Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12]C(OCC2C=CC=CC=2)=O)=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>CO.C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1nc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.2 %

Procedure:
Under a nitrogen atmosphere, to a mixture of benzyl 2-{[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]carbonyl}hydrazinecarboxylate (14.6 g) in methanol (150 mL) and THF (100 mL) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. To a mixture of the residue in ethanol (200 mL) and THF (400 mL) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (3.9 g). The solvent in the mother liquor was evaporated under reduced pressure, and the residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (2.6 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22]CC)=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([OH:22])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: Oc1cc(F)ccc1Br
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 2-bromo-5-fluorophenol, triphenylphosphine and di-tert-butyl azodicarboxylate.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>CCCCCC>[C:9]1([NH:8][C:5](=[O:7])[CH3:6])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1cccc2c1CCCC2
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Acetic anhydride (100 ml, 1.06 mole) was added rapidly to neat 1-amino-5,6,7,8-tetrahydronaphthalene (25 g, 0.17 mole) (Aldrich) with stirring. The mixture quickly solidified and was allowed to stand overnight. The broken mass was suspended in hexane (200 ml), filtered, then resuspended in methylene chloride (150 ml). After stirring 10 minutes, the suspension was diluted with an equal volume of hexane, filtered, and the solid dried at 95° C. under reduced pressure to give N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (23 g). 1H NMR (CDCl3, 200 MHz) δ: 1.68-1.90 (m, 4H, CH2 's), 2.20 (s, 3H, CH3), 2.52-2.68 (m, 2H, ArCH2), 2.70-2.84 (m, 2H, ArCH2), 3.94 (br s, 1H, NH), 6.92 (d, J=8 Hz, 1H, Ar), 7.10 (t, J=8 Hz, 1H, Ar), 7.53 (d, J=8 Hz, 1H, Ar). Anal. Calculated for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.13; H, 8.04; N, 7.40.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1.N([O-])=O.[Na+].[Na+].[Cl-:18]>OP(O)(O)=O.O>[Cl:18][C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1
Reactant: [Cl-]
Reactant: Cc1ccc(Cl)c2sc(N)nc12
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)c2sc(Cl)nc12
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a slurry of 2-amino-4-methyl-7-chlorobenzothiazole (77.2) (6.37 g) in H3PO4 (85%, 213 ml) in a 500 ml 3-necked flask with mechanical stirring and an internal temperature of <−10° C., was added dropwise a solution of NaNO2 (6.87 g) in water (11 ml). The mixture was warmed to 0° for 30 minutes and then recooled. The slurry was then slowly added to a cold (˜5° C.) solution of CuSO4.5H2O (32 g) and NaCl (40 g) in water (128 ml) with vigorous mechanical stirring. After the foaming subsides and warming to RT, the solids were collected by filtration and rinsed with water. The solids were dissolved in ether leaving some insoluble residue. The ether solution was washed with water, and sodium bicarbonate solution. After the organic layer was concentrated, the residue was purified by flash chromatography with 10% methylene chloride in hexane to afford 2-chloro-4-methyl-7-chlorobenzothiazole (77.3) (4.48 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][C:4]1=[O:19])[CH3:2].[CH2:20](Br)[CH3:21].[I-].[Na+].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH2:20][CH3:21])[CH2:5][C:4]1=[O:19])[CH3:2]
Reactant: CCN1C(=O)CNCc2cc(OC)c([N+](=O)[O-])cc21
Reactant: CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CC(=O)N(CC)c2cc([N+](=O)[O-])c(OC)cc2C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 1-Ethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.42 g, 0.0016 mol), Ethyl bromide (0.244 mL, 0.00329 mol), Sodium iodide (0.0033 g, 0.000022 mol) and N,N-Diisopropylethylamine (1.14 mL, 0.00654 mol) in N,N-Dimethylformamide (4 mL, 0.05 mol) was stirred at room temperature for 22 hrs. The reaction was evaporated and the residue taken up in DCM/water, separated, washed, dried and evaporated to give 1,4-Diethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one the product as a red oil. (0.44 g, 95%). LCMS (m/e) 294 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.95 (s, 1H), 7.45 (s, 1H), 3.95 (s, 3H), 3.87-81 (q, 2H, J=6.82 Hz), 3.61 (s, 2H), 2.98 (s, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.59-52 (q, 2H, J=7.07 Hz), 1.08-1.00 (quin, 6H, J=7.07 Hz).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14].C(=O)(O)[O-].[Na+]>ClCCl>[F:7][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCF)ccc43)ncn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
(Diethylamino)sulfur trifluoride (DAST, 34 μL, 0.260 mmol) was added at −78° C. to a dichloromethane (5 mL) solution of the tert-butyl 4-[(6-{5-[(2-hydroxyethyl)sulfonyl]indolin-1-yl}pyrimidin-4-yl)oxy]piperidine-1-carboxylate (43.1 mg, 0.0855 mmol) produced in Example 84, and the mixture was stirred at −78° C. for 1 hour and further stirred for 30 minutes with heating to 0° C. To the reaction solution, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate three times. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-7:3, V/V) to obtain the title compound as white foam (17.0 mg, yield: 39%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-:8].[O:21]1CCOCC1>Br>[NH2:1][C:2]1[C:3]([C:19]([NH2:20])=[O:21])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-:8]
Reactant: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C#N)n2)ccc1=O
Reactant: C1COCCO1
Agent: Br
Product: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (9 g) was dissolved in 25% hydrogen bromide solution of ACOH (90 ml) at 20-25° C. The reaction mixture was stirred for 2 hours at ambient temperature. To the reaction mixture was added dioxane (180 ml). The suspension was stirred for 2 hours at ambient temperature. The precipitate was collected by filtration and washed with dioxane, and dried in the air at ambient temperature. The above powder was suspended in water (90 ml). The pH of the suspension was adjusted to 8-8.5 with 1N NaOH (70 ml). The suspension was stirred at ambient temperature. The precipitate was collected by filtration and washed with water, and dried in vacuo at 50° C., to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (8.80 g).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:20](#[N:23])[CH:21]=[CH2:22]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:21](=[CH2:22])[C:20]#[N:23])=[CH:6][C:7]([CH2:10][CH3:11])=[CH:8][N:9]=1
Reactant: C=CC#N
Reactant: CCc1cnc(Cl)c(C=O)c1
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(CC)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.20 g.).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4](C2C=CC(CCC)=CC=2)[CH2:3]1.Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=2)[CH:19]=1>>[CH3:29][O:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([N:4]1[CH2:5][CH2:6][NH:7][C@H:2]([CH3:1])[CH2:3]1)[CH:27]=[CH:26]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCCc1ccc(N2CCN[C@H](C)C2)cc1
Product: COc1ccc2cc(N3CCN[C@H](C)C3)ccc2c1

Procedure:
The title compound was prepared following the procedure of Intermediate 17, but starting from 2-bromo-6-methoxynaphthalene. Purification by chromatography (DCM/MeOH 80/20) afforded the title compound as an off white solid (43%). HPLC (Condition A), Rt: 2.2 min (HPLC purity: 98.4%). M+(ESI): 257.2
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[CH:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=1.Cl>C(#N)C>[OH:27][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])=[CH:20][CH:21]=1
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Nc1ccc(O)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Into a 1 liter flask 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester were added. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in cool bath. Stirring was continued for 1 hour at room temperature and 120.0 g (1 mol) of p-aminophenol was added. The mixture was heated for 5 hours at 5020 C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 99.35 g of N-(4-Hydroxyphenyl)methacrylamide.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].ClC(Cl)(Cl)C(=N)O[CH2:13][CH:14]=[CH2:15].FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:15]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH:14]=[CH2:13]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Product: C=CCO[C@@H](C)C(=O)OCC
Reaction time: 16 h
Yield: 72.7 %

Procedure:
7.08 g (60 mmol) of ethyl (S)-(−)-lactate are introduced into 120 ml of cyclohexane, and 25.0 g (120 mmol) of allyl trichloroacetimidate, dissolved in 30 ml of cyclohexane, are added thereto. 0.55 ml (6 mmol) of trifluoromethanesulfonic acid are then added and the mixture is stirred for 16 h. When the reaction is complete, the precipitated trichloroacetamide is filtered off with suction and washed with cyclohexane. The filtrate is washed with saturated NaHCO3 solution, after which the organic phase is dried over Na2SO4, filtered and evaporated on a rotary evaporator. Flash-chromatographic purification (cyclohexane/EtOAc=10:1; Rf=0.27) gives 6.9 g (72%) of a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.C(O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCc1ccccc1
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(COc1ccc(C(=O)Nc2ccc(F)cc2)cn1)OCCc1ccccc1
Yield: 4.2 %

Procedure:
A solution of [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid methyl ester (0.020 g, 0.66 mmole), phenethyl alcohol (0.078 mL, 0.66 mmol) and sulfuric acid (1 drop) in toluene (3 mL) was heated at reflux. After 4 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by trituration using ethyl acetate/hexanes gave 0.011 g (42%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s. H); 8.65 (m, 1H); 8.23 (m, 1H); 7.74 (m, 2H); 7.01–7.27 (m, 8H); 4.94 (s, 2H); 4.27 (m, 2H); 2.85 (m, 2H); MS (EI) m/z 393.03 (M−H)−.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[CH2:30][CH2:31]O>ClCCl>[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[CH2:30][CH2:31][I:25]
Reactant: II
Reactant: OCCC(O)C(F)(F)F
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: OC(CCI)C(F)(F)F
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (1.09 g, 4.16 mmol) in dichloromethane (14 mL) was treated with imidazole (0.283 g, 4.16 mmol) and iodine (1.06 g, 4.16 mmol), respectively, to give an orange suspension. A solution of 4,4,4-trifluoro-1,3-butanediol (0.500 g, 3.47 mmol) in dichloromethane (4 mL) was added to the suspension and stirred for 20 minutes. The solid was removed by filtration and the filtrate was concentrated under reduced pressure without heat to yield a black oil. The crude oil was purified by silica gel chromatography, eluting with 100% dichloromethane, to give the product as an oil (0.640 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].I[CH2:33][CH3:34]>CN(C)C=O>[CH2:33]([N:11]([C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)[CH2:16][CH2:15]1)=[O:13])[CH3:34]
Reactant: CCI
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.0 mg, 0.25 mmol) was added, followed by stirring at room temperature for 15 min and then iodoethane(39.2 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].[CH3:26]I>C1COCC1.CO>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:19]([CH3:26])[C:20]#[N:21])[CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(CC#N)c3)nc21
Reactant: CI
Solvent: CO
Solvent: C1CCOC1
Product: CC(C#N)c1cccc(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask, {3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl}acetonitrile (14-48) (45 mg, 0.14 mmol) was added and dissolved in THF (1.3 ml) under nitrogen and cooled to −78° C. 1 M Sodium bis(hexamethylsilyl)amide (0.18 ml, 0.18 mmol) was added slowly to the cooled solution, followed by Methyl iodide (25 mg, 0.18 mmol). The cooled solution was stirred for 30 minutes, allowed to warm to room temperature and stirred for 10 minutes. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-{3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl}propanenitrile (33-1), HRMS (M+H)+: observed=349.2032, calculated=349.2023 and 2-{3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl}-2-methylpropanenitrile (33-2); HRMS (M+H)+: observed=363.2186, calculated=363.2179.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:15](=[O:18])[N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:13](=[O:25])[N:12]([CH2:26][C:27]4[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=4)[C:11]=3[CH:10]=2)=[C:5]([O:35][CH3:36])[CH:4]=1.[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[CH:54][C:55]([C:56]([N:22]4[CH2:23][CH2:24][CH:19]([N:14]5[C:15](=[O:18])[C:16]6[S:17][C:9]([C:6]7[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=7[O:35][CH3:36])=[CH:10][C:11]=6[N:12]([CH2:26][C:27]6[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=6)[C:13]5=[O:25])[CH2:20][CH2:21]4)=[O:57])=[CH:59][CH:60]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38]
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nc(COC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(4-fluoro-2-methoxyphenyl)-1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (415 mg; compound B84) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (383 mg; compound C10) and HBTU (322 mg) in DCM (10 ml) in the presence of DIPEA (498 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc, 100/0/to 0/100 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:10][C@@H:11]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[S:14][CH:12]1[OH:13])(=[O:9])[CH3:8].C(=O)(O)[O-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:12]1([S:14][C@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]1[O:10][C:7](=[O:9])[CH3:8])[OH:13]
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1SC(O)(C2CCCCO2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
3,4-Dihydro-2H-pyran (1.5 mL, 16.5 mmol) and p-toluenesulfonic acid monohydrate (104 mg, 0.549 mmol) were added to a chloroform (40 mL) solution of 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.0 g, 5.49 mmol) and stirred at room temperature for one hour. The reaction mixture was added with a saturated sodium bicarbonate aqueous solution and extracted with chloroform, and after the organic layer was washed with brine, it was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain pale yellow amorphous tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.56 g).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:9]1[CH2:14][CH2:13][C:12]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)[CH2:11][CH2:10]1)[CH2:2]2.[C:31](Cl)(=[O:38])[O:32][C@@H:33]1[CH2:37][CH2:36][O:35][CH2:34]1.C(N(CC)CC)C.Cl>CCOCC>[O:35]1[CH2:36][CH2:37][C@@H:33]([O:32][C:31]([N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([N:9]2[CH2:10][CH2:11][C:12]4([C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]4)[CH2:13][CH2:14]2)[CH2:2]3)=[O:38])[CH2:34]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4)CC2)C1
Reactant: O=C(Cl)O[C@@H]1CCOC1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 1′-(8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4c (205 mg, 0.5 mmol) was suspended in Et2O (10 mL) and treated with the (R)-tetrahydrofuran-3-yl carbonochloridate (150 mg, 1 mmol) and triethylamine (0.21 mL, 1.5 mmol, 3 eq). The reaction was stirred at room temperature for 30 min and was then treated with 1N aq. HCl. The phases were separated, the aqueous phase was brought to a basic pH by adding solid KOH, and the resulting suspension was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide crude tert-butyl 1′-(8-(((R)-tetrahydrofuran-3-yloxy)carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4d as a colorless, viscous oil (230 mg, 88% yield). LC/MS m/z [M+H]+ 526.2, retention time 2.54 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min.