Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([BH3-])#N.[Na+].[ClH:30]>O.CO>[ClH:30].[CH2:18]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCC=O
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCCN)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCNCCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 1 l. of methanol is added 10.0 g (0.0389 mole) of N-(2-aminoethyl)-4-[(methylsulfonyl)amino]benzamide. The suspension is refluxed for 1 hour, then cooled. To the suspension is added 4.66 g (0.0408 mole) heptaldehyde, the mixture is then stirred over ice for 30 minutes. To the chilled mixture is added 10.26 g (0.1632 mole) of sodium cyanoborohydride. The reaction is stirred at room temperature for 24 hours, conc. HCl is added to keep the pH at about 6.0. After about 24 hours the pH of of the reaction is adjusted to pH=1.0 and reduced to 1/3 volume. 100 ml of water is added and the solid is filtered. The resultant solid is suspended in 100 ml DMF, heated to 120° C. and filtered hot. The solution is cooled and the resultant solid is filtered and dried to yield the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:13][C:14]([F:18])([F:17])[CH2:15]I>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][C:14]([F:18])([F:17])[F:13])[CH:6]=1
Reactant: FC(F)(F)CI
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 90 °C
Yield: 75.8 %

Procedure:
In a microwave vial 4-iodo-1H-pyrazole (1.00 g, 5.16 mmol) and cesium carbonate (6.72 g, 20.6 mmol) were suspended in DMF (8.0 mL) and 1,1,1-trifluoro-2-iodoethane (2.06 mL, 20.6 mmol) was added. The mixture was heated at 90° C. by microwave for 60 minutes then the mixture was filtered and the filter cake rinsed with EtOAc. The filtrate was concentrated then taken up in EtOAc and 50% saturated aqueous NH4Cl. The organic layer was washed with sat LiCl and sat NaCl then dried over MgSO4. The solution was concentrated and the residue purified by SiO2 chromatography (5-35% EtOAc/heptane) to afford 1.08 g (76%) of 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[ClH:31].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:37]([CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)[CH3:36])=[CH:9][CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CNC1CCCCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)cc2)C3)cc1
Solvent: CCN(CC)CC
Product: CN(CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)cc2)C3)cc1)C1CCCCC1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylcyclohexanamine and triethylamine as described in general procedure 2 to give a yellow solid. M.p.=159-162° C. 1H NMR 400 MHz (DMSO-d6) δ 9.96 (s, br, 1H), 9.59 (s, 1H), 8.28 (m, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.49-7.43 (m, 2H), 7.30 (m, 2H), 7.23 (d, J=8.8 Hz, 4H), 7.09 (m, 4H), 4.41 (t, J=6.0 Hz, 1H), 3.29-2.94 (m, 8H), 2.72 (d, J=5.2 Hz, 3H), 2.03-1.10 (m, 10H). LCMS m/e 523 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:20]1([S:26][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 70 °C
Yield: 96.9 %

Procedure:
To a solution of 12.0 g (41.6 mmol) of N-[(4-fluorophenyl)sulfonyl]glycine, 1,1-dimethylethyl ester from Example 5a and 12.8 mL (125 mmol) of thiophenol in 80 mL of anhydrous dimethylformamide, previously degassed by passing nitrogen through the solution, was added 17.3 g (125 mmol) of powdered potassium carbonate. The mixture was vigorously stirred and warmed to 70° C. and maintained there for 13 hours, cooled and ethyl acetate and water added. The organic layer was separated, washed four times with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford crude product. This was triturated with diethyl ether and hexanes, and the solids filtered and air dried to yield 15.3 g of title compound N-[[4-(phenylthio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, m/e=386 (M+H).
Reaction SMILES: O1CCC[CH2:2]1.[Cl:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]([F:15])=[C:9]([Cl:16])[N:8]=1.[H-].[Na+].COCCl>C(OCC)(=O)C.O>[Cl:16][C:9]1[C:10]([F:15])=[CH:11][C:12]([CH2:13][O:14][CH3:2])=[C:7]([Cl:6])[N:8]=1
Reactant: OCc1cc(F)c(Cl)nc1Cl
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 100 mL of a tetrahydrofuran solution containing 5.8 g of (2,6-dichloro-5-fluoropyridin-3-yl)methanol, 1.8 g of 60% sodium hydride and 2 mL of a tetrahydrofuran solution containing 2.4 mL of chloromethyl methyl ether were added under cooling with ice, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added thereto, the organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 5.6 g of a colorless oily substance, 2,6-dichloro-3-fluoro-5-((methoxy)methyl)pyridine.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.[C:22]([O-])([O-])=O.[K+].[K+].BrC[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33]>CN(C=O)C>[CH3:34][CH:32]([CH2:31][CH3:30])[CH2:33][CH2:22][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)CCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 55.6 mg, 0.20 mmol), K2CO3 (54.2 mg, 0.39 mmol), and 1-bromo-4-methylpentane (43 uL, 0.29 mmol) in DMF (1.0 mL). Heat at 80° C. overnight. Remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 70:25:5 EtOAc/CH2Cl2/2.0 M NH3 in MeOH to afford the title compound (43.1 mg, 60%): MS ES+ 368.4 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2330, time 0.39 min; Anal. Calcd for C22H29N3O2.0.1CH2Cl2.0.1MeOH: C, 70.32; H, 7.87; N, 11.08. Found: C, 70.05; H, 7.52; N, 11.01.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[S:4][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1>O1CCCC1>[Cl:2][C:3]1[S:4][C:5]([S:9]([NH2:1])(=[O:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1S(N)(=O)=O

Procedure:
At −10° C., 117.7 g (1.8 mol) of a 26% strength aqueous ammonia solution are added dropwise to a solution of 208 g (95% strength, 0.9 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulphonyl chloride in 1000 ml of tetrahydrofuran. The mixture is stirred without further cooling for 2 h and the reaction mixture is then concentrated using a rotary evaporator. The crude product is used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].Cl.[NH2:28]O.Cl>CO.CO.O.O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:28][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CCC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A solution of cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.78 g, 5.22 mmol) in MeOH (3.9 mL) was added to a solution of NaOH (288 mg, 7.2 mmol) in MeOH/H2O (4.4 mL/0.3 mL) at −30° C. After 10 min was added hydroxylamine hydrochloride (726 mg, 10.45 mmol) and NaOH (418 mg, 10.45 mmol) in MeOH (5.2 mL) and H2O (5.2 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (7.7 mL) at 80° C. and heated at 80° C. for 1 h. Concentration of the organic solvent and extraction with DCM (×2), drying using a phase separator and evaporation gave an orange oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 30-60% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (717 mg, 44%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.79 (s, 9H), 1.01-1.19 (m, 2H), 1.23-1.48 (m, 2H), 1.83-1.96 (m, 2H), 1.98-2.11 (m, 2H), 2.94-3.04 (m, 1H), 3.09-3.19 (m, 1H), 3.70 (s, 3H), 3.91-4.06 (m, 2H), 5.71 (d, 1H). MS m/z 311 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]3[CH2:14][CH2:13]3)[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]3[CH2:13][CH2:14]3)[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][OH:29])[C@H:21]([OH:22])[C@@H:16]3[OH:17])[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34]
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC3CC3)nc3c(Br)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: OC[C@@H]1O[C@H](n2c(NC3CC3)nc3c(Br)c(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Yield: 35.5 %

Procedure:
4-Bromo-2-(cyclopropylamino)-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.01 g, 1.74 mmol), sodium carbonate (0.265 g, 2.50 mmol), water (4 mL), methanol (5 mL), and ethanol (8 mL) were used according to general procedure III. The product was purified using silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.28 g (36%) of a white solid: m.p. 205-208° C. Anal. calcd for C15H16Cl2BrN3O4-(0.25 C4H7O2): C, 40.45; H, 3.82; N, 8.84 Found: C, 40.38; H, 3.95; N, 8.90.
Reaction SMILES: OO.[Si]([O:10][CH2:11][CH:12]1[CH2:27][C:26]2[C:14](=[CH:15][C:16]3[N+:21]([O-:22])=[N:20][C:19]([CH2:23][CH3:24])=[N:18][C:17]=3[CH:25]=2)[CH2:13]1)(C(C)(C)C)(C)C.CC(O)=[O:30].O>CO.CCN(CC)CC>[CH2:23]([C:19]1[N:20]=[N+:21]([O-:22])[C:16]2[CH:15]=[C:14]3[C:26]([CH2:27][CH:12]([CH2:11][OH:10])[CH2:13]3)=[CH:25][C:17]=2[N+:18]=1[O-:30])[CH3:24]
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO[Si](C)(C)C(C)(C)C)C3
Reactant: CC(=O)O
Agent: OO
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(CO)C3
Temperature: 80 °C
Reaction time: 20 h
Yield: 18 %

Procedure:
H2O2 (70%, 1.5 mL, ca. 30.0 mmol) was added dropwise to a stirred solution of 1-oxide 135 (273 mg, 0.76 mmol) and HOAc (6 mL) at 50° C. and the reaction was stirred at 80° C. for 20 h. The mixture was cooled, water (50 mL) was added and the mixture was extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated to give a yellow oil which was treated with Et3N (3 mL) in MeOH (20 mL) at 20° C. for 66 h. The solvent was evaporated and the residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 136 (35 mg, 18%) as a yellow solid: mp (MeOH/DCM) 157-158° C.; 1H NMR δ 8.31 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.72 (br d, J=5.8 Hz, 2H, CH2O), 3.25-3.35 (m, 2H, CH2), 3.20 (q, J=7.5 Hz, 2H, CH2), 3.00-3.10 (m, 2H, CH2), 2.81-2.92 (m, 1H, H-7H), 1.43 (t, J=7.5 Hz, 3H, CH3), OH not observed; HRMS calcd for C13H15N3O3 (M+) m/z 261.1113, found 261.1115. Anal. calcd for C13H15N3O3: C, 59.8; H, 5.8; N, 16.1. Found: C, 59.6; H, 5.9; N, 15.9%.
Reaction SMILES: C([Li])(CC)C.[Si:6]([O:23][CH2:24][C:25]1[C:30]([N:31]2[CH2:36][C@H:35]([CH3:37])[O:34][C@H:33]([CH3:38])[CH2:32]2)=[C:29]([F:39])[C:28]([F:40])=[CH:27][CH:26]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CON(C)[C:44]([C:46]1[N:47]=[C:48]([CH3:51])[O:49][CH:50]=1)=[O:45]>C1COCC1>[Si:6]([O:23][CH2:24][C:25]1[C:30]([N:31]2[CH2:36][C@H:35]([CH3:37])[O:34][C@H:33]([CH3:38])[CH2:32]2)=[C:29]([F:39])[C:28]([F:40])=[C:27]([C:44]([C:46]2[N:47]=[C:48]([CH3:51])[O:49][CH:50]=2)=[O:45])[CH:26]=1)([C:19]([CH3:21])([CH3:22])[CH3:20])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1coc(C)n1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(F)c2F)co1
Reaction time: 2 h

Procedure:
sec-Butyl lithium (1.4 M in cyclohexane, 3.2 eq) was added to a stirred solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 1.0 g, 2.02 mmol) in anhydrous THF (10 mL) at −78° C., and the mixture was stirred for 2 h. N-methoxy-N,2-dimethyl-1,3-oxazole-4-carboxamide (1.0 g, 6.46 mmol) in THF (5 mL) was added dropwise and stirring was continued for an additional 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was purified by silica gel chromatography using ethylacetate-pet. ether gradient to obtain product. Yield: 600 mg, (50%)
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:13]=2[OH:21])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:21][C:13]3[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:22][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2nc3cccc([N+](=O)[O-])c3o2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 4-tert-butyl-N-(2-hydroxy-3-nitrophenyl)benzamide (0.35 g, 1.11 mmol) and pyridinium p-toluenesulfonate (200 mg, 0.8 mmol) in xylenes (25 mL) was heated in a 135° C. bath for 72 h. The solution was cooled to room temperature, and CH2Cl2 (100 mL) and H2O (25 mL) were added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound (0.260 g) as a golden solid. MS (ESI-POS): [M+H]+=297; Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 69.02; H, 5.43; N, 9.00.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH:14](O)[CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28].[OH2:42]>C1COCC1.C(OCC)(=O)C>[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=1)[C:33]([O:42][CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:18]=[CH:19][C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[O:34])([O-:29])=[O:28]
Reactant: CCC(O)Oc1ccc([C@H]2CC[C@H](CC)CC2)cc1
Reactant: O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H](c2ccc(OCCCOC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
In a 500-ml three-necked flask equipped with a stirrer was placed 300 ml of THF, and 18.0 g (0.068 mol) of 4-(trans-4-ethyl-cyclohexyl)phenoxypropanol obtained in the above-mentioned manner and 11.4 ml of triethylamine were added, followed by stirring at 0° C. Afterward, a solution obtained by dissolving 15.7 g (0.068 mol) of 3,5-dinitrobenzoyl chloride in 50 ml of THF was added dropwise to the flask over 30 minutes, and under this state, reaction was carried out for 6 hours. After the completion of the reaction, this solution was poured into 1 liter of water, and extraction was then made with 1.5 liters of ethyl acetate. In succession, the resultant organic layer was washed with 3N hydrochloric acid three times, a saturated sodium bicarbonate solution three times and water. The resultant ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. Next, the resultant crystal was recrystallized from ethyl acetate twice to obtain 23.3 g (0.051 mol) of [4-(trans-4-ethyl-cyclohexyl)phenoxypropyl] 3,5-dinitrobenzoate. Its melting point was in the range of 108.0° to 109.4° C. The structure of this compound was confirmed by IR and NMR.
Reaction SMILES: CCCC[N+](CC[CH2:16][CH3:17])(CCCC)CCCC.[F-].[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1.C1[CH2:28][O:27][CH2:26]C1>>[C:16]([C:19]1[CH:20]=[C:21]([CH2:26][O:27][CH3:28])[O:22][CH:23]=1)#[CH:17]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [F-]
Product: C#Cc1coc(COC)c1
Reaction time: 0.5 h

Procedure:
A mixture of partially purified 4-bromo-2-(methoxymethyl)furan (1.9 g) as obtained in Example 18-(2), AcOBu (16 mL), CuI (0.33 g), PdCl2(PPh3)2 (0.60 g), triisopropylsilylacetylene (9.6 mL) and TEA (12 mL) was stirred in a nitrogen atmosphere for 7.5 hours at 110° C. After the reaction mixture was allowed to cool, ethyl acetate (0.10 L), OH type silica gel (1.9 g), cellpure (0.95 g) and activated carbon (10 mg) were added. The insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=100/0→80/20) to obtain a yellow oil (1.7 g). THF (4.0 mL) was added to this oil (0.80 g), and a 1 mol/L TBAF-THF solution (4.1 mL) was added dropwise to the mixture under ice cooling. The mixture was stirred for 30 minutes under ice cooling, and then stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=100/0→90/10) to obtain 4-ethynyl-2-(methoxymethyl)furan (yellow oil) (0.24 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[CH2:14](Br)[C:15]#[CH:16].C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:16][C:15]#[CH:14])[CH:10]=2)[C:5]([CH3:13])=[N:4][N:3]=1
Reactant: Cc1nnc(Cl)c2cc(O)ccc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(C)nnc(Cl)c2c1
Temperature: 68 °C
Reaction time: 23 h
Yield: 55.4 %

Procedure:
The mixture of 4-chloro-6-hydroxy-1-methylphthalazine (5) (195 mg, 1.00 mmol), 80% propargyl bromide (1.30 mmol) in toluene (145 μL), K2CO3 (187 mg, 1.35 mmol), and acetone (8 mL) is stirred at 68° C. under argon for 23 h, then cooled to room temperature, and concentrated. The residue is diluted with H2O (50 mL) and extracted with ethyl acetate (70 mL and 60 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (33% to 50% ethyl acetate/hexane) to give 129 mg (55%) of 6 as a light-yellow solid, mp 169-171° C. IR 3077, 1401, 1217 cm−1; 1H NMR (CDCl3) δ 2.66 (t, J=2.4 Hz, 1H, C≡CH), 2.97 (s, 3H, CH3), 4.96 (d, J=2.4 Hz, 2H, CH2C≡CH), 7.62 (dd, J=9.3, 2.7 Hz, 1H, 7-PhthH), 7.69 (d, J=2.7 Hz, 1H, 5-PhthH), 8.05 ppm (d, J=9.3 Hz, 1H, 8-PhthH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].Cl>C(Cl)Cl>[C:41]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN)nc32)cc1OCc1c(F)cccc1OC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CNC(C)=O)nc32)cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a mixture of 2-aminomethyl-9-[2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (94 mg) and pyridine (0.1 mL) in methylene chloride (3 mL) was added acetic anhydride (0.055 mL), and the mixture was stirred at room temperature for 5 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate). The obtained product was suspended in diethyl ether, and collected by filtration. The collected material was dried under reduced pressure to give the title compound (44 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-])=O.BrC1C2C(Cl)=NC=NC=2N(C2CCCC2)C=1.[NH2:29][C:30]1[C:31]2[C:38](C(C3C=CC=C(N)C=3)=O)=[CH:37][N:36]([CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:32]=2[N:33]=[CH:34][N:35]=1>>[NH2:29][C:30]1[C:31]2[C:38]([C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[NH2:1])=[O:7])=[CH:37][N:36]([CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: Clc1ncnc2c1c(Br)cn2C1CCCC1
Product: Nc1ccccc1C(=O)c1cn(C2CCCC2)c2ncnc(N)c12

Procedure:
The title compound was prepared from 2-Nitrobenzoyl chloride and 5-Bromo-4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine by procedures analogous to those described for the preparation of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone. MS: 322.3 (MH+); HPLC Rf: 5.52 min. (HPLC method 4).