Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1([C:11]2[CH:12]=[CH:13][C:14](/[C:19](/[C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)=[CH:20]/[CH2:21][CH2:22][NH2:23])=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1.Cl>N1C=CC=CC=1>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14](/[C:19](/[C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)=[CH:20]/[CH2:21][CH2:22][NH:23][C:1](=[O:3])[CH3:2])=[N:15][C:16]=2[O:17][CH3:18])[CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc(/C(=C/CCN)c2ccc(SC)cc2)ccc1C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: COc1nc(/C(=C/CCNC(C)=O)c2ccc(SC)cc2)ccc1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (85 mg) was added to a solution of (3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-amine (95 mg) in pyridine (1 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to give N-{(3E)-4-(5-cyclopropyl-6-methoxypyridin-2-yl)-4-[4-(methylsulfanyl)phenyl]but-3-en-1-yl}acetamide as a colorless amorphous (87 mg, 81%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[CH3:15][NH2:16]>CO>[CH3:13][N:12]([CH3:14])[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:16][CH3:15])[CH:7]=1
Reactant: CN(C)c1cccc(OCCCCl)c1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
The crude (3-(3-chloropropoxy)phenyl)dimethylamine (4.06 g, 19.01 mmol) was dissolved in methanol (30 mL) and added to a 40 wt % aqueous solution of methylamine (75 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred at ambient temperature for 16 h, followed by heating at 87° C. (oil bath temperature) for 3 h. After cooling, the solution was concentrated by rotary evaporation to a lavender-brown semi-solid. Saturated NaCl solution (35 mL) was added. The mixture was acidified to pH 1 with 10% HCl solution and extracted with CHCl3 (5×30 mL) to remove impurities. The dark-brown aqueous layer was basified to pH 7 with 30% NaOH solution and extracted with ether (4×40 mL) to remove impurities. The brown aqueous layer was basified with 30% NaOH solution to pH 12 and extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation, producing an oil. The product was dried briefly under high vacuum to afford 2.24 g (56.6%) of a dark-brown oil.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[C:3]=1[CH:19]=[O:20].[O:21]1CCC[CH2:22]1.CO.[H-].[Na+]>O>[CH:19]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[N:5][N:6]([CH3:7])[C:2]=1[O:21][CH3:22])=[O:20]
Reactant: C1CCOC1
Reactant: Cc1cc(-c2nn(C)c(Cl)c2C=O)ccc1OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C=O)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Reaction time: 3 h

Procedure:
At room temperature, to a mixture of 5-chloro-4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 96) 4.8 g and tetrahydrofuran 100 ml was added methanol 0.6 g and 55% sodium hydride 0.8 g, and the resulting mixture was stirred for three hours. To the reaction mixture was added water 50 ml, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole 4.5 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=[C:4]([CH3:21])[N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH3:21])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]2=[O:18]
Reactant: CCOC(=O)C(=CNc1ccc(C)nc1Cl)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2c(Cl)nc(C)cc2c1=O
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-(((2-chloro-6-methyl-3-pyridinyl)amino)methylene)malonate (Preparation 42, 0.59 g) is added to diphenyl ether (15 mL) and the mixture is degassed by alternately bubbling in nitrogen then subjecting to high vacuum. The mixture is heated rapidly to reflux and after 30 minutes cooled to room temperature. Diphenyl ether is distilled away under high vacuum and the residue taken up in CH2Cl2 (40 mL). The solid is collected by filtration and washed with CH2Cl2 with a second crop obtained by reducing the solvent volume of CH2Cl2 filtrate and collecting more solid. The title compound is obtained as a pale green powder, 0.24 g (47%). Physical characteristics: MS (ESI+) m/z 267 (M+H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:2]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]([NH:12][C:19](=[O:20])[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][C:9]([C:13]([F:15])([F:14])[F:16])=[N:8]2)[CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)c1
Yield: 57.6 %

Procedure:
Following the procedure in Example 118A, 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.58 mmol) and phenyl chloroformate (0.60 mL, 4.74 mmol) were reacted to give phenyl 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate (330 mg, 0.91 mmol, 58%). 1H NMR (300 MHz, DMSO-d6) δ 10.4 (br s, 1H), 7.62-6.85 (m, 10H), 2.46 (s, 3H); LC-MS (ESI) m/z 362 (M+H)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH:7]=[N:6]2.Br[CH:16]([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C>[CH2:20]([O:19][C:17]([CH2:16][CH2:22][CH2:23][CH2:24][CH2:25][N:9]1[C:10]2[C:5](=[CH:4][C:3]([Cl:2])=[C:12]([Cl:13])[CH:11]=2)[N:6]=[CH:7][C:8]1=[O:14])=[O:18])[CH3:21]
Reactant: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CCCCC(Br)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCCCn1c(=O)cnc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 10.5 %

Procedure:
Under a nitrogen atmosphere sodium (0.148 g, 6.42 mmol) was dissolved in 50 ml of abs. ethanol and 6,7-dichloroquinoxalin-2(1H)-one (1.20 g, 5.58 mmol) (Liebigs Ann. Chem., (1982), 754) was added. The mixture was stirred until the compound dissolved, and ethyl 2-bromohexanoate (1.30 ml, 7.1 mmol) was added. The reaction mixture was refluxed for 72 h, cooled to room temperature, then poured onto crushed ice and acidified by dilute hydrochloric acid (pH=2). The precipitated compound was extracted with ethyl acetate and purified by column chromatography on silica gel (eluent 15% THF in heptane) to afford 0,21 g of 1-((1-ethoxycarbonyl)pentyl)-6,7-dichloroquinoxalin-2(1H)-one 1H-NMR(DMSO-d6):δ 0.78(t, 3H), 1.1(t, 3H), 1.15-1.35(m, 4H), 2.0-2.25(m, 2H), 4.02-4.18(m, 2H), 5.58-5.75(m, 1H), 8.02-8.36(broad, 1H), 8.18(s, 1H), 8.33(s, 1H).
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:25][CH3:26])=[C:22]([Pb+3])[CH:23]=2)=[CH:16][CH:15]=1.[CH:29]12[CH2:36][CH:33]([CH:34]=[CH:35]1)[C:32](=[O:37])[CH2:31][C:30]2=[O:38].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:25][CH3:26])=[C:22]([CH:31]3[C:32](=[O:37])[CH:33]4[CH2:36][CH:29]([CH:35]=[CH:34]4)[C:30]3=[O:38])[CH:23]=2)=[CH:16][CH:15]=1
Reactant: O=C1CC(=O)C2C=CC1C2
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C=CC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4′-chloro-4-ethylbiphen-3-yllead triacetate (0.478 g, 0.80 mmol) in chloroform (5 ml) is added bicyclo[3.2.1]oct-6-ene-2,4-dione (0.097 g, 0.72 mmol) (preparation described by R. Beaudegnies et al., WO2005/123667) and 4-dimethylaminopyridine (0.36 g, 2.86 mmol), and the reaction mixture is stirred at room temperature for 5 minutes. Next toluene (1 ml) is added, and the mixture is stirred at 80° C. for 2 hours (pre-heated oil bath). The reaction mixture is allowed to cool to room temperature, quenched with 2M hydrochloric acid and the inorganic precipitate removed by filtration. The organic phase is separated, and the aqueous phase is further washed with dichloromethane (×2), and again the phases are separated. All organics are combined then evaporated under reduced pressure to give a brown gum. This crude product is first purified by preparative reverse-phase HPLC, then also by flash column chromatography on silica gel (20% to 100% ethyl acetate/hexane eluant ratio) to afford 3-(4′-chloro-4-ethylbiphen-3-yl)bicyclo[3.2.1]oct-6-ene-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([O:13]CC)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([S:22][C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[O:28][CH3:29])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([N:26]2[C@H:23]([S:22][C:19](=[O:21])[CH3:20])[C@@H:24]([O:28][CH3:29])[C:25]2=[O:27])[OH:13])=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(C)=O
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
714 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 4 g of molecular sieve A4 are added to a solution of 245 mg of (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 8 ml of toluene and 2 ml of dimethylformamide and the mixture is stirred overnight at room temperature. The molecular sieves are filtered off from the mixture and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel, and by elution with toluene/ethyl acetate (9:1 and 4:1) the title compound, contaminated with some glyoxylate, is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.O.[OH-].[Li+]>CO>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CCCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CCCC2)c1Cl
Temperature: 80 °C
Yield: 92.2 %

Procedure:
5-Chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.710 g, 2.93 mmol) was dissolved in methanol (4.3 mL). Water (4.3 mL) and lithium hydroxide (0.097 g, 4.05 mmol) were added and the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, methanol was removed in vacuo. Tetrahydrofuran was added to the residue and then removed in vacuo to ensure complete removal of the methanol. The residue was diluted with water and treated with 6N HCl to pH 2-3, resulting in precipitation of a milky solid. The solid was collected, washed with water and dried under house vacuum at 45° C., yielding 5-chloro-1-cyclopentyl-1H-pyrazole-4-carboxylic acid (0.580 g, 91%). This material was used as is without any further purification.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH2:21][CH2:22][O:23][CH2:24][CH:25]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1>[Pd].CO>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(C3=CCOCC3)cc12
Agent: [Pd]
Solvent: CO
Product: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(C3CCOCC3)cc12
Reaction time: 60 h

Procedure:
A 25-mL flask was charged with (S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (211 mg, 0.601 mmol) and MeOH (7507 μL). The mixture was sonicated for 1 min to give an opaque mixture. Palladium on carbon (63.9 mg, 0.060 mmol) was added, and H2 (g) was bubbled through the mixture for 1 min. The mixture was stirred further under a balloon of H2 (g) for 60 hours. The mixture was filtered through celite with the aid of methanol. The filtrate was evaporated, and the residue was chromatographed on a 40-g Redi-Sep column with 0-100% of a 90:10:1 mix of DCM/MeOH/NH4OH to give (S)-2′-amino-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4N4C=NN=N4)=[CH:20][CH:19]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:35]1[CH:39]=[N:38][N:37]=[N:36]1>>[CH:1]1([CH2:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:39]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:20][CH:19]=3)[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1nnn[nH]1
Reactant: CCCCc1nc(CC2CCCCC2)nn1Cc1ccc(-c2ccccc2-n2cnnn2)cc1
Product: CCCCc1nc(CC2CCCCC2)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The slower moving isomer from Example 73 was deprotected to provide 51 mg of 5-[4′-[(3-cyclohexylmethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl]([1,1-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ 0.84 (t, J=8 Hz, 3H), 0.92 (q, J=8 Hz, 2H), 1.05–1.22 (m, 3H), 1.22–1.36 (m, 2H), 1.52–1.69 (m, 8H), 2.5–0 (d, J=7 Hz, 2H), 2.63 (t, J=8 Hz, 2H), 5.18 (s, 2H), 7.05 (q, J=8 Hz, 4H), 7.35–7.55 (m, 3H), 7.68 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 456 (90), 413 (10), 281 (10), 243 (10), 222 (35), 207 (100), 192 (35); HRMS. Calc'd for M+H: 456.2876. Found: 456.2849.
Reaction SMILES: C([CH:8]([CH2:22]CCCN)[CH:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:14][N:15]=1)O)(OC(C)(C)C)=O.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28].[CH2:34](Cl)Cl>>[OH:33][C:27]([C:29]([F:32])([F:31])[F:30])=[O:28].[N:19]1[CH:18]=[CH:17][C:16]([C:13]2[O:12][C:11]([CH:9]([CH3:34])[CH2:8][CH2:22][CH2:29][CH2:27][OH:33])=[N:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)C(CCCCN)C(O)c1nnc(-c2ccncc2)o1
Solvent: O=C(O)C(F)(F)F
Product: CC(CCCCO)c1nnc(-c2ccncc2)o1
Reaction time: 1 h

Procedure:
2-(2-Boc-amino-1-hydroxyhexyl)-5-(4-pyridyl)-1,3,4-oxadiazole (950 mg, 2.62 mmol) and MeCl2 (5 ml) were mixed and TFA (1 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 2-amino-1-(5-(4-pyridyl-[1,3,4]oxadiazol-2-yl)-1-hexanol TFA salt (1 g); MS: 263.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(OC([NH:33][C@@H:34]([CH3:41])[CH2:35]OS(C)(=O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:33][C@@H:34]([CH3:41])[CH2:35][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with methanesulfonic acid (S)-2-tert-butoxycarbonylamino-propyl ester (described in WO 2005100321) gave, after treatment with TFA and subsequent neutralization, the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[F:20][CH:21]([F:24])[CH2:22][NH2:23].CO>C1COCC1>[F:20][CH:21]([F:24])[CH2:22][NH:23][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: NCC(F)F
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1cccc(F)c1)Nc1nc(CNCC(F)F)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Iodomethyl-thiazol-2-yl)-3-(3-fluorobenzyl)-urea (Intermediate 7, 1 eq.) was taken up in THF (0.3 M) and 2,2-difluoroethanamine (20 eq.) was added. The reaction was stirred overnight at ambient temperature. Some of the starting material, Intermediate 7 remained. Added additional 2,2-difluoroethanamine (10 equivalents). The reaction was complete after 2-4 hours. Removed solvent; coevaporated twice with MeOH. Crude is a 1:1 mixture of title compound and bis addition impurity. (used as is in subsequent step).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:5][C:6]2[O:11][C:10](=[O:12])[CH:9]=[CH:8][C:7]=2[CH:13]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.CO.Cl>C(O)(C)C>[OH:17][CH:16]([CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:34])[F:19])[CH:22]=2)[CH2:32][CH2:31]1)[CH2:15][O:14][C:4]1[C:3]([O:2][CH3:1])=[CH:13][C:7]2[CH:8]=[CH:9][C:10](=[O:12])[O:11][C:6]=2[CH:5]=1
Reactant: COc1cc2ccc(=O)oc2cc1OCC1CO1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2ccc(=O)oc2cc1OCC(O)CN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 80 %

Procedure:
Method C (1.5 d at 45° C.); starting materials: 6-methoxy-7-(oxiranylmethoxy)-2H-1-benzopyran-2-one (example 86) and 1-(3-trifluoromethylphenyl)piperazine; yield 80%; fusion point 133°-135° C. (from methanol). Hydrochloride: method F; yield 83%; fusion point 125°-128° C. (decomposes; from isopropanol).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17](O)=[O:18])[CH2:12][CH2:11]3)=[O:5].[CH3:29][NH:30][CH3:31].N>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17]([N:30]([CH3:31])[CH3:29])=[O:18])[CH2:12][CH2:11]3)=[O:5]
Reactant: O=C(Nc1sc2c(c1C(=O)O)CC1CCC2O1)c1c(F)cccc1C(F)(F)F
Reactant: CNC
Agent: N
Product: CN(C)C(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 4A and dimethylamine according to the procedure described for Example 4B. MS (DCI/NH3) m/z 443 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.C(OCC)(=O)C>O.Cl.[Fe]>[NH2:12][C:5]1[C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[C:2]([Cl:1])=[CH:3][C:4]=1[F:15]
Reactant: Cc1nc2c(Cl)cc(F)c([N+](=O)[O-])c2s1
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2c(Cl)cc(F)c(N)c2s1
Temperature: 80 °C

Procedure:
6 g of iron powder were added to a suspension of 8 g (32 mmol) of 4-chloro-6-fluoro-2-methyl-7-nitrobenzothiazole in 100 ml of water and 9 ml of concentrated hydrochloric acid, which suspension had been heated to 80° C., after which the mixture was refluxed for 3 hours. 200 ml of ethyl acetate were then added to the reaction mixture. The solid was filtered off. The remaining organic phase was washed with water, dried over magnesium sulfate and finally evaporated down. Yield: 4.5 g.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOCC>[CH2:1]([C@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C1CC[C@H](Cc2ccccc2)C1
Yield: 90.7 %

Procedure:
Prepared according to the general procedure from 3-benzylcyclopent-2-enone (172 mg, 1 mmol) for 24 h at 0° C. After the reaction mixture was passed though a short pad of silica gel, the resulting mixture was poured into 5 mL of a 10% HCl solution and diluted with 5 mL of Et2O. The organic layer was washed with 5 mL of a 10% HCl solution (4×) and with 5 mL of water (1×). The resulting solution was dried over MgSO4 and concentrated in vacuo to provide the title compound as a colorless oil (158 mg, 91% yield, 90% ee) after purification by flash chromatography on Iatrobeads® (2% Et2O/benzene). The physical data were identical in all respects to those previously reported (Yanagisawa et al. (1994), J. Am. Chem. Soc. 116:6130; and Moritani et al. (2000), J. Am. Chem. Soc. 122:6797 (reported an optical rotation of −96° for the (S) isomer that is 96% ee)). The enantiomeric ratio was determined by GLC using a Hydrodex-B-TBDAc (50 m×0.25 mm) column (145° C. isotherm, 1 mL/min.); (S) isomer tr=91.5 min. and (R) isomer tr=90.1 min. [α]D2=+83.9 (c=1.00, CHCl3).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (101 mg, 90%), MS (ISP) m/z=449.3 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]=2)[C:6]([CH3:24])=[CH:5][C:3]=1[NH2:4].CO.O([CH:29](OC)[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[S:14][N:13]=[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]=2)[C:6]([CH3:24])=[CH:5][C:3]=1/[N:4]=[CH:29]\[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(OC)N1CCCCC1
Reactant: Cc1cc(N)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(/N=C\N2CCCCC2)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Yield: 34.6 %

Procedure:
0.30 g (0.79 mmol) of 2-chloro-4-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-thiadiazol-5-yl}oxy)-5-methylaniline is dissolved in 3 ml of toluene and 0.75 ml of methanol and treated with 0.37 g (2.37 mmol) of 1-(dimethoxylmethyl)piperidine. The reaction mixture is refluxed for 18 h, subsequently cooled, freed from the solvent under vacuum and purified by column chromatography. 0.13 g of product is obtained (84.2% purity, 29.3% yield, log P (pH 2.3)=2.64).