Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH:14]1([N:20]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=O)c1cccn1C
Reactant: NC1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)C(=NC1CCCCC1)c1cccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 25 g ethyl 1-methylpyrrole-2-glyoxylate and 44.5 g cyclohexylamine in 700 ml ether under nitrogen at 0° C. is added 8.8 ml of titanium tetrachloride in 80 ml pentane. After stirring at room temperature overnight, the precipitate is removed by filtration. The filtrate is evaporated and the resulting oil distilled. The fraction collected at 111°-117° C. (5 millitorr) is crystallized from hexane to afford a 15% yield of ethyl α-cyclohexylimino-1-methylpyrrole-2-acetate, m.p. 35°-36° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]#[N:13])[CH2:11][CH2:10]1.C(=O)([O-])[O-:15].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([NH2:13])=[O:15])[CH2:10][CH2:11]1
Reactant: N#CC1(c2ccc(Cl)cc2Cl)CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(2,4-Dichloro-phenyl)-cyclopropanecarbonitrile (2.1 g, 10 mmol) was dissolved in DMSO (10 ml) and the solution cooled to 0° C. using an ice bath. Potassium carbonate (0.2 g, 1.5 mmol) was then added, followed by commercial 30% aqueous hydrogen peroxide (2 mL). The reaction was then allowed to warm to room temperature with stirring over 1 h. Water (20 mL) was added and the 1-(2,4-dichloro-phenyl)-cyclopropanecarboxylic acid amide collected as a white solid. Yield: 2.1 g (90%).
Reaction SMILES: [CH:1](=O)[CH3:2].Cl.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][NH:32][CH2:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:15](=[O:34])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][N:32]([CH2:1][CH3:2])[CH2:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:15](=[O:34])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCCC2
Reactant: CC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
Acetaldehyde (50 μL, 0.88 mmol) and picoline borane complex (47 mg, 0.43 mmol) were added to a suspension of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (64 mg, 0.18 mmol) in 10:1 CH2Cl2/AcOH (5.0 mL), and the resulting solution was stirred at ambient temperature for 2 h. Additional acetaldehyde (50 μL, 0.88 mmol) was added to the solution, and the resulting mixture was stirred for 18 h. The mixture was neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) provided the title compound (34 mg, 54%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.39-7.37 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.14 (s, 2H), 3.88 (s, 2H), 3.66 (s, 3H), 3.03-3.01 (m, 2H), 2.94 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 2H), 1.78-1.76 (m, 2H), 1.01 (t, J=7.0 Hz, 3H); ESI MS m/z 428 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH:28]([S:30]([CH:33]=C)(=[O:32])=[O:31])=[CH2:29]>>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][CH2:28][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: C=CS(=O)(=O)C=C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CCS(C)(=O)=O)C3)cc1OCC2

Procedure:
Following the procedure for 152, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with vinyl sulfone to give 191 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1H, d, J=8.28 Hz), 7.84 (1H, s), 7.60 (1H, s), 7.05 (1H, dd, J=8.32, 1.83 Hz), 6.94 (1H, d, J=1.78 Hz), 5.99-5.89 (1H, m), 4.48-4.39 (4H, m), 3.78-3.70 (2H, m), 3.71-3.62 (1H, m), 3.25-3.18 (2H, m), 3.04 (3H, s), 3.02-2.95 (4H, m), 1.56 (6H, d, J=6.64 Hz). LCMS: RT=5.58 min, M+H+=457
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][O:23][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 1,4-di(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (5.05 g) and p-toluenesulfonyl chloride (4.34 g) in methylene chloride (200 ml) was cooled to 0° C., followed by the dropwise addition of triethylamine (11 ml). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure. After dilution with ethyl acetate, the residue was washed with 1N hydrochloric acid, water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane=1/4 to 1/1) using, as a carrier, silica gel, whereby the title compound (4.82 g) was obtained as a colorless solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:22]=[CH:21][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.O>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Sodium azide (210 mg, 1.15 eq) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene (901 mg) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours, poured into water, and extracted with diethyl ether (3×). The organic phase was washed with water (3×), dried (MgSO4), and evaporated to dryness. Chromatography on silica gel, eluting with hexane/ethyl acetate, gave 4-(4-azidomethylbenzyl)-nitrobenzene (492 mg, 62%) as a yellow oil.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=1)=[O:19].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:15][C:16]2[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:29])[F:30])[CH:22]=2)=[O:19])=[CH:9][CH:8]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccccc2C(=O)Nc2ccc(Br)c(C(F)(F)F)c2)cn1
Reaction time: 16 h

Procedure:
Sodium cyanoborohydride (8.80 g of 95%, 133 mmol) is added in portions over 30 minutes to a stirred mixture of acetic acid (3.8 mL), 6-methoxy-3-pyridinecarboxaldehyde (Fluka, Buchs, Switzerland; 7.80 g, 57 mmol) and 2-amino-N-(4-bromo-3-trifluoromethylphenyl)-benzamide (step 1.2; 13.65 g, 38 mmol) in methanol (380 mL) at 25° C. The mixture is stirred for 16 hours. The solvent is evaporated under reduced pressure to give a residue which is treated with a saturated aqueous solution of sodium hydrogen carbonate (500 mL) and extracted with dichloromethane (3×150 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product that is purified by column chromatography on silica gel, eluent 5% ethyl acetate in dichloromethane and recrystallised from diethylether-hexane to give the title compound as a beige crystalline solid, m.p. 101–103° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20]([N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([CH3:1])[CH2:3]2)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(Cl)c1Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cc(Cl)c(Cl)c(C(=O)O)c2)C1
Reaction time: 1.5 h

Procedure:
To cis-3,5-dimethylpiperidine (374 mg.; 3.3 m moles) in 3 ml. of methylene chloride is added 192 mg. (0.66 m moles) of 2,3-dichloro-5-chlorosulfonylbenzoic acid and the mixture heated to refluxfor 1.5 hrs. The solvent is removed under reduced pressure, and the residueis partitioned between 25 ml. of 1N sodium hydroxide solution and diethyl ether. The aqueous layer is separated, acidified with 6N hydrochloric acidand the resulting precipitated product filtered and dried, 230 mg., m.p. 235°-238° C. Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH:22]=[CH:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.O>[C:30]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: N[n+]1ccc2occc2c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)nn2ccc3occc3c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.9 %

Procedure:
To a mixture of 5-aminofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.00 g, 3.14 mmol) and potassium carbonate (608 mg, 4.40 mmol) in dimethylformamide (20 mL) was added methyl 3-phenylpropiolate (509 μL, 3.45 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (467 mg, yield 51%).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)=[CH2:2].I[C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1.C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)/[CH:2]=[CH:1]/[C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: C=Cc1cnc(Nc2ccc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cn1
Reactant: Oc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Nc3cnc(/C=C/c4cccc(O)c4)cn3)cc2)CC1
Temperature: 120 °C
Yield: 78.5 %

Procedure:
A mixture of tert-butyl 4-(4-(5-vinylpyrazin-2-ylamino)phenylsulfonyl)piperazine-1-carboxylate (40 mg, 0.09 mmol), 3-iodophenol (19 mg, 0.09 mmol), Pd(OAc)2 (1.2 mg, 0.005 mmol), tri-p-tolylphosphine (2.5 mg, 0.008 mmol), and DIEA (31 μL, 0.18 mmol) in DMF (3 ml) was heated at 120° C. for 18 h after which, it was filtered with a pad of celite and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (20% to 40% Ethyl acetate/Hexane) as a solvent to afford title compound (38 mg, 78% yield). MS m/z: 538 [M+1].
Reaction SMILES: CON(C)[C:4](=[O:18])[C@H:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:20]([Mg]Br)=[CH2:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:4](=[O:18])[CH:20]=[CH2:21])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: C=C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: C=CC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
A solution of 1.01 g (3.69 mmol) of the resultant compound of Example 29 in 50 ml of anhydrous tetrahydrofuran was cooled under N2 atmosphere to -78° C. and treated with 16 ml (9.6 mmol) of vinylmagnesium bromide (0.6M in tetrahydrofuran). The resulting solution was allowed to warm to ambient temperature, stirred for 1.5 h, and poured over a mixture of ice and 10% aqueous citric acid. The mixture was extracted with ether, washed with saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 12% ethyl acetate in hexane provided 0.48 g (58%) of the desired compound (Rf 0.48, 7:3 hexane:ethyl acetate). 1H NMR (CDCl3) δ 0.93 (d, J=7 Hz, 3 H), 1.00 (d, J=7 Hz, 1 H), 1.3-1.45 (m, 2 H), 1.43 (s, 9 H), 1.74 (m, 1 H), 4.65 (td, J=9, 4 H, 1 H), 5.09 (br d, 1 H), 5.88 (dd, J=10, 2 Hz, 1 H), 6.38 (dd, J=18, 2 Hz, 1 H), 6.48 (dd, J=18, 10 Hz, 1 H). Mass spectrum: (M+H)+ =242.
Reaction SMILES: [CH3:1][O:2][C:3]([O:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=C.[O:12]=[O+][O-]>CO>[CH3:11][O:10][C:3]([O:2][CH3:1])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:12]
Reactant: C=CC(CCCC)(OC)OC
Reactant: O=[O+][O-]
Solvent: CO
Product: CCCCC(C=O)(OC)OC

Procedure:
1 liter of a solution of 237 g (1.5 moles) of n-butylacrolein dimethylacetal in methanol is reacted with ozone analogously to the procedure indicated in Example 1 and is then hydrogenated. The absorption of H2 is 29 standard liters.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[O:22][CH2:21][CH2:20][CH2:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(OCC)(=O)C>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[O:22][CH2:21][CH2:20][CH2:19]4)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CCCO4)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6c(c5O4)CCCO6)CC3)c2c1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of 0.55 g (1.5 mmole) of (2R)-2,3,9,10-tetrahydro-8H-[1,4]-dioxino[2,3-f]chromen-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (4.6 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 6 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0.5% methanol in chloroform to give 0.34 g of the desired product as a pale yellow foam. This was crystallized from ethanol with the addition of 0.10 g of fumaric acid to give 0.24 g of the (S)-enantiomer of the title compound as a pale yellow solid, m.p. 205-206° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]([F:17])([F:16])[C:13](O)=O>>[CH3:10][O:9][C:3]1[C:2]2[NH:1][C:13]([C:12]([F:17])([F:16])[F:11])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(N)c1N
Product: COc1cccc2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,3-diaminoanisole (1.0 g) in trifluoroacetic acid (15 ml) was refluxed for 5 h and then stirred at room temperature overnight. Excess trifluoroacetic acid was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase was washed with saturated sodium bicarbonate solution (50 ml) and water (50 ml). Drying over anhydrous sodium sulfate and removal of the solvent in vacuo gave a brown residue. Purification by column chromatography eluting with 50% ethyl acetate in hexane gave the title compound as a yellow solid (1.4 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH3:11])[CH2:7][CH2:8][OH:9].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.NC(C)CCCN(CC)CCO>>[CH3:11][CH2:10][N:6]([CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:14]1[CH:15]=[CH:16][N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][C:20]([Cl:24])=[CH:19]2)[CH3:12]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CCN(CCO)CCC[C@H](C)N
Agent: CCN(CCO)CCCC(C)N
Product: CCN(CCO)CCC[C@H](C)Nc1ccnc2cc(Cl)ccc12

Procedure:
(S)-(+)-Hydroxychloroquine was prepared by condensing (S)-(+)-2-[(4-aminopentyl)ethylamino]ethanol with 4,7-dichloroquinoline. The latter compound is known. The (S)-(+)-2-[(4-aminopentyl)ethylamino]ethanol was prepared by resolving known racemic 2-[(4-aminopentyl)ethylamino]-ethanol by forming a salt thereof with known (S)-(+)-mandelic acid and separating the (S)-(+)-mandelic acid salts of the two enantiomers by crystallization.
Reaction SMILES: [C:1]([C:5]([NH:7][C@@H:8]([C@@H:13]([C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=2[Cl:30])[N:16]=1)[CH3:14])[C:9]([O:11]C)=[O:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[OH-].[Li+]>O>[C:1]([C:5]([NH:7][C@@H:8]([C@@H:13]([C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=2[Cl:30])[N:16]=1)[CH3:14])[C:9]([OH:11])=[O:10])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](NC(=O)C(C)(C)C)[C@H](C)c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the ester from Step C (1 g, 2.11 mmol) in 50 mL of a 4:1 solution of tetrahydrofuran:water at 0° C. was added a solution of lithium hydroxide monohydrate (0.3 g, 6.33 mmol) in 8 mL of water. After stirring at 0° C. for 1 h, the THF was removed by evaporation under reduced pressure and 10 mL of 2N hydrochloric acid was added. The aqueous solution was extracted with three portions of ethyl acetate. The combined organic layers were washed with saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo to afford the product which was used in the next step without purification. LC/MS 360.0 (M+1-BOC).
Reaction SMILES: [S:1]([CH:4]([CH2:8][CH2:9][Cl:10])[C:5](=O)[CH3:6])[C:2]#[N:3].P(=O)(O)(O)[OH:12]>O>[OH:12][C:2]1[S:1][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:6])[N:3]=1
Reactant: CC(=O)C(CCCl)SC#N
Reactant: O=P(O)(O)O
Solvent: O
Product: Cc1nc(O)sc1CCCl
Temperature: 20 °C
Yield: 95 %

Procedure:
355,3 g (2 moles) of distilled 3-thiocyanato-5-chloro-2-pentanone are added into 360 cm3 of 85% phosphoric acid under stirring. The temperature of the reaction mixture is increased to 95° C. in water bath within about 1 hour and then it is stirred for half and hour between 95° to 100° C. The brown solution is cooled to 20° C. and poured into 660 cm3 of water. The precipitated beige crystals are removed by suction after a stirring for half an hour, washed neutral with water and dried in vacuo at a temperature of 60° C. 337 g (95%) of pale beige 2-hydroxy-4-methyl-5-(2-chloroethyl)thiazole are obtained, m.p.: 151°-152° C. After recrystallization from benzene the melting point is 157°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH2:14])=[N:11][C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCBr)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
9-Fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-amine (150 mg, 0.640 mmole) was dissolved in 3 ml of dry THF, mixed with triethylamine (135 μl, 0.970 mmole), cooled in an ice bath and treated with 5-bromovaleryl chloride (90 μl, 0.67 mmole). The mixture was stirred at room temperature for 3 days. TLC analysis of the mixture showed 50% completion. Hence, a catalytic amount of DMAP was added and stirring was continued for 16 hours. There was no change in the TLC of the mixture. 5-Bromovaleryl chloride (90 μl) was added and stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and saturated sodium carbonate and the aqueous phase separated and extracted with 2×3 ml ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution, concentrated and chromatographed (silica, Ethyl acetate/hexanes) to give 179 mg of the desired product as a white foam (70%): 397, 399 (ESMS, MH+).