Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17](Cl)[C:16]=2[N:15]=[C:14]1[OH:27])(C(C)(C)C)(C)C.[NH3:28]>CO>[NH2:28][C:17]1[C:16]2[N:15]=[C:14]([OH:27])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCn1c(O)nc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(O)n2CCCCO
Temperature: 150 °C

Procedure:
1-[4-(tert-Butyldimethylsilanyloxy)butyl]-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol (5.0 g, 12 mmol) and ammonia (200 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 150° C. for five days, allowed to cool, and concentrated under reduced pressure. The crude product was triturated with hexane for 15 minutes, and the resulting solid was isolated by filtration, washed with hexane (500 mL), and dried under vacuum to provide 3.53 g of 4-amino-1-(4-hydroxybutyl)-1H-imidazo[4,5-c]quinolin-2-ol as a light gray solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:16][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1cc(C(=O)c2cccnc2)oc1C
Solvent: CO
Product: Cc1cc(O)c(-c2cccnc2)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(3-pyridyl)-methanone (1.8 g), methanol (30 ml), and a 28% aqueous ammonia solution (30 ml) were placed in a sealed tube and were stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using hexane-ethyl acetate to give 5,6-dimethyl-[2,3′]-bipyridin-3-ol (1.1 g, yield 63%).
Reaction SMILES: C([NH:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[C:9]([Cl:24])=[C:8]([F:25])[N:7]=1)(C)(C)C>FC(F)(F)C(O)=O>[NH2:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[C:9]([Cl:24])=[C:8]([F:25])[N:7]=1
Reactant: CC(C)(C)Nc1nc(F)c(Cl)c(N2C(=O)c3ccccc3C2=O)c1F
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(F)c(Cl)c(N2C(=O)c3ccccc3C2=O)c1F
Temperature: 70 °C

Procedure:
To 80 ml of trifluoroacetic acid was added all amount of the N-[2-(t-butylamino)-5-chloro-3,6-difluoropyridine-4-yl]phthalimide, and the mixture was stirred at 70° C. for 5 and half hours. The solution was concentrated under reduced pressure. The precipitate was dispersed in chloroform, and collected by filtration to obtain 19.5 g of the title compound as a colorless powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:21])=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[N:14]=1)=O)C.[NH3:22]>CO>[Cl:21][C:9]1[N:8]=[N:7][C:6]([C:4]([NH2:22])=[O:3])=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[N:14]=2)[CH:10]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(CC)n1
Solvent: CO
Product: CCc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reaction time: 3 h
Yield: 100 %

Procedure:
6-Chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (241 mg, 0.786 mmol) was suspended in 7M ammonia in methanol (9 mL). After 3 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (218 mg, 100%) as an off-white solid which was used directly in the next step without purification. LCMS (EI/CI) m/z: 278 [M+H].
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[N:5][N:6]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([O:7][C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[N:5][N:6]=1
Reactant: COc1ccc(Oc2nnc(Br)s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Oc2nnc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of Example 24A (1.63 g, 5.67 mmol) in CH2Cl2 (75 mL) was cooled to −78° C. and the resulting suspension was treated with BBr3 (22.67 mmol, 2.14 mL) drop wise over 2 minutes. The reaction was stirred at 25° C. for 2 hours and was poured into a 200 mL ice/water mixture. The resulting bilayer was stirred vigorously for 0.5 hours and a white precipitate formed. The solids were filtered, washed with water (1×20 mL) and dried in a vacuum oven to provide 1.35 g (87%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.79 (br. s, 1H) 7.27 (d, J=9.19 Hz, 2H) 6.84 (d, J=9.19 Hz, 2H); MS (DCI) m/z 275 (M+H)+.
Reaction SMILES: [F:1][CH:2]([C:21]1[O:22]CC(C)(C)N=1)[CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(Cl)(Cl)Cl.[OH2:32]>Cl>[F:1][CH:2]([CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:21]([OH:22])=[O:32]
Reactant: CCCCCC=CCCCCC#CCC#CCCC(F)C1=NC(C)(C)CO1
Reactant: O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\CCCCC#CCC#CCCC(F)C(=O)O
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A suspension of 2-(1-fluorononadec-13-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole (86 mg) in 3 ml of 3 N HCl was refluxed with stirring under argon for 15 min. It was cooled to about 23° C., diluted with 3 ml of water, and extracted three times with ether. The ether extracts were combined, washed with brine, and dried over MgSO4. Concentration of ether at 35° C./35 mmHg gave the crude acid which was purified by flash chromatography on silica gel (8 g, 230-400 mesh). Elution with HOAc-CH3OH--CHCl3 under nitrogen afforded 49 mg (66% yield by weight) of (Z)-2-fluoro-14-eicosene-5,8-diynoic acid as a colorless oil.
Reaction SMILES: [ClH:1].O=C1C2C3C(=CC=CC=3C(=O)N1CCCC[N:21]1[CH2:26][CH2:25][CH:24]([N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]1)C=CC=2.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]1[C:54](=[O:55])[C:53]2[CH:56]=[CH:57][CH:58]=[C:51]3[C:52]=2[C:47](=[CH:48][CH:49]=[CH:50]3)[C:46]1=[O:59].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[O:59]=[C:46]1[C:47]2[C:52]3[C:51](=[CH:58][CH:57]=[CH:56][C:53]=3[C:54](=[O:55])[N:45]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][N:21]1[CH2:22][CH2:23][CH:24]([N:27]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:25][CH2:26]1)[CH:50]=[CH:49][CH:48]=2
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: CCC(=O)N(c1ccccc1)C1CCN(CCCCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1

Procedure:
Following the procedure of part (b) of example 31 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains N-[1-[6-(1,3-dihydro-1,3-dioxo-2H-benz[de]isoquinolin-2-yl)hexyl]-4-piperidinyl]-N-phenylpropanamide, hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2C=CC=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)C>CN(C=O)C.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:51][CH2:52][CH3:53])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and ethylamine (41.3 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26.2 mg, 78%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]=2[CH:20]=1.O>ClCCl>[C:5]([C:12]1[C:13]2[O:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]=2[CH:20]=[C:10]([Br:9])[CH:11]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A stirred, cooled (ice-bath) suspension of aluminum chloride (0.25 g, 1.7 mmol) in 3 mL of anhydrous dichloromethane was treated with acetyl chloride (0.2 mL, 2.6 mmol) under argon. A solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 0.22 g) in 1.5 mL of anhydrous dichloromethane was cannulated into the clear solution, and the resulting deep red solution was allowed to warm to ambient temperature over 1 h. The reaction mixture was poured onto iced water and extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a dirty white solid. Flash column chromatography on silica gel (230-400 mesh) using 6% ethyl acetate in hexane as the eluent afforded the title compound as a white solid (0.177 g, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][CH2:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].B.C1COCC1>>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CSc2ccc([N+](=O)[O-])cc2N1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)NCCS2
Temperature: 25 °C

Procedure:
6-nitro-2H-benzo[b][1,4]thiazin-3(4H)-one (4 g, 19 mmol) was stirred in BH3-THF (285 mL, 258 mmol) at reflux overnight. After this time the reaction mixture was cooled to rt and quenched with MeOH. The reaction was partitioned between EtOAc and water. The separated organic layer was dried over Mg2SO4 and evaporated in vacuo to give 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine that was used without further purification in the next step. Mass Spectrum (ESI) m/e=197 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36](OCC)=[O:37])(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:45])(=[O:44])[N:19]=1.[OH-].[NH4+:47]>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([NH2:47])=[O:37])(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:45])(=[O:44])[N:19]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)Nc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4cccnc4n(CCC(C)C)c2=O)N3)c1
Agent: [OH-]
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)Nc4cccc(C(N)=O)c4)ccc3N2)c(O)c2cccnc21

Procedure:
A solution of the product of Example 454 (7.6 mg, 0.012 mmol) in 1 mL of ammonium hydroxide was stirred at 25° C. for 17 hours. The solvent was evaporated under a stream of warm nitrogen to provide the title compound (7.4 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=6.62 Hz, 6 H) 1.47 (m, 2 H) 1.64 (m, 1 H) 4.30 (m, 2 H) 7.14 (m, 1H) 7.28 (m, 6 H) 7.43 (s, 1 H) 7.49 (d, J=7.72 Hz, 1 H) 7.66 (s, 1 H) 7.87 (s, 1 H) 8.36 (dd, J=7.54, 1.65 Hz, 1 H) 8.54 (s, 1 H) 10.45 (bs, 1 H) 10.51 (bs, 1 H) 15.89 (bs, 1 H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[C:16](=[O:25])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CCOCC.[ClH:33]>CO.C(Cl)Cl.CCOCC>[ClH:33].[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C@H:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[C@H:16]([OH:25])[CH2:15]3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O[C@@H]1C[C@@H](CN2CCC(c3ccccc3)CC2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.7 g (2.1 mmol) of (±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one were dissolved in 40 mL of MeOH and 0.35 g of NaBH4 were added portionwise. The reaction mixture was stirred 2 h at room temperature, the MeOH removed in vacuo, then the residue was taken up in 1N NaOH and extracted with CH2Cl2. The organic phase was dried and the solvent was removed in vacuo. The crude product was purified by chromatography, eluting with CH2Cl2 and then with a mixture CH2Cl2/MeOH 100:3 respectively, yielding 100 mg of trans isomer which was dissolved in a mixture CH2Cl2/Et2O: The solution was brought to acidic pH with Et2O/HCl and the solvent was removed in vacuo. The resulting solid was triturated with hot acetone, filtered and dried, yielding 90 mg of the title compound. m.p.>250° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:23][CH2:24]Cl.O>CS(C)=O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([C:13]2([C:14]([O:16][CH3:17])=[O:15])[CH2:24][CH2:23]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
The compound (1.76 g) obtained in step 1 was dissolved in DMSO (30 mL), sodium hydride (0.59 g) was added at 0° C., and the mixture was stirred for 5 min. To the reaction mixture was added 2-bromo-1-chloroethane (0.77 mL), and the mixture was stirred at room temperature for 45 min. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (10% ethyl acetate/hexane) to give methyl 1-[3,5-bis(trifluoromethyl)phenyl]cyclopropanecarboxylate (1.80 g, 94%).
Reaction SMILES: F[C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[CH3:15][OH:16].C[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:16][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccsc2cc1F
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2ccsc2cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In 35 ml of N,N-dimethylformamide is dissolved 7.00 g of methyl 6-fluorobenzo[b]thiophene-5-carboxylate, to which is added 7.1 mL of a 28% methanol solution of sodium methoxide. The mixture is stirred at 80° C. for 4 hours. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: hexane:ethyl acetate=20:1 to 3:1) to obtain 6.30 g of methyl 6-methoxybenzo[b]thiophene-5-carboxylate as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
3-Bromophenyl isocyanate (21.12 g, 107 mmol) was added slowly to a stirred solution of 2,2,2-trifluoroethyl amine (40 ml, 0.5 mol) in THF (100 mL) at 0° C. under N2, rinsing with THF (25 mL). The reaction was allowed to warm slowly to RT and kept at this temperature for 16 hours. The volatiles were removed under reduced pressure to give the title compound (31.6 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (1H, s), 7.80 (1H, t), 7.31-7.24 (1H, m), 7.20 (1H, t), 7.16-7.08 (1H, m), 6.83 (1H, bt), 3.98-3.85 (2H, m).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.O=[C:8]1[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])[CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[N:1]1[N:2]=[C:3]([NH:6][CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])[CH2:9]2)[NH:4][CH:5]=1
Reactant: CCCOC(=O)C1CC(=O)C1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOC(=O)C1CC(Nc2nnc[nH]2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a solution (100 mL) of 1H-1,2,4-triazol-3-amine (6.7 g) and propyl 3-oxocyclobutanecarboxylate (14 g) in acetic acid was added sodium cyanoborohydride (14 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (8.8 g, 49%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].[C:30]([C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.O>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([S:40][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:38][CH:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product from Example 242a (600 mg, 1.828 mmol) was dissolved in DMF (20 ml) to which K2CO3 (505 mg, 3.656 mmol), and 4-tert-Butyl-benzenethiol (304 mg, 1.828 mmol) were added. This reaction mixture was then heated to 80° C. for 1 hr. At this time the reaction mixture was cooled to room temperature, diluted with water, and the title compound collected by filtration (311 mg, 35%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:16][C:15](=[O:17])[O:14][C:11]3=2)[O:6][CH2:5]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:18]([NH:2][CH2:3][CH:4]1[O:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:16][C:15](=[O:17])[O:14][C:11]3=2)[O:6][CH2:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H]1COc2ccc3[nH]c(=O)oc3c2O1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2ccc3c(c2o1)OC(CNCc1ccccc1)CO3
Temperature: 50 °C

Procedure:
(8S)-8-Aminomethyl-7,8-dihydro-3H-1,6,9-trioxa-3-aza-cyclopenta[a]-naphthalen-2-one hydrochloride (0.49 g, 1.8 mmole), benzyl bromide (0.20 mL, 1.8 mmole) and 0.31 mL (1.8 mmole) of N,N-diisopropylethylamine were combined in 20 ml DMSO and heated at 50° C. under nitrogen for 6 hours. After completion, the reaction was cooled to room temperature and partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed and washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using first methylene chloride, then 1% methanol in methylene chloride to elute the dialkylated product and finally 3% methanol in methylene chloride to elute the monoalkylated product (0.16 g, 28%). The latter was recrystallized from ethanol with the addition of a solution of fumaric acid (0.065 g) in hot ethanol to give 0.06 g of the (S)-enantiomer of the title compound as an off-white solid hemifumarate, one-quarter hydrate, m.p. 220° C.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:9]1[CH:13]=[N:12][C:11]([SH:14])=[N:10]1.C[O-].[Na+]>CO>[NH:9]1[CH:13]=[N:12][C:11]([S:14][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10]1
Reactant: Sc1nc[nH]n1
Reactant: BrCC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CCCCC2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Cyclohexylmethyl bromide (42 ml; 0.30 mol) was added over 5 min to 1,2,4-triazole-3-thiol (30.3 g; 0.30 mol) and sodium methoxide (17.3 g; 0.32 mol) in dry methanol (250 ml) under dry nitrogen. The mixture was refluxed for 4 h, stirred at room temperature overnight and evaporated. The residue was dissolved in ethyl acetate (400 ml) and water (200 ml). The organic phase is separated, washed with water (100 ml), dried (Na2SO4), filtered and its volume reduced by evaporation, causing a solid to precipitate. The solid was filtered off and dried, to afford cyclohexylmethyl 1,2,4-triazol-3-yl sulfide (48.0 g; 81%) as white plates, m.p. 74°-78° C. (Found, C: 54.98; H: 7.85; N: 21.32; S: 16.13. C9H15N3S requires C: 54.79; H: 7.66; N: 21.30; S: 16.25%). NMR - d(CDCl3 ; 90 MHz) 0.50-2.10 (11H, m), 3.1 (2H, d, J=6.4 Hz), 8.13 (1H, s) and 13.9 (1H, br s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:11]([C:21]([O:23]CC)=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>C(O)(=O)C>[ClH:26].[CH2:1]([N:8]1[CH2:13][C:12]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:11]([C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(c2ccc(F)cc2)CN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C1=C(c2ccc(F)cc2)CN(Cc2ccccc2)CC1
Temperature: 100 °C
Yield: 78 %

Procedure:
To the compound (11.1 g) obtained in step 1 were added acetic acid (25 mL) and hydrochloric acid (25 mL), and the mixture was heated at 100° C. for 2 hr. The reaction mixture was cooled and concentrated to give 1-benzyl-5-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid monohydrochloride (8.82 g, 78%). 1H-NMR (DMSO-d6): δ 2.70-2.80 (2H, m), 3.10-3.60 (2H, m), 3.85-4.00 (2H, m), 4.30-4.50 (2H, m), 7.18-7.25 (4H, m), 7.42-7.48 (3H, m), 7.62-7.68 (2H, m), 11.3-11.5 (1H, brs), 12.4-13.0 (1H, br)