Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16].[CH:24](=O)[C:25]([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:20][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:16]
Reactant: CC(C)(C)C=O
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(CNCC(C)(C)C)OCC
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (5.30 g) was added to a cooled at 0° C. solution of aminoacetaldehyde diethyl acetal (2.91 mL) and pivalaldehyde (2.21 mL) in dichloromethane (50 mL). The reaction was stirred for 16 h, allowing the temperature to warm to ambient conditions. Water (50 mL) was added, followed by portionwise addition of sodium bicarbonate (8.40 g), causing effervescence. The mixture was stirred vigorously for 1 h, then allowed to partition. The phases were then separated and the aqueous phase extracted with further dichloromethane (20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford N-(2,2-diethoxyethyl)-2,2-dimethylpropan-1-amine (3.79 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.63 (t, J=5.6 Hz, 1H), 3.71 (dq, J=9.5, 7.1 Hz, 2H), 3.55 (dq, J=9.4, 7.1 Hz, 2H), 2.73 (d, J=5.6 Hz, 2H), 2.37 (s, 2H), 1.22 (t, J=7.1 Hz, 6H), 0.91 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].O.C(O)C.N>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH3:11])[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: N
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)cc1Br
Temperature: 70 °C
Yield: 69.7 %

Procedure:
2-Bromo-4-nitrotoluene (10.0 g, 46.3 mmol) was added to a mixture of water (60 mL), ethanol (130 mL) and acetic acid (40 mL) under nitrogen. The mixture was heated to 70° C. and iron powder (10.3 g, 185 mmol) was added portionwise. After the mixture was heated at refluxed for 2 hours, it was cooled and aqueous ammonia (34%, 180 mL) was added slowly. The mixture is filtered through celite and the aqueous phase was extracted with ethyl acetate. It was dried over MgSO4, filtered, and solvent was removed to give the product as a brown oil (6.0 g, 71%). LCMS (ESI): M+H=185.8.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8](SC)=[N:9][C:10]([C:14]([F:23])([F:22])[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=4)=[N:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>C(Cl)Cl.C1COCC1>[CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([NH:43][C:40]4[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=4)=[N:9][C:10]([C:14]([F:23])([F:22])[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=4)=[N:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(N)n[nH]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C3CC3)ccc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(C4CC4)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 7.7 %

Procedure:
To 7-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Step A (137 mg, 0.378 mmol) in DCM (5 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (139 mg, 0.567 mmol). The mixture was stirred for at 0° C. for 20 min, then DCM (15 mL) was added and the mixture was washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. To the residue was added 5-methyl-1H-pyrazol-3-amine (0.107 g, 1.01 mmol) in THF (5 mL) and the mixture was stirred at room temperature for 40 min and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% AcOH/CH3CN and solvent A=0.05% aq AcOH) to afford 7-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (12 mg, 8%) 1H NMR (300 MHz, DMSO-d6) δ 12.07-12.19 (m, 1H), 10.51-10.63 (m, 1H), 8.66 (s, 1H), 8.54 (d, J=8.7 Hz, 1H), 7.94-8.04 (m, 2H), 7.51 (s, 1H), 7.36 (d, J=8.7 Hz, 1H), 5.97 (s, 1H), 2.10-2.21 (m, 4H), 1.09 (dd, J=2.3, 8.1 Hz, 2H), 0.87-0.94 (m, 2H); LC-MS (ESI) m/z 411 (M+H)+
Reaction SMILES: IC.[CH2:3]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH2:21][C:22]([C:24]3[C:25]([C:31]([O:33][CH3:34])=[O:32])=[C:26]([CH3:30])[NH:27][C:28]=3[CH3:29])=[O:23])[CH:17]=[CH:18][C:19]=2[F:20])=[O:13])[CH2:8][CH2:7]1)[CH3:4].[C:35](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:3]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH2:21][C:22]([C:24]3[C:25]([C:31]([O:33][CH3:34])=[O:32])=[C:26]([CH3:30])[N:27]([CH3:35])[C:28]=3[CH3:29])=[O:23])[CH:17]=[CH:18][C:19]=2[F:20])=[O:13])[CH2:8][CH2:7]1)[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C)[nH]c(C)c3C(=O)OC)ccc2F)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C(=O)OC)c(C)n(C)c3C)ccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Iodomethane (0.056 mL, 0.90 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (53) (0.200 g, 0.45 mmol) and potassium carbonate (0.249 g, 1.80 mmol) in DMF (10 mL). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was poured into water (75 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a yellow gum (0.158 g, 77% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.14 (3H, t), 1.43-1.65 (2H, m), 1.72 (1H, m), 1.85 (1H, m), 2.05 (3H, s), 2.38 (3H, s), 3.06 (1H, m), 3.32 (3H, s), 3.45 (5H, m), 3.74 (3H, s), 3.91 (2H, s), 3.99 (1H, m), 6.93 (1H, t), 7.08 (1H, m), 7.17 (1H, m); m/z (LC-MS, ESI+), RT=2.15 min (M+H=459.36).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:25])[CH:17]=3)[O:12]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
TEA (0.25 ml, 1.8 mmol) was added to a suspension of (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (430 mg, 1.20 mmol) in DCM (13 ml) and the reaction mixture was stirred at RT for 5 min. The resulting clear solution was cooled down to 0° C., EDC (344 mg, 1.80 mmol) and HOBt (243 mg, 1.80 mmol) were added and the mixture was stirred at 0° C. for 2 h. NH2OTHP (168 mg, 1.43 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was washed with 5% aqueous NaHCO3 solution and brine, the organic layer was dried over Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (eluent: DCM/MeOH 98:2) to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (0.40 g) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:27]=[CH:26][C:25]=1[S:40](Cl)(=[O:42])=[O:41]>C1COCC1.CN(C=O)C>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:40]([C:25]3[CH:26]=[CH:27][C:28]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])=[CH:29][C:24]=3[O:23][CH3:22])(=[O:42])=[O:41])[C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Yield: 80.7 %

Procedure:
0.5 g of sodium hydride as a 60% dispersion in oil was added in small portions, at room temperature, to a solution of 2.4 g of 5-ethoxy-3-cyclohexyl-1,3-dihydro-2H-benzimidazol-2-one in 50 ml of THF and 50 ml of DMF and the mixture was stirred for half an hour, still at room temperature. 3.4 g of 2-methoxy-4-benzyloxycarbonylbenzenesulfonyl chloride were then added and the reaction medium was stirred for 4 hours at room temperature. It was concentrated under vacuum to remove the residual THF and the residue was taken up with water. It was then extracted with AcOEt and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. The residue obtained was then purified by chromatography on silica using DCM as the eluent. 4.2 g of the expected product were obtained in the form of a white solid by crystallization from iso ether. M.p.=131° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[OH:23])[CH:8]=[N:7][CH:6]=1)[CH3:2].[Cl:25][CH:26](Br)[C:27]1C=CC=C[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:40][C:41](=O)[CH2:42][CH3:43]>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH2:40][C:41]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:43][CH:42]=2)[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cncc(C2=C(c3cc(Cl)ccc3O)CCC2)c1
Reactant: ClC(Br)c1ccccc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cncc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)c1

Procedure:
5-{2-[5-Chloro-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-nicotinic acid ethyl ester (138 mg, 0.43 mmol) was treated with 4 chlorobenzyl bromide (0.130 g, 60 mmol) and potassium carbonate (1.000 g) and 2-butanone (5 mL) at reflux for 18 hrs. Upon cooling, the mixture was filtered through highflo and reduced down to an oil. The product was purified using a Water's sep-pak cartridge (10 g) to give (90 mg, 44%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.O>ClCCl>[OH:3][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C=O
Reactant: C=CCCCCCCCCCCCCCC
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC=CCC(O)C(=O)OC
Temperature: 25 °C

Procedure:
Methyl glyoxalate (8.80 g, 0.1 mol, 1.0 eq) and 1-hexadecene (44.80 g, 0.2 mol, 2.0 eq) are dissolved in dry dichloromethane (200 ml, freshly distilled from calcium hydride) under a nitrogen atmosphere. Stannic chloride (3.51 ml, 0.03 mol, 0.3 eq) is added dropwise with stirring and cooling at 0° C. (ice/water bath). After half an hour the reaction mixture is allowed to warm to room temperature and stirred for a further 21 hours before being neutralised with triethylamine (4.2 ml, 0.03 mol, 0.3 eq) with a further 5 minutes stirring. Water (50 ml) and dichloromethane (100 ml) are added, the organic layer is separated, washed in turn with water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulphate and evaporated. The crude oil is purified by short path distillation (bp 220-230° C./0.7 mm Hq) to furnish the ester product as a colourless liquid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[CH:13][CH:14]=2)[C:9]1([CH2:23][CH3:24])[CH2:21][CH3:22])(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:7][C@@H:8]1[C:9]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:10]2[CH:11]=[C:12]([OH:20])[CH:13]=[CH:14][C:15]=2[CH2:16][C@H:17]1[O:18][CH3:19]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.2 %

Procedure:
To a solution of trans-(1,1-diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (6.0 g, 17.2 mmol) in dichloromethane (60 mL) was added a solution of 4.0 N HCl in dioxane (21.5 mL, 86 mmol) over approximately 2 min. After stirring at room temperature overnight, the reaction mixture was concentrated at reduced pressure and dried under vacuum to give the hydrochloride salt of the title compound (5.5 g) (m/z): [M+H]+ calcd for C15H23NO2 250.36. found 250.2. 1H NMR (d6-DMSO, 400 mHz) δ (ppm) 9.26 (s, 1H), 8.09 (br s, 3H), 6.92 (d, J=8.0 Hz, 1H), 6.61 (m, 2H), 3.77 (m, 1H), 3.41 (s, 3H), 3.30 (dd, J=15.8 Hz, 5.9 Hz, 1H), 3.17 (m, 1H), 2.43 (dd, J=15.5 Hz, 9.6 Hz, 1H), 1.85 (m, 2H), 1.66-1.50 (m, 2H), 0.66 (t, J=7.4 Hz, 3H), 0.54 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.[CH3:30][PH:31](=[O:33])[CH3:32]>>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:21]2[CH:26]=[CH:25][C:24]([P:31]([CH3:32])([CH3:30])=[O:33])=[CH:23][CH:22]=2)[CH:3]=1)[CH3:11]
Reactant: CC(Oc1cc(Br)cnc1N)c1cc(F)ccc1Cl
Reactant: OB(O)c1ccc(Br)cc1
Reactant: C[PH](C)=O
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cc2)cnc1N)c1cc(F)ccc1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2-chloro5-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromophenylboronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[Br:8][CH2:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11].COC(C)(C)C>C(O)C>[Br-:8].[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10](=[O:11])[CH2:9][N+:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][CH:4]=1
Reactant: Cc1ncsc1C
Reactant: O=C(CBr)c1cccs1
Solvent: CCO
Solvent: COC(C)(C)C
Product: Cc1sc[n+](CC(=O)c2cccs2)c1C
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4,5-dimethylthiazole (2.2 g, 19.4 mmol) and 2-bromoacetylthiophene (4 g, 19.4 mmol) in ethyl alcohol (20 mL) was refluxed for 3 hours. It was cooled to room temperature and t-butyl methyl ether (10 mL) was added. The reaction mixture was left at room temperature overnight with stirring. The white product separated and was filtered and dried. It was crystallized from ethyl alcohol (4.42 g, 73%), m.p. 203-205° C.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]3[C:14](=[O:22])[N:13]([CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]5[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33]([C:39]6[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=6)=[C:32]([CH:46]6[CH2:48][CH2:47]6)[CH:31]=5)[CH2:25][CH2:24]4)[CH2:12][CH2:11][C:10]=3[N:9]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]3[C:14](=[O:22])[N:13]([CH:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]5[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33]([C:39]6[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=6)=[C:32]([CH:46]6[CH2:47][CH2:48]6)[CH:31]=5)[CH2:27][CH2:28]4)[CH2:12][CH2:11][C:10]=3[N:9]=2)[CH2:6][CH2:7]1
Reactant: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(C4CC4)c(C(=O)OC)cc3C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(C4CC4)c(C(=O)O)cc3C2=O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 2-cyclopropyl-6-(1-((2-cyclopropyl-5-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (480 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (320 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:23][SiH:24]([Cl:26])[Cl:25].C1(C)C=CC=CC=1>C(Cl)Cl>[C:11]1([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH2:3][Si:24]([Cl:26])([Cl:25])[Cl:23])=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cl[Si](Cl)(Cl)CCCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 30 °C

Procedure:
To a solution of 17 (0.18 g, 0.65 mmol) in 25 mL dry CH2Cl2 at 25° C. under inert atmosphere was added H2PtCl6.xH2O (0.001 g), followed by trichlorosilane (0.88 g, 6.5 mmol). The reaction solution was warmed to 30° C. and monitored by NMR until the completion of reaction after 4 h. Removal of the solvent in vacuum yielded a oil. 20 mL dry toluene was added to the residue and filtered into a Schlenk flask by cannula. The filtrate was concentrated under vacuum to give 18 as a oil. Yield, 98%. 1H NMR (benzene): δ0.90 (t, J=8 Hz, 2H), 1.55 (m, 2H), 2.20 (t, J=8 Hz, 2H), 6.75-6.83 (m, 4H), 6.98-7.14 (m, 10H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[S:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:24]1[CH:25]=[C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[S:22][CH:23]=1
Reactant: Cc1csc(OB([O-])[O-])c1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3cc(C)cs3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (800 mg), and to the solution were added 4-methyl-2-thienyl borate (524 mg) and potassium carbonate (935 mg). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (152 mg). The mixture was stirred at 100° C. for 16 hours and cooled to room temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-(4-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (510 mg).
Reaction SMILES: [C:1]([C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5])([OH:3])=O.C(Cl)CCl.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:40]=1[NH2:41]>CN(C=O)C.Cl>[Cl:17][C:10]1[CH:11]=[N+:12]([O-:16])[CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:26])[F:27])=[C:20]([O:28][CH2:29][CH:30]2[CH2:31][CH2:32]2)[CH:19]=1)[O:6][C:4](=[O:5])[C:1]([NH:41][C:40]1[CH:42]=[CH:43][C:44]([N+:46]([O-:48])=[O:47])=[CH:45][C:39]=1[O:38][CH3:37])=[O:3]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(O)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
(S)-4-(2-(carboxycarbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.10 mmol) was dissolved in DMF (5 ml), then EDC (29.2 mg, 0.15 mmol) was added. 2-methoxy-4-nitroaniline (34.2 mg, 0.2 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 2 hours. The reaction was diluted with HCl 1M and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 21 mg of the title product. (Yield: 32%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][OH:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][O:22][CH3:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(CO)Oc2ccccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CI
Product: COCC1CN(C(=O)OCc2ccccc2)c2ccccc2O1

Procedure:
The title compound is prepared analogously to Example 87b) starting from 3.0 g of N-benzyloxycarbonyl-2(R,S)-hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine, 2.4 g of sodium bis(trimethylsilyl)amide and 0.94 ml of methyliodide: Rf (3:1 mixture of toluene and ethyl acetate)=0.56; Rt (I)=27.9 min.
Reaction SMILES: C1(O[N:8]=[C:9]([C:11]2[N:12]=[CH:13][N:14]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:15]=2[NH2:16])[NH2:10])CCCCC1.CN(C)C=O.[C:31](=S)=[S:32]>>[CH:13]1[N:14]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:15]2[C:11](=[C:9]([NH2:10])[NH:8][C:31]([N:16]=2)=[S:32])[N:12]=1
Reactant: S=C=S
Reactant: NC(=NOC1CCCCC1)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Solvent: CN(C)C=O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 76 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-cyclohexyl-oxime was dissolved in 4 ml of an aqueous solution containing 3 ml of N,N-dimethylformamide, and 1 ml of carbon disulfide was added to the solution. The resulting mixture was allowed to react in an autoclave at 125° C for 5 hours under autogenous pressure (about 10 Kg/cm2), and the reaction product was worked up in the same manner as described in Example 1 to obtain 0.305 g of 2-thioadenosine having a melting point of 197° C (with decomposition) in 76% yield.