Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)=O.[S:5]([O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[CH:12][C:11]=1[CH3:20])(=[O:8])(=[O:7])[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[S:5]([O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19][CH3:1])=[CH:12][C:11]=1[CH3:20])(=[O:7])(=[O:8])[CH3:6]
Reactant: CC(C)=O
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C)c(OS(C)(=O)=O)cc1[N+](=O)[O-]
Yield: 77 %

Procedure:
To 200 ml of acetone, were added 19.1 g (77.3 mmol) of 2-methyl-4-hydroxy-5-nitrophenyl mesylate, 31.2 g of sodium carbonate and 19.2 g of dimethyl sulfate. The obtained mixture was heated under reflux for 3 hours. The reaction mixture was cooled and 700 ml of water was poured thereto. Then the mixture was extracted with 700 ml of chloroform, and the extract was washed with water and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the residue was recrystallized from a solvent mixture (hexane/acetone (2:1, by volume)) to thereby give 15.4 g (59.1 mmol) of 2-methyl-4-methoxy-5-nitropheyl mesylate. The yield was 77%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(Nc1ccccc1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to aniline via General Procedure B. The product was purified via reverse phase HPLC to give 6.4 mg of 247. MS (Q1) 456.8 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(OC(F)(F)F)cc1C=O
Yield: 85.1 %

Procedure:
The 2-amino-5-trifluoromethoxybenzyl alcohol from Step 2 (9.7 g, 47 mmol) and manganese (IV) oxide (21 g, 240 mmol) were refluxed in chloroform (200 mL) for 1 hour. The contents were allowed to cool and filtered. The filtrate was concentrated in vacuo leaving an amber oil (8.2 g) which solidified. The oil was distilled (bulb to bulb apparatus) at 50° C. (0.1 mm) to afford a yellow solid (7.2 g). The solid was recrystallized from hexanes to afford the desired 2-amino-5-(trifluoromethoxy)-benzaldehyde as yellow crystals (4.4 g, 46%): mp. 42–44° C. 1H NMR (CDCl3, 300 MHz) 9.81 (s, 1H), 7.36 (s, 1H), 7.20 (d, 1H, J=9.0 Hz), 6.64 (d, 1H, J=9.0 Hz). EIHRMS m/z 205.0328 (M+, Calc'd 205.0350).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C@@H:10]([C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[CH2:9]1)(=[O:7])=[O:6].[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[I-].[K+]>CN(C=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[S:18][C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)(=[O:7])=[O:6])[CH2:9][C@@H:10]3[C:29]([NH:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[O:30])(=[O:16])=[O:15])=[CH:21][CH:20]=2)=[CH:23][CH:24]=1
Reactant: C1CCNCC1
Reactant: O=C(NOC1CCCCO1)[C@H]1CN(S(=O)(=O)CCCCl)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)[C@H]1CN(S(=O)(=O)CCCN2CCCCC2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.4 %

Procedure:
A mixture of (2R)-4-(3-chloropropanesulfonyl)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (200 mg), piperidine (279 mg) and potassium iodide (65 mg) in DMF (3 ml) was stirred at ambient temperature for 2 days. The mixture was concentrated in vacuo. The residue was partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography eluted with MeOH in CHCl3 gradually from 0% to 5%, to give 165 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-[3-(-piperidino) propanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>ClCCl>[CH3:2][N:3]([CH3:4])[C:17]([C:16]1[CH:20]=[CH:21][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:18]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a mixture of dimethylamine hydrochloride (2.79 g) and triethylamine (6.92 g) in dichloromethane (50 ml) was added 4-bromobenzoyl chloride (5 g) was added slowly under ice-cooling, and the mixture was stirred for 20 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated invacuo to give 4-(dimethylcarbamoyl)-1-bromobenzene (5.20 g) as brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](OB(O)O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1cccc(OCc2ccccc2)c1
Reactant: O=C1C=CCC1
Product: O=C1CC[C@@H](c2ccc(OCc3ccccc3)cc2)C1
Yield: 104.5 %

Procedure:
3-Benzyloxyphenylboric acid (15.0 g, 66 mmol) and cyclopentenone (2.5 mL, 30 mmol) were used and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (8.35 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C@H:5]1[C:18](=[O:19])[N:8]2[C@@H](C3C=CC=CC=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1.C(O)=O.O>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[CH2:6][C@@H:7]([CH2:11][OH:10])[NH:8][C:18]1=[O:19]
Reactant: O=C1[C@H](CCCCl)C[C@H]2CO[C@H](c3ccccc3)N12
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1N[C@H](CO)C[C@H]1CCCCl
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
The (3R,6R,7aS)-6-(3-chloropropyl)-3-phenyl-dihydropyrrolo[1,2-c]oxazol-5(1H, 3H, 6H)-one (13.6 g, 47.9 mmol, 1.0 equiv) was dissolved in a mixture of THF (100 mL):formic acid (85%, 62.5 mL):H2O (31 mL) and the solution heated to 40° C. for 3.5 h. After this time the animal was consumed and the desired alcohol was contaminated with varying amounts of the formate ester. The solution was evaporated using a rotory evaporator, maintaining the bath temperature below 25° C. A solution of 1.9 M LiOH was added to the residue till a pH>12 was achieved and the mixture stirred for 20 min. After this time no formate ester was observed. EtOAc (250 mL was added and the mixture transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with 4×50 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered and evaporated. Hexanes (˜200 mL) were added to the residue and the biphasic mixture heated to ˜40° C. The hexanes were decanted off and the procedure repeated twice. The resulting syrup was placed on a vacuum line where it solidified to yield (3R,5S)-3-(3-chloropropyl)-5-(hydroxymethyl)pyrrolidin-2-one as an off-white solid (7.51 g 82% yield). An additional 0.80 g of material may be obtained by saturating the above aqueous solution with NaCl and extracting with 4×50 mL of CH2Cl2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)=[O:14])[CH2:9][CH2:8]1>C(#N)C.ClCCl>[CH:7]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:16]=[N:17][C:18]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:19][CH:20]=2)=[O:14])[CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Yield: 74.8 %

Procedure:
A mixture of piperazine (1.48 g, 17.2 mmol) and 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (1.29 g, 5.73 mmol) in acetonitrile (60 mL) was heated at reflux for 16 hours. After the reaction mixture was cooled, the gummy material was diluted with dichloromethane (50 mL), washed with water (2×20 mL), dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane (100%) then with methanol:dichloromethane (1:9) to obtain 1.18 g (75%) of the product as a solid.
Reaction SMILES: [N+:1]([C:4]1[NH:12][C:11]2[C:10](=[O:13])[NH:9][C:8]([NH2:14])=[N:7][C:6]=2[N:5]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>Cl.[Zn]>[NH2:1][C:4]1[NH:12][C:11]2[C:10](=[O:13])[NH:9][C:8]([NH2:14])=[N:7][C:6]=2[N:5]=1
Reactant: Nc1nc2nc([N+](=O)[O-])[nH]c2c(=O)[nH]1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1nc2nc(N)[nH]c2c(=O)[nH]1

Procedure:
The product of this reaction was analyzed in comparison with data on the published spectra of 8-nitroguanine. The reaction product was reduced by zinc-HCl or sodium hydrosulfite. Under these conditions, 8-nitroguanine is reduced to form 8-aminoguanine. This reduced product was compared by HPLC and spectral analysis with 8-aminoguanine synthesized by acid hydrolysis of commercially available 8-aminoguanosine.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:16])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)=O.[BH4-].[Li+]>O1CCCC1.O>[C:12]([O:11][C:9]([N:7]1[CH2:8][C:5]([CH2:3][OH:2])([CH3:16])[CH2:6]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO2006/73361 A1, 2006) (1.1 g) is dissolved in 20 mL of tetrahydrofurane. Lithiumborohydride (16.8 mL of a 2 M solution in tetrahydrofurane) is added dropwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water, washed with a saturated ammonium chloride water solution and the organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (hexane/ethyl acetate 100:0→50:50) to give the title compound. Yield: 970 mg.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:8][C:7]1[C:2]([F:1])=[C:3]([CH3:11])[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([F:10])[C:6]=1[CH3:9]
Reactant: Cc1cc(F)c(C)c(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)c(C)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
To 2,3,5-trifluoro-4-methyltoluene (1.9 g) is added conc. sulfuric acid (19 ml) and the mixture is cooled to 0° C., to which a solution of potassium nitrate (1.71 g) in conc. sulfuric acid (4.6 ml) is added dropwise below 10° C. and the mixture is stirred for 15 minutes. The mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloro-methane: n-hexane=1:6) to give 2,3,6-trifluoro-4-methyl-5-nitrotoluene (1.9 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:33].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:33].[ClH:33].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CN1CCN(CCCNc2ccc(N)cc2)CC1

Procedure:
The N-[3-(4-methyl-piperazin-1-yl)propyl]-4-nitro-1-aminobenzene (9) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20]I)[CH2:10][CH2:9][N:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) and 4′-hydroxy-4-biphenyl carbonitrile to afford the racemate as a white solid (181 mg, 79.6%)
Reaction SMILES: [C:1]12([CH2:8][O:9][C:10]3[C:22](Cl)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:24])[CH:11]=3)C[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:25]12[CH2:30][CH:29]1CC(COC1C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=1)C2>>[CH:5]12[CH2:4][CH:3]1[CH2:2][CH:1]([CH2:8][O:9][C:10]1[C:22]([CH:25]3[CH2:30][CH2:29]3)=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([F:24])[CH:11]=1)[CH2:6]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CC3CC3C2)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as a colourless solid (1.20 g, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 6.43 (d, J=12.7 Hz, 1H), 3.78 (d, J=7.4 Hz, 2H), 2.88-2.74 (m, 2H), 2.16-2.07 (m, 1H), 1.98-1.89 (m, 1H), 1.55 (s, 9H), 1.50 (d, J=4.5 Hz, 1H), 1.46 (d, J=4.5 Hz, 1H), 1.30-1.25 (m, 2H), 0.88-0.82 (m, 2H), 0.58-0.53 (m, 2H), 0.09-0.05 (m, 1H); MS (ES+) m/z 369.1 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[F:11][B-:12]([F:15])([F:14])[F:13].[H+].[N:17]([O-])=O.[Na+]>O>[F:11][B-:12]([F:15])([F:14])[F:13].[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([N+:6]#[N:17])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)cc(C)c1N
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cc(C)c1[N+]#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
21.2 g (0.104 mol) 4-bromo-2,6-dimethylaniline in 58.0 mL (0.444 mol) tetrafluoroboric acid (48% in water) were diluted with water to form a stirrable suspension. 7.18 g (0.104 mol) sodium nitrite, dissolved in water, were slowly added dropwise to the reaction mixture which was cooled to 0° C. After the addition had ended the mixture was stirred for 1 h at RT. The product precipitated as a solid was suction filtered, washed three times with diethyl ether and dried.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:1][CH:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1)[CH2:3][N:19]1[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]1
Reactant: c1ccc(-c2cc(C3CO3)no2)cc1
Reactant: OC1CCNCC1
Product: OC1CCN(CC(O)c2cc(-c3ccccc3)on2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of 3-(1,2-epoxyethyl)-5-phenylisoxazole (580 mg) and 4-hydroxypiperidine (625 mg) is stirred for 0.5 hour at 80°C and then the mixture is subjected to a column chromatography using silica gel to give 3-[1-hydroxy-2-(4-hydroxypiperidino ) ethyl]-5-phenylisoxazole (450 mg). Recrystallization from ethyl acetate-hexane gives colorless prisms (259 mg). M. p. 117-119°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[CH:12]=1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(C(C)C)CC)(C)C>>[CH2:22]([O:21][C:19](=[O:20])[NH:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:12]=[C:2]([Cl:1])[CH:3]=[C:4]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[C:5]=2[O:9]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1)OCc1ccccc1
Yield: 80.2 %

Procedure:
Treatment of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.45 g, 8.11 mmol) with benzyl chloroformate (2.07 g, 12.15 mmol) and diisopropylethylamine (3.43 g, 24.32 mmol) generally according to the procedure described for Intermediate 12 provided 2.6 g (81%) of (±)-benzyl(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 90-92° C.; Anal. calcd. for C21H18ClNO3S: C, 63.07; H, 4.54; N, 3.50. Found: C, 63.44; H, 4.51; N, 3.43. Chiral HPLC separation of (±)-benzyl(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt=11.538 min, (Chiralpak AD, hexane:ethanol 1:1); Fraction 2 (Rt=17.694 min, (Chiralpak AD, hexane:ethanol 1:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:21]=[C:22]=[O:23])(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:22]([NH2:21])=[O:23])[CH2:15][CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CCN(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 51.9 %

Procedure:
4-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) was dissolved in anhydrous dichloromethane (10 mL) and trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixture was stirred under argon at 25° C. for 3.25 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, evaporated to dryness and chromatographed on a silica gel column (15×5 cm) using 5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (308.2 mg, 52%): FABMS: m/z 272.0 (MH+); HRFABMS: m/z 272.1965 (MH+). Calcd. for C13H26O3N3: m/z 272.1974; δH (CDCl3) 1.20 (2H, m, CH2), 1.47 (9H, s, —COOC(CH3)3), 1.45–1.55 (3H, m, CH/CH2), 1.75 (2H, m, CH2), 2.82 (2H, m, CH2), 3.19 (2H, m, CH2), 3.96 (2H, m, CH2), 4.64 (2H, m, CH2) and 4.70 ppm (1H, bm, NH); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 31.8, 31.8, 36.7, 38.0, 44.5, 44.5; CH: 33.4; C: 79.2, 156.7, 158.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH:21]=O.[BH3-]C#N.[Na+].CC(O)=O>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][NH:11][C:10]1[CH:9]=[CH:8][NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1nc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1NCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A reaction mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.77 g, 4.99 mmol), 1H-benzoimidazole-2-carboxaldehyde (0.88 g, 5.99 mmol), NaCNBH3 (0.31 g, 4.99 mmol) and HOAc (0.57 mL, 9.99 mmol) in methanol (15 mL) was stirred at r.t. overnight. The mixture was then heated at 50° C. for 5 h. Cooled to r.t. and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate (1:0 to 0:1), obtaining 1.15 g (81%) of the title compound.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[S:28][CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:31]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[S:28][CH:29]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1nc(-c2ccccc2)cs1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc(-c4ccccc4)cs3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercapto-4-phenylthiazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(=O)C.O>[O:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:19]1[C:18]1[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Yield: 7.6 %

Procedure:
In an acetic acid solvent in the presence of sodium acetate (NaOAc) (3.0 eq.), a solution including 2-aminophenol (1.0 eq.) and 4-hydroxybenzaldehyde (1.0 eq.) was refluxed. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (4:1) to obtain a solid Compound 123.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:14]([NH:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c3c(cccc13)CC2
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c3c(cccc13)CC2
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
50 ml of glacial acetic acid was added to 6.77 g (0.04 mol) of 5-aminoacenaphthene and the mixture was stirred at 60° C. to dissolve, and 8.16 g (0.08 mol) acetic anhydride was dropwise added thereto for 15 minutes. After finishing the dropwise addition, the mixture was stirred at the same temperature for 2 hours. The reaction was determined to be finished when disappearance of 5-aminoacenaphthene was identified. The reaction product was poured into 500 ml of ice water to precipitate a crystal, which was then filtrated, washed with water and dried. As this result, 8.15 g (yield: 96.4%, melting point: 180.0°-186.0° C.) of 5-(N-acetylamino)acenaphthene was obtained.