Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:13]([OH:24])[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:24][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:25])([F:26])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[C@@H:14]([NH:16][C:17]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:23])[CH3:15])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl ((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamate (2.0 g, 5.16 mmol) and triethylamine (1.15 ml, 8.26 mmol) at 0° C. in DCM (20 ml) was added methanesulfonyl chloride (0.48 ml, 6.2 mmol). The reaction was stirred at 0° C. for 1 hour and then was quenched with a saturated solution of NH4Cl. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The product was purified by column chromatography to yield (2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate. The crude material was judged to have a 9:1 diastereomeric ratio by 1H NMR analysis. 1H NMR (500 MHz, CDCl3): δ 7.91 (s, 1H); δ 7.87 (s, 0.1H); δ 7.84 (s, 2H); 5.73 (d, J=4.3 Hz, 1H); δ 5.21 (d, J=7.0 Hz, 0.1H); δ 4.58 (s, 1H); 4.18 (br s, 1H); 3.02 (s, 3H); 1.39 (s, 9H); 1.25 (d, J=6.9 Hz, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O>CN(C=O)C>[N:1]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Temperature: 90 °C
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, sodium azide (29.8 g, 458 mmol) was added to a solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (118 g, 416 mmol) in DMF, and the reaction was heated at 90° C. for six hours. The reaction was allowed to cool to room temperature overnight, and then the solvent was removed under reduced pressure. Water (1 L) was added, and the resulting solution was extracted with diethyl ether (4×500 mL). The combined extracts were washed with water (1×250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 93.0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH3:41])[CH:44]=3)(=[O:51])=[O:50])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2Cl)c1
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran (5 mL), 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) under ice-cooling and the mixture was stirred for 45 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 501 mg, 98%).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)C(C)C)(C)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:4][CH2:1][C:2]#[CH:3])(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A solution of propargylamine (2 mL, 29 mmol) and N,N-diisopropylethylamine (10 mL, 57.4 mmol) in methylene chloride (100 mL) was cooled to 0° C. 2-nitrobenzenesulfonyl chloride (6.46 g, 29.2 mmol) was added portionwise. Upon complete addition, the solution was allowed to warm to room temperature and was further stirred at room temperature overnight. The reaction solution was concentrated in vacuo and the residue obtained was directly purified on silica chromatography (20-50% EtOAc/hexane) to afford Intermediate 14 as white solid (5.90 g, 84%). LC-MS: (FA) ES+241; 1H NMR (400 MHz, CDCl3) δ 8.22-8.17 (m, 1H), 7.94-7.89 (m, 1H), 7.79-7.73 (m, 2H), 5.71 (s, 1H), 4.02 (dd, J=5.9, 2.4 Hz, 2H), 1.97 (t, J=2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11][O:12]CC)[C:6](OCC)=O)[CH3:2].[CH3:16][S:17][C:18](=[NH:20])[NH2:19].CC[O-].[Na+]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:11]([OH:12])=[N:19][C:18]([S:17][CH3:16])=[N:20][CH:6]=1)=[O:15])[CH3:2]
Reactant: CSC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1O
Temperature: 5 °C
Reaction time: 3 h
Yield: 158.1 %

Procedure:
To a solution of 2-ethoxymethylenemalonic acid diethyl ester (59.0 g, 273 mmol) in EtOH (300 mL) was added 2-methyl-isothiourea (41.5 g, 150 mmol) in an ice-H2O bath. An EtOHic solution of EtONa (2M, 300 mL) was added dropwise maintaining the reaction temperature under 5° C. The mixture was warmed to RT and stirred for 3 h. After standing overnight, the solvent was removed under reduced pressureand the residue was dissolved in H2O (800 mL) at 0° C. The solution was acidified to pH 3 with conc. HCl and the precipitate collected by filtration and air-dried to yield 4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a white solid (50.8 g, 87.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 4.20 (q, J=9.6 Hz, 2H), 2.51 (s, 3H), 1.23 (t, J=9.6 Hz, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:18]=[C:17]([C:19]2[O:24][C:23](=[O:25])[C:22]3[CH:26]=[C:27]([N+:31]([O-:33])=[O:32])[CH:28]=[C:29]([CH3:30])[C:21]=3[N:20]=2)[N:16]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[N:15]=1>O.CN(C)C=O>[Br:13][C:14]1[CH:18]=[C:17]([C:19]([NH:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([N+:31]([O-:33])=[O:32])=[CH:26][C:22]=2[C:23]([N:4]([CH3:3])[NH:5][CH3:6])=[O:25])=[O:24])[N:16]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[N:15]=1
Reactant: Cc1cc([N+](=O)[O-])cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CNNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNN(C)C(=O)c1cc([N+](=O)[O-])cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.26 g of N,N′-dimethylhydrazine dihydrochloride, 2 ml of water, 0.5 g of potassium carbonate and 10 ml of N,N-dimethylformamide was added 0.20 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-6-nitro-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-bromo-1-(3-chloro-2-pyridinyl)-N-[2-(N,N′-dimethylhydrazinocarbonyl)-6-methyl-4-nitrophenyl]-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[CH2:30]([NH2:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].CCN(C(C)C)C(C)C>C1C=CC=CC=1.C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:36][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:25])=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCCCN
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCNC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a solution of 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.050 g, 0.132 mmol) in benzene (2 mL) was added thionyl chloride (1.5 mL) at 5-10° C. The reaction mass was refluxed for 3 h. To a solution of hexan-1-amine (0.020 g, 0.198 mmol) in THF (5.0 mL), DIPEA (0.086 g, 0.663 mmol) was added under N2-atmosphere at RT. The solution was stirred for 1 h at RT and above prepared solution was added to reaction mixture. The whole reaction mass was stirred at RT for 1 h. Thionyl chloride was removed under vacuum and stripped out with THF. The reaction mass was quenched in ice water and extracted with ethyl acetate. The organic layer was concentrated. The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 0.83-0.85 (s, 3H), 1.26 (s, 6H), 1.51-1.54 (m, 2H), 2.61 (s, 3H), 3.30 (m, 2H), 7.30 (s, 1H), 7.57 (s, 3H), 7.90 (s, 1H), 9.30 (s, 1H), 11.40-11.50 (s, 1H); MS [M+H]+: 460.41
Reaction SMILES: [N:1]1C=C2C(N=CN2)=NC=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[N:17]=[C:18]([CH2:29][N:30]3[C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=4[N:32]=C3)[N:19]([C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:21])[C:12]=12>>[NH2:39][C:38]1[C:33]2[N:32]=[N:1][N:30]([CH2:29][C:18]3[N:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH3:28])[C:20](=[O:21])[C:12]4[C:13](=[CH:14][CH:15]=[CH:16][C:11]=4[CH3:10])[N:17]=3)[C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: c1ncc2[nH]cnc2n1
Reactant: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(C)c2c1=O
Product: Cc1ccccc1-n1c(Cn2nnc3c(N)ncnc32)nc2cccc(C)c2c1=O

Procedure:
1H NMR (300 MHz, d6-DMSO) δ: 8.43 (br s, 1H), 8.19 (s, 1H), 8.10 (br s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.49-7.28 (m, 5H), 7.22 (d, J=8.1 Hz, 1H), 5.49 (d, J=17.0 Hz, 1H), 5.19 (d, J=17.0 Hz, 1H), 2.73 (s, 3H), 2.11 (s, 3H). Alkylation at purine N7 determined by similarity to nmr spectrum of D-030. LRMS (ES pos.) m/z=399 (M+1).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[O:22]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=2)[O:13][C:11]2([CH2:12][NH:9][CH2:10]2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CNC1)O2)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4 M HCl in dioxane (1.90 ml) was added dropwise to a solution of (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (360 mg, 0.78 mmol) in DCM (14 ml). The mixture was stirred at RT overnight. The formed precipitate was filtered off, washed with DCM, dried under vacuum to give (E)-3-[4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (154 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=3[N:9]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH:22]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[C:10](=O)[CH2:11][C:5]2=[N:4][N:3]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O>[CH3:1][C:2]1[N:6]2[C:7]3[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=3[N:9]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH:22]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[CH2:10][CH2:11][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1ccccc1N(CCCN1CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC1)C(=O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1ccccc1N(CCCN1CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC1)CC2
Yield: 28 %

Procedure:
To 1.1 g of the compound of Example 211, 20 ml of tetrahydrofuran is added and then 0.17 g of lithium aluminum hydride is added. The resulting mixture is heated to reflux for 30 minutes. To the resultant, 0.82 g of lithium aluminum hydride is added and the mixture is heated to reflux for 20 minutes. To the resulting mixture, ethyl acetate and water are added and the precipitate is removed by filtration using Celite. The filtrate is condensed and purified by silica gel column chromatography (ethyl acetate:methanol=7:1-6:1) to obtain 0.30 g of (213).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]([OH:23])=[O:22])=[O:17].[CH3:24]O>S(Cl)(Cl)=O>[CH3:24][O:22][C:21]([CH:19]1[CH2:20][CH:18]1[C:16](=[O:17])[NH:15][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:7][C:2]=1[F:1])=[O:23]
Reactant: CO
Reactant: O=C(O)C1CC1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CC1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A stirred suspension of (1RS,2SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid (140 mg) in MeOH (5 ml) was cooled to 0° C. and treated with thionyl chloride (10 drops). The mixture turned immediately into a clear solution. Stirring was continued for 3 hrs at 0° C. Then the reaction mixture was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2−>CH2Cl2/MeOH) to give (1RS,2SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid methyl ester (84 mg) as colorless amorphous solid. MS: 353.4 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[C:8]1([C:14]2[O:18][N:17]=[C:16]([CH2:19][NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][C:22]=3[NH2:31])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>C(#N)C>[CH2:1]([O:3][CH2:4][C:5]1[N:20]([CH2:19][C:16]2[CH:15]=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:18][N:17]=2)[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCc1cc(-c2ccccc2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOCc1nc2cnc3ccccc3c2n1Cc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A solution of ethoxyacetyl chloride (0.87 g, 7.1 mmol) in acetonitrile (10 mL) was added to a solution of N4-[(5-phenylisoxazol-3-yl)methyl]quinoline-3,4-diamine (2.05 g, 6.48 mmol) in acetonitrile (100 mL), and the solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in 3:1 ethanol:water (100 mL). Solid sodium hydroxide (389 mg, 9.72 mmol) was added, and the solution was heated at reflux overnight. The ethanol was removed under reduced pressure, and the resultant aqueous solution was adjusted to pH 5 with the additional of dilute hydrochloric acid. The acidic solution was extracted several times with dichloromethane, and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 4% to 6% methanol in dichloromethane to provide 0.650 g of 2-(ethoxymethyl)-1-[(5-phenylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 5-methyl-3-(2-methyl-5-nitrophenylsulfonyloxy)phenol (1.46 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.6 g, 8.0 mmol) and 1,3-propanediol (2.3 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (2.0 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (80 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a yellow oil (920 mg, 48%). 1H-NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.37 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.89 (s, 3H), 2.25 (s, 3H), 1.99 (m, 2H), 1.58 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([CH3:14])=[C:7]([CH:13]=1)[C:8]([O:10]CC)=[O:9])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([CH3:14])=[C:7]([CH:13]=1)[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCOC(=O)c1cc(CC)cnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1cnc(C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 1.4 %

Procedure:
A solution of 260 g of ethyl 5-ethyl-2-methylnicotinate 81.34 mol) in 250 mL methanol is treated in 1 portion with a solution of 80 g of sodium hydroxide (2 mol) in 1 L water. The reaction is stirred at room temperature for 2 days, then concentrated in vacuo to a volume of about 700 mL, and acidified with 167 mL of concentrated hydrochloric acid (2 moles). The precipitated solid is filtered, washed with cold water, and dried in vacuo at 75° C. to afford 184 g of the title product, mp 218°-220° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1.[H-].[Na+].P(O)(O)([O-])=O.[Na+].C(Cl)Cl.O1C[CH2:30][CH2:29][CH2:28]1>>[O:1]=[C:2]1[N:6]([CH2:30][C:29]#[CH:28])[C:5]([C:7]([F:8])([F:9])[F:10])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)F
Reactant: C1CCOC1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCn1c(C(F)(F)F)c(C(=O)OCC)sc1=O

Procedure:
6.9 g of ethyl 2,3-dihydro-2-oxo-4-trifluoromethyl-5-thiazole-carboxylate [prepared by the process of CA 92 110 998P] were dissolved in 70 ml of tetrahydrofuran at 0° ± 5° C. and then, 1.44 g of 50% sodium hydride in oil were added. Once the gaseous evolution ended, 15 ml of 2-bromopropyne were added and the mixture was refluxed for 48 hours. The mixture was poured on to an iced solution of monosodium phosphate and extraction was carried out with methylene chloride, then drying, filtering and concentrating under reduced pressure. The residue was chromatographed and elution with a hexane-ethyl acetate mixture (85-15) yielded 5.57 g of the expected product.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]1=[O:12].C(O)(=O)C.CO>[Cl-].[Na+].O.[Zn]>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:4][C:3](=[O:12])[CH2:2][C:10]=12
Reactant: O=C1Nc2nccc(Cl)c2C1(Br)Br
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Cc2c(Cl)ccnc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A mixture of 3,3-dibromo-4-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (0.745 g, 2.3 mmol), zinc dust (1.49 g, 23 mmol), acetic acid (10 mL) and methanol (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with brine and extracted with ethyl acetate. The organic layer was further washed with brine, dried over anhydrous sodium sulfate, concentrated and dried in a vacuum oven to give 0.3 g (78%) of 4-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a tan solid. 1H NMR (360 MHz, DMSO-d6) δ 11.21 (s, br, NH), 8.01 (d, J=5.66 Hz, 1H), 7.23 (d, J=5.66 Hz, 1H), and 3.59 (s, 2H, CH,). MS m/e 168 [M+].
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:31].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:31].[ClH:31].[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(NCCCN2CCCC2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCCN2CCCC2)cc1

Procedure:
The N-(3-pyrrolidin-1-ylpropyl)-4-nitro-1-aminobenzene (13) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:3])[CH3:2].[CH:10]1[CH:11]=[CH:12][C:13]2[NH:18][CH:17]=[C:16]([CH2:19][CH2:20]O)[C:14]=2[CH:15]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:2][C:1]1([CH:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[C:17]2[NH:18][C:13]3[C:14]([C:16]=2[CH2:19][CH2:20][O:3]1)=[CH:15][CH:10]=[CH:11][CH:12]=3
Reactant: CC(=O)C1CCOC1=O
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21

Procedure:
To a solution consisting of 3-acetyldihydro-2(3H)-furanone (25.6 g, 0.2 mole), tryptophol (32.2 g, 0.2 mole) and benzene (700 ml), p-toluenesulfonic acid (0.50 g) is added. The flask is equipped with a water separator and a condenser. The mixture is stirred at reflux for one hr. More p-toluenesulfonic acid (0.50 g) is added and the solution is refluxed for 18 hr. The dark solution is cooled and stirred in presence of silica gel (100 g) for 5 min. The mixture is filtered on diatomaceous earth and charcoal. The silica gel is washed with diethyl ether (2×100 ml) and the filtrates are evaporated to afford an oil which is a mixture of two diasteroisomers of the title compound. If desired, the latter oil can be crystallizated from methanol to obtain crystals (17 g) of isomer A of the title compound, mp 162°-164° C. The mother liquor of this crystallization is evaporated to obtain a residue (20 g) containing mainly isomer B of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:9]([C:10]([O:12]C)=[O:11])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:15][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:9]=1[C:10]([OH:12])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
The title compound was prepared in analogy to example 2.10 from methyl 5-(methanesulfonyl)salicylate and benzylalcohol. MS (m/e): 305.3 (M−H, 100%)