd/C (480 mg) in MeOH (100 mL) and CH3COOH (50 mL) was stirred at room temperature for 16 h with connection to a balloon of H2. LCMS showed no methyl 2-amino-6-morpholino-3-nitroisonicotinate left and the desired product formed. It was then filtered and the filtrate was concentrated in vacuo. The residue (4.3 g) was used for next step without purification. LC/MS: MS (ES+) m/e 253 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:13]([NH:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(F)cc1N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(F)cc1NCc1ccccc1

Procedure:
Methyl 2-amino-4-fluorobenzoate (0.90 g), benzaldehyde (0.54 mL), sodium triacetoxyborohydride (1.58 g) and acetic acid (0.3 mL) in CH2Cl2 (20 mL) were stirred for 3 hours. The reaction was quenched with methanol, concentrated, and chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCCCCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Product: CCCCCCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 54.6 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-hexyloxybenzaldehyde 1.88 g were dissolved in methanol 60 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 2.5 hours. After the solution was cooled to room temperature, the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.34 g.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[CH:29]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:11]1[CH:12]=[C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[CH:15][C:10]=1[CH2:9][N:6]1[C:7](=[O:8])[C:2]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:34][CH:35]=2)=[C:3]([CH3:28])[N:4]=[C:5]1[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a solution of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.65 g) and 4-isopropoxyphenylboronic acid (0.40 g) in 1,4-dioxane (16 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.06 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.49 g, 67%) as a colorless amorphous solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Si:13]([O:30][CH2:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34]O)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]1(=[O:67])[NH:61][C:60](=[O:62])[C:59]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:58]12.[Cl-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[Si:13]([O:30][CH2:31][CH2:32][C:33]([CH3:36])([CH3:37])[CH2:34][N:61]1[C:57](=[O:67])[C:58]2[C:59](=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:60]1=[O:62])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(CO)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diethyl azodicarboxylate in toluene (2.2 M, 14.0 mL) was added to a solution of 4-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethylbutan-1-ol (J. Am. Chem. Soc., 2007, vol. 129, p. 4456) (9.15 g), triphenylphosphine (7.40 g), and phthalimide (4.15 g) in tetrahydrofuran (150 mL) with stirring at room temperature. The mixture was stirred overnight at room temperature, and sodium chloride solution was then added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and diethyl ether was then added to the residue. Insoluble matter was filtered off through celite, and the filtrate was concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (11.8 g).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:31])[C:16]([CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:17][N:18]=3)[S:13][C:6]=12.Cl>C(Cl)Cl>[F:1][C:2]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:31])[C:16]([CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1c(CNCCCC(=O)OC(C)(C)C)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl
Solvent: ClCCl
Product: Cn1c(CNCCCC(=O)O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of 132 (272 mg, 0.502 mmol) in DCM (10 mL) was added HCl (4 M in Et2O) (0.502 mg, 2.009 mmol) and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was then concentrated to afford title compound 133 as a yellow solid (244 mg, 100% yield, crude) that was used in the next step with no additional purification. MS (m/z)=486.1 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2C
Yield: 95.6 %

Procedure:
Hydrogenolysis of intermediate 14, ethyl 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.610 g, 1.77 mmol) in a mixture of ethyl acetate (75 ml) and ethanol (75 ml) at 25° C. over 10% palladium on activated carbon (0.20 g) under 1 atm of hydrogen for 2 h gave 0.430 g (95% yield) of the title ester as white crystals; mp 119–121° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ ppm: 1.46 (3H, t, J=7.1 Hz, CH3), 1.67 (3H, d, J=6.6 Hz, CH3), 3.90 (2H, m, CH2), 4.13–4.32 (2H 4.51 (2H, m, OCH2), 4.70 (1H, q, J=6.6 Hz, CH), 10.7 (1H, broad, OH). Anal. Calcd for C11H14N2O5: C, 51.96; H, 5.55; N, 11.01. Found: C, 51.60; H, 5.61; N, 10.70.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH:21]=[CH:22][CH2:23]Br>CC(C)=O>[Br:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: BrCC=CCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OC/C=C/CBr
Temperature: 55 °C
Yield: 41.1 %

Procedure:
A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 59 mmoles), K2CO3 (10 g, 1.2 q) and 1,4-dibromo-2-butene (>95% trans, Aldrich, 18 g, 1.2 eq) in acetone (500 ml) was heated at 55° C. for 3 hr. At the end of the reaction, the solvent was concentrated. The crude product was extracted into dichloromethane (750 ml) and the insolubles were filtered; then the solution was concentrated again to an oil. Purification on a silica gel column (SiO2, 100 g, eluted with dichloromethane) yielded 7.25 g (40%) of white solid. Recrystallization from ether gave analytically pure (E)-1-[4-[4-(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.91 g), m.p.=71°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[CH3:14][O:15]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1
Reactant: COC(Cl)Cl
Reactant: COc1cccc2c1NC(=O)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
8-Methoxy-3,4-dihydro-1H-quinolin-2-one (5 g) was dissolved in dichloromethane (100 ml), and dichloromethyl methyl ether (6.4 ml) was added at room temperature, followed by cooling in an ice water bath. Titanium tetrachloride (85 ml) was added dropwise at a temperature not higher than 10° C., and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, and the aqueous layer was subjected to extraction with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Diethyl ether was added to the residue and the produced solid was collected by filtration and dried to thereby obtain 5.2 g (yield: 90%) of 8-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:21]([OH:23])[CH3:22])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([N:9]3[C:13]4=[C:14]5[S:20][CH:19]=[CH:18][C:15]5=[N:16][CH:17]=[C:12]4[N:11]=[C:10]3[C@@H:21]([OH:23])[CH3:22])[CH2:7][O:8]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: C[C@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c([C@H](C)O)nc4cnc5ccsc5c43)CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of (1S)-1-{1-[(3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (48.0 mg, 0.144 mmol) in methylene chloride (2.09 mL) and pyridine (70.4 μL, 0.871 mmol) was added p-toluenesulfonyl chloride (35.0 mg, 0.184 mmol) and 4-dimethylaminopyridine (1.1 mg, 0.0092 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (42 mg, 60%). LCMS calculated for C23H26N3O5S2 (M+H)+: m/z=488.1. Found: 488.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][NH2:29])[CH2:24][CH2:23]1>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:15])[N:28]([CH:25]3[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]3)[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NNC1CCNCC1
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
1000 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) are dissolved in 10.5 l of methanol. 2500 g piperidin-4-yl-hydrazine dihydrochloride, solved in 4 l of water are added rapidly. The mixture is heated to reflux and kept at reflux temperature for 4 days. The reaction mixture is cooled to 20° C., 10 l of water are added and then methanol is removed by distillation in vacuum. The aqueous solution is allowed to stand overnight at RT. The solution is cooled and aqueous sodium hydroxide (c=10 mol/l) (about 2 l) is added during 4 to 5 h by keeping the temperature below 20° C. and the pH should be higher than 13. The product crystallizes during adding of sodium hydroxide. The mixture is stirred 1 h at 10° C., filtered over a filter press and washed with 0.5 l of water. The product is dried at 50° C. in a circulating air dryer resulting in the title compound. (compound B1)