Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CCCCCI
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Yield: 43.8 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopentane (0.130 mL, 1.0 mmol) to give the title compound (0.072 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([C:27]3[C:28]4[C:23](=[C:22]([N:21]([CH3:36])[CH3:20])[CH:31]=[CH:30][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCCn3cnc4c(N)nc5ccccc5c43)cccc12
Temperature: 60 °C

Procedure:
A suspension of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 2.0 mmol) in pyridine (250 mL) was warmed to 60° C. to dissolve the amine. The solution was allowed to cool to about 30° C. and then 5-dimethylamino-1-naphthalenesulfonyl chloride (0.5 g, 1.8 mmol) was slowly added. After 1 hour 0.3 g of 5-dimethylamino-1-naphthalenesulfonyl chloride was added. The reaction mixture was warmed to 60° C. and maintained at that temperature overnight. The reaction mixture was concentrated under vacuum. The residue was recrystallized from propyl acetate to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamide as a solid, m.p. 200-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24]([NH:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: COc1ccc(-c2csc(N)n2)cc1
Product: COc1ccc(-c2csc(NS(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)n2)cc1

Procedure:
The title compound was prepared from 4-(4-methoxy-phenyl)-thiazol-2-ylamine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic MEIHOD B to give a white-yellow solid (58.2 mg) with purity >90%. MS (pos) m/z 449.1, 451.1, 453.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]1([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:18][NH:17][C:15](=[O:16])[CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: NNC(=O)Cc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCCl)NNC(=O)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
To 4-chlorobutyryl chloride (1.12 ml, 10 mmol) in dry DCM (10 ml) was added, dropwise, over 40 min, a mixture of phenylacetic hydrazide (1.5 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (40 ml) at room temperature. A dense white precipitate formed. After a further 20 min. 2M HCl (30 ml) was added and the title compound (white solid) was filtered off, washed with water and dried (2.24 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].C1COCC1.Br[CH2:28][CH:29]([O:32][CH3:33])[O:30][CH3:31]>CN(C)C=O>[CH3:31][O:30][CH:29]([O:32][CH3:33])[CH2:28][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: Oc1ccc2ncccc2c1
Reactant: COC(CBr)OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(COc1ccc2ncccc2c1)OC
Reaction time: 6 h

Procedure:
To a cooled (0° C.) solution of quinolin-6-ol (5.81 g, 40 mmol) in N,N-dimethylformamide (30 mL) was slowly added a 1M solution of sodium hexamethyldisilazane in THF (40 mL, 40 mmol). The mixture was stirred for 15 min after which 2-bromo-1,1-dimethoxyethane (5.18 mL, 44 mmol) was added. The reaction mixture was then refluxed conditions for 6 h. The solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (100 mL) and washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes. (0-50%) to give the desired product. (9 g, 96%) LCMS: (M+H)+=233.9.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:16])[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]1)[CH3:2].[ClH:17]>>[ClH:17].[ClH:17].[CH2:1]([NH:3][CH2:4][C:5]1([OH:16])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH3:2]
Reactant: CCNCC1(O)CCN(C(=O)OCC)CC1
Agent: Cl
Product: CCNCC1(O)CCNCC1

Procedure:
4.6 g (20 mmol) of ethyl 4-ethylaminomethyl-4-hydroxypiperidine-1-carboxylate is heated overnight under reflux with 35 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are triturated with acetone, filtered off with suction and dried in a vacuum desiccator over P4O10.
Reaction SMILES: F[C:2]1[C:22]([F:23])=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CS(C)=O>[F:23][C:22]1[C:2]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[CH:3][C:4]2[N:13]=[CH:12][C:11]3[N:10]([CH3:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=3[C:5]=2[CH:21]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3c2c1=O
Temperature: 90 °C
Reaction time: 96 h
Yield: 34.1 %

Procedure:
A suspension of 1.5 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 1.7 g of 1-(4-fluorophenyl)piperazine in 30 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 4 days. After cooling to 20° C., the mixture was poured into 150 cm3 of ice-cold water. The medium was extracted 3 times with 150 cm3 of dichloromethane. The organic extracts were washed 3 times with 100 cm3 of water and dried over sodium sulphate. After filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was purified by chromatography on silica gel (0.06-0.20 mm). Elution was carried out with 7.8 liters of a dichloromethane-ethanol mixture (97-3 by volume), and 200 cm3 fractions were collected. The fractions between 5.6 and 7.8 liters were concentrated under reduced pressure (5.2 kPa). 0.77 g of ethyl 9-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of yellow crystals, which melted at 300° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:12][CH:11]([C:13]2[O:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:10]2=[C:19]3[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]3=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[N:9]2[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>C(#N)C.O>[N:43]1([CH2:6][C@@H:7]2[O:12][C@@H:11]([C:13]3[O:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:10]3=[C:19]4[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]4=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[N:9]3[CH2:8]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: c1c[nH]cn1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](COS(C)(=O)=O)C3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)[C@H](c1ccc(Cl)o1)O[C@@H](Cn1ccnc1)C3
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of ((8R)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl methanesulfonate (117 mg, 0.217 mmol), cesium carbonate (142 mg, 0.435 mmol) and imidazole (22.51 mg, 0.331 mmol) in acetonitrile (6 mL) was heated at 80° C. for 16 hours, then at 85° C. for 3.5 hours. Further portions of imidazole (22.51 mg, 0.331 mmol) and cesium carbonate (142 mg, 0.435 mmol) were added and the mixture heated for a further 2 hours. The mixture was cooled to room temperature, diluted with water (30 ml) and extracted with DCM (2×30 ml). The combined organic extracts were washed with brine (30 ml) passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane then with 0-10% MeOH/DCM, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9]2)[CH2:5][CH2:4]1)#[N:2].[OH-:26].[Na+]>C(COC)OC.Cl>[C:1]([N:3]1[CH2:4][CH2:5][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9]2)[CH2:7][CH2:8]1)(=[O:26])[NH2:2]
Reactant: [OH-]
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)N1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Temperature: 0 °C

Procedure:
9.93 g of 1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] of Example 37 in 150 ml glyme and 100 ml 6 M aqueous hydrochloric acid is heated at reflux under nitrogen for 1.5 hours. The mixture is cooled to 0° C., made basic with 50% aqueous sodium hydroxide (40 ml) and concentrated. The residue is dissolved in hot chloroform, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and contrated to give a crude product. Recrystallization from hot dimethylsulfoxide-dioxane-ether affords 1'-carbamoyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], mp 217.5°-219.0° C.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:15][CH2:16][CH2:17][C:18](=O)[C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[F:27][C:21]1[CH:20]=[C:19]([C@H:18]2[NH:9][C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][CH2:17]2)[CH:24]=[C:23]([F:25])[C:22]=1[F:26]
Reactant: COC(=O)[C@@H](CCCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (20 mL) was added to a solution of methyl(R)-2-tert-butoxycarbonylamino-6-oxo-6-(3,4,5-trifluorophenyl)hexanoate (4.0 g) in ethyl acetate (20 mL), and the reaction solution was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. Then, ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the resulting residue in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for six hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 2.7 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: OCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-amino-1-propanol according to general procedure 1 providing the amino compound (493 mg, 84%) as a yellow solid: Rf=0.56 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.56 (d, J=9.7 Hz, 1H), 7.41 (s, 1H), 6.71 (d, J=9.7 Hz, 1H), 3.71 (t, J=6.3 Hz, 2H), 3.50 (t, J=6.8 Hz, 2H), 1.93 (quin, J=6.6 Hz, 2H); ES-MS: (M+H)=271, 273 m/z.
Reaction SMILES: CO.[C:3]([O:7]OC(C)(C)C)(C)(C)C.[C:13]([CH:17]=[CH:18][F:19])([F:16])([F:15])[F:14]>>[C:13]([CH2:17][CH:18]([CH2:3][OH:7])[F:19])([F:16])([F:15])[F:14]
Reactant: FC=CC(F)(F)F
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: CO
Product: OCC(F)CC(F)(F)F
Yield: 616.1 %

Procedure:
Under nitrogen, into a quartz tube equipped with a dry-ice condenser was added anhydrous methanol (20 g, 0.62 mol) and di-tertiarybutylperoxide (.79 g, 0.003 mol). The quartz tube was placed in a Rayonet UV photochemical reactor and HFC 1234zc, CF3CH═CFH (5 g, 0.044 mol) was added drop-wise via a dry-ice condenser (−78° C.) over a period of ˜1 hour while being irradiated at (UV wavelength) 254 nm. After complete addition, the reaction mixture was irradiated for ˜1 hour. The reaction mixture was concentrated under reduced pressure. The residue was extracted in diethyl ether (˜50 mL), washed with 20 mL aq. Na2SO3 (20%) and brine (10 mL). The ether layer was then concentrated to afford 7 g of the crude material. Distillation of this material under reduced pressure (24-28 mm Hg) afforded CF3CH2CFHCH2OH (2.7g) as a colorless liquid; yield=42% based on HFC 1234 zc. Boiling point, 58° C./24 mm Hg. GC-MS: m/e at 146 (C4H6F4O) for M+; 19 F and 1H NMR spectra are consistent with the structure. 19 F NMR (CDCl3)δ=−64.6 (3F, m), −191.2 (1F, m) ppm; 1H NMR (CDCl3)δ=2.2 (1H, br), 2.4(1H, m), 2.6 (1H, m), 3.7-3.9 (2H, m), 4.9 (1H, dm) ppm.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C@H:6]([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CS(C)=O>[OH:13][C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: CCCCCC[C@@H](O)CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCC[C@@H](O)CC#N
Yield: 86.5 %

Procedure:
Under nitrogen atmosphere, 6.2 g (126 mM) of sodium cyanide and 50 ml of dimethyl sulfoxide (DMSO) were placed in two-necked round-bottomed flask and dissolved by heating, followed by stirring. The solution was left standing and a solution of 10.4 g of (R)-1-chloro2-octanol in 20 ml of DMSO was added dropwise to the solution at 50° C., followed by stirring for 20 hours at 50° C. After the reaction, distilled water was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with distilled water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent under reduced pressure to obtain 8.48 g (54.7 mM) of (R)-3-hydroxynonanenitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:13][C:14](=O)[C@H:15]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:46]2)=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[N:13]=[C:14]([C@H:15]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[S:46][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:36]
Reactant: COC(=O)C(NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc([C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)sc1-c1ccccc1
Yield: 72.9 %

Procedure:
2-((2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionylamino)-3-oxo-3-phenylpropionic acid methylester (2.2 g; 4.069 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (4.1 g; 10.17 mmol) were refluxed 6 hours in 50 ml tetrahydrofuran. The solvent was removed in vacuo and the residue was chromatographed on silica; (4×40 cm) using ethyl acetate/heptane (1:1) as eluent and the residue was recrystalised from ethyl acetate/heptane (1:1; 50 ml) to afford 1.45 g of 2-((1R)-1-(tert-butoxycarbonylamino)-2-(2-naphthyl)-ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid methyl ester.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:23]([CH3:34])=[CH:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd].C(OCC)(=O)C>[OH:15][C:13]1[CH:12]=[C:11]([CH:23]([CH3:34])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=[C:9]([OH:8])[CH:14]=1
Reactant: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CCCOc1ccccc1)c1cc(O)cc(O)c1
Reaction time: 12 h

Procedure:
A solution of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene (51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), ethyl acetate (160 ml.) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10% Pd/C. Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields 30.8 g. (100%) of product as a viscous oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[NH:11][C:10](=O)[CH2:9]1>C1COCC1.C(OCC)C>[CH3:7][C:8]1([CH3:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[NH:11][CH2:10][CH2:9]1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCNc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
To 23.5 ml of 1.0M (23.5 mmol) lithium aluminum hydride in THF, heated to reflux under nitrogen, was added a solution of 4.95 g (19.48 mmol) of 4,4-dimethyl-6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline in 50 ml of dry THF and 100 ml of dry diethyl ether via a double-ended needle. The mixture was heated at reflux for 2 hours and then cooled to room temperature. The reaction mixture was then quenched by the slow addition of 25 ml of water followed by 50 ml of 5% NaOH solution. The mixture was extracted with 2×25 ml of ether, the organic extracts were combined and washed successively with 25 ml each of water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexanes) to give the title compound as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[N:25]=[N:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[N:24]=[N:25][C:20]([O:19][CH2:18][C:17]([F:16])([F:31])[CH3:30])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)nnc1OCC(C)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)nnc1OCC(C)(F)F
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (712 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (687 mg, 2.47 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (600 mg, 2.24 mmol, Amine-78, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH:1]1([C:5](=[O:20])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[O:30]>C1COCC1>[CH2:33]([O:32][C:28](=[O:31])[CH:29]([OH:30])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:11][CH:12]=1)[C:5]([CH:1]1[CH2:2][CH2:3][CH2:4]1)=[O:20])[CH3:34]
Reactant: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CCC1
Reactant: CCOC(=O)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)C(C(=O)C1CCC1)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To a stirred solution of 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (3.60 mmol, 0.98 g) and triethylamine (3.60 mmol, 0.51 mL) in THF (2.0 mL) was added a solution of ethyl glyoxylate (50% in toluene, 18.0 mmol, 3.82 mL) and continued stirring for 12 h at room temperature. After removal of volatiles under reduced pressure, the crude product was pre-absorbed onto 10 g SiO2 followed by purification on a 24 g SiO2 cartridge using a 0-30% ethyl acetate/hexanes gradient to give 4-cyclobutyl-3-(4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-butyric acid ethyl ester (0.42 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH2:16][OH:17])([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@:9]([CH2:16][O:17][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@@](CO)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@](CO[Si](C)(C)C(C)(C)C)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1.3 g of (S)-2-tert-butoxycarbonylamino-2-hydroxymethylpent-4-enoic acid were dissolved in 10 ml of dimethylformamide. 1.44 g of imidazole and 1.7 g of tert-butyl-dimethylsilyl chloride were added thereto. The mixture was stirred at room temperature for 14 h and then partitioned between 150 ml of water and 200 ml of diethyl ether. The aqueous phase was extracted twice with 100 ml of diethyl ether each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was taken up in 20 ml of THF and 60 ml of methanol. 11 ml of a 1 M potassium carbonate solution were added, and the mixture was stirred at room temperature for 2 h. Then 150 ml of a saturated sodium chloride solution were added, and the pH of the solution was adjusted to 2 with 1 M HCL solution. The aqueous phase was extracted 3 times with 100 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo, and the crude product was employed without further purification in the next reaction.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[NH:9]([C:11]1[N:12]=[N:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:15]([CH3:17])[N:16]=1)[NH2:10]>C(Cl)Cl.CO>[NH2:2][C:1]1[N:9]([C:11]2[N:12]=[N:13][C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:15]([CH3:17])[N:16]=2)[N:10]=[C:4]([S:5][CH3:6])[N:3]=1
Reactant: CSC(=NC#N)SC
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CSc1nc(N)n(-c2nnc(-c3ccccc3)c(C)n2)n1
Reaction time: 40 h
Yield: 89.2 %

Procedure:
A solution of dimethyl N-cyanodithioimidocarbonate (2.65 g) in methylene chloride (15 ml) was added to a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.52 g) in methanol (20 ml) and stirring was continued for 40 hours at room temperature. The resultant precipitates were collected by filtration, washed with methanol, and dried to give 3-(5-amino-3-methylthio-1,2,4-triazol-1-yl)-5-methyl-6-phenyl-1,2,4-triazine (4.67 g).