Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:39][CH2:40][CH:41](CO)[OH:42]>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:41]([OH:42])[CH2:40][OH:39])=[O:23])=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 180 °C

Procedure:
A mixture of 2.25 g of methyl 4-(n-hexadecylamino)benzoate, 280 mg of glycerol, and 1.37 g of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40].[OH-].[Na+].Cl>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([OH:41])=[O:40]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(F)cc4)cc3CCc3ccccc3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(F)cc4)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
The oil obtained in Example 142 was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and 2 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 6 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (61 mg, yield 11%, 2 steps) as colorless crystals. 1H NMR (CDCl3) δ: 2.62 (2H, t, J=7.5 Hz), 2.79-2.93 (6H, m), 4.98 (2H, s), 5.24 (2H, s), 6.37 (1H, s), 6.59-6.68 (2H, m), 7.03-7.14 (7H, m), 7.18-7.38 (5H, m), 7.76 (2H, dd, J=8.9, 5.5 Hz).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:38][N:37]([CH3:39])[S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)S(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N,N-dimethyl-benzenesulfonamide [CAS 6274-18-6; commercially available] according to general procedure II. Yellow solid. MS (ISP) 558.3 [(M+H)+]; mp 210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[C:9]([CH3:10])[N:4]2[N:3]=1.O[N:16]=[C:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.N>>[CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]([C:11]3[O:13][N:24]=[C:17]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:16]=3)=[C:9]([CH3:10])[N:4]2[N:3]=1
Reactant: NC(=NO)c1cccnc1
Reactant: Cc1cc2ncc(C(=O)O)c(C)n2n1
Agent: N
Product: Cc1cc2ncc(-c3nc(-c4cccnc4)no3)c(C)n2n1

Procedure:
The title compound was prepared according Method C using 2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ2.52 (s, 3 H), 3.27 (s, 3 H), 6.77 (s, 1 H), 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 8.48 (dt, J=8.6, 1.9 Hz, 1 H), 8.84 (dd, J=4.7, 1.7 Hz, 1 H), 9.06 (s, 1 H), 9.30 (dd, J=2.2, 0.8 Hz, 1 H), 9.30 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 293 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Reactant: Cc1ncc[nH]1
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[C:14]1([N:20]2[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23](=[O:31])[NH:22][C:21]2=[O:32])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:32]=[C:21]1[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23](=[O:31])[N:22]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCCCCCCCO
Reactant: O=C1NC(=O)N(c2ccccc2)C1c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCN1C(=O)C(c2ccccc2)N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
Diethyl axodicarboxylate (1.39 g, 8 mmol) in THF (5 mL, was added dropwise to a stirred solution of methyl 9-hydroxynonanoate (1.50 g, 8 mmol), 3,4-diphenylimidazolidine-2,5-dione (2.02 g, 8 mmol) obtained according to the procedure of K. C. Joshi, et al., J. Het. Chem., 18, 1651-1653 (1981) and triphenylphosphine (2.10 g, 8 mmol) in THF (35 mL). The mixture was stirred at room temperature for 72 hours, the THF removed in vacuo and the residue triturated with a mixture of hexanes and diethyl ether. The mixture was filtered, the filtrate concentrated and subjected to chromatography on a column of silica gel using a mixture of hexanes and ethyl acetate (3:2) as eluent. Elution gave methyl 2,5-dioxo-3,4-diphenyl-1-imidazolidinenonanoate (2.78 g, 82%), mp 69°-72° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH2:13])[C:8]([F:11])=[N:9][CH:10]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH:12]([C:7]1[C:8]([F:11])=[N:9][CH:10]=[C:5]([OH:4])[CH:6]=1)=[CH2:13]
Reactant: C=Cc1cc(OC(C)=O)cnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=Cc1cc(O)cnc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a stirred solution of the 5-acetoxy-2-fluoro-3-ethenylpyridine from b above (1.40 g, 7.70 mmol) in MeOH (50 mL) was added K2CO3 (0.53 g, 3.90 mmol). The reaction mixture was allowed to stir at room temperature 24 h. The solvent was evaporated and the residue was diluted with Et2O (100 mL) and water (100 mL). The phases were separated and the aqueous phase was neutralized (pH 7) by the addition of 1 N aqueous HCl, and extracted with Et2O (2×100 mL). The combined ethereal extracts were washed with brine (50 mL), dried (MgSO4), and the solvent was evaporated. The crude product was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the desired material as an off-white solid (0.81 g, 76%): 1H NMR (CDCl3, 300 MHz) δ 5.50 (d, J=11.0 Hz, 1H), 5.87 (d, J=17.5 Hz, 1H), 6.75 (m, 1H), 7.72 (dd, J=3.0, 5.0 Hz, 1H), 7.69 (m, 1H); MS (CI/NH3) m/z 140 (M+H)+, 157 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:10]=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCl
Reactant: Cc1cccc(-c2nnn[nH]2)c1
Product: COC(=O)Cn1nnnc1-c1cccc(C)c1

Procedure:
Feed materials: 5-(3-methylphenyl)tetrazole and methyl chloroacetate.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([Pb+3])=[C:31]([CH2:38][CH3:39])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH2:38][CH3:39])[CH:30]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: CCc1cc(Br)cc(CC)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(CC)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 4.2 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (1 g, 6.5 mmol) and 4-dimethylamino-pyridine (3.96 g, 32.5 mmol) are added to a mixture of chloroform (20 ml) and toluene (5 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2,6-diethylphenyllead triacetate (4.25 g, 7.14 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2,6-diethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.1 g).
Reaction SMILES: [CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:31]4[C:30]5[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=5)[N:34]=[CH:33][N:32]=4)[CH:42]=3)=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCC2)nn1-c1ccccc1)Oc1ccccc1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C5CCC5)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea was prepared from phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) according to the procedure given in Example 352B. 1H NMR (400 MHz, DMSO-d6) S9.24 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 7.78 (s, 1H), 7.22-7.53 (m, 10H), 6.38 (m, 1H), 3.99 (s, 6H), 3.44 (m, 1H), 2.14-2.50 (m, 4H), 1.23-1.99 (m, 2H); LC-MS (ESI) m/z 553 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH3:1][CH2:2][C:3]1[C@H:8]2[N@+:9]3([O-:34])[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1
Reactant: CCC1=C[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(C2)[C@@H]13
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC1=C[C@H]2C[C@]3(C(=O)OC)c4[nH]c5ccccc5c4CC[N@+]([O-])(C2)[C@H]13
Reaction time: 0.25 h

Procedure:
To a solution of catharanthine (201 mg, 0.60 mmol) in methylene chloride (40 ml) at -15° C. was added a solution of m-chloroperbenzoic acid (111 mg, 0.65 mmol) and the solution stirred for 15 min. To the catharanthine N-oxide thus formed was added a solution of vindoline (270 mg, 0.59 mmol) in methylene chloride. The atmosphere in the reaction flask was then replaced with nitrogen and the remainder of the coupling carried out in this inert atmosphere. Trifluoroacetic anhydride (0.41 ml, 3.01 mmol) was added to the stirred solution maintained at -15° C. After 22 hours this mixture was added to a solution of sodium borohydride in ethanol. After the initial vigorous evolution of gas, water and additional methylene chloride was added to the reaction mixture. The organic phase was separated and the aqueous layer washed with a second portion of methylene chloride. The organic portions were combined and washed with a solution of K2CO3. The organic phase was separated and dried with Na2SO4. The solvent was evaporated in vacuo and the residue dissolved in hot acetone. The solution was cooled and crystals of 3'4'-dehydrovinblastine were isolated. The mother liquors from the crystallization were chromatographed on silica gel plates using methanol-ethyl acetate as the eluting solvent. The combined fractions of 3'4'-dehydrovinblastine, mp 171°-173° obtained from these purifications amounted to 226 mg (0.29 mmol). Calc. for C46H56O8N4 : 792.410. Found: 792.405.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].C(=O)(O)[O-].[Na+].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ncccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ncccc1C(=O)OCC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a mixture of 54 g (0.26 mole) of 3-carboxy-2-pyridineacetic acid ethyl ester* and 24.4 g (0.29 mole) of sodium bicarbonate in 300 ml of dimethylformamide was added 60.8 g (0.39 mole) of ethyliodide. The mixture was stirred at 50° C. for 24 hr; cooled to 25° C. and treated with 300 ml of water. The aqueous solution was extracted 3 times with isopropyl ether. The isopropyl ether solution was extracted with dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted with isopropyl ether. The ether layer was dried over anhydrous sodium sulfate, concentrated and the residue was distilled to give 47 g (76%), b.p. 128°-130° C./0.5 mm.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+].Cl>O1CCCC1.CO>[CH3:20][O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[CH:14][C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:16][CH:17]=1
Reactant: COc1cnc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc(N2CCOCC2)cc1NC(N)=S
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a stirred solution of 5.80 g (15.6 mmol) 1-benzoyl-3-(5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea in 100 ml tetrahydrofuran and 25 ml methanol heated at 60° C. was added dropwise 1.15 ml (6.23 mmol) 5.4 M sodium methylate solution and stirring continued for 2 h at 60° C. 1.2 ml concentrated hydrochloric acid was then added and the reaction mixture concentrated in vacuo. The residue was triturated in 25 ml ether to afford 3.51 g (84%) (5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea as alight brown crystalline solid. ES-MS m/e (%): 269 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1>Cl.[Fe].CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1N
Yield: 76.3 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-28 by using 3-(2-chloro-6-fluorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one (0.100 g), iron powder (catalytic), conc.HCl (5-6 drops) and methanol (5 mL) to afford 0.070 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.77 (s, 3H), 4.81 (s, 2H), 6.66 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.50-7.57 (m, 2H), 7.68 (m, 1H), 12.39 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[C:17]([O:25][C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:66]>C1COCC1.O1CCOCC1>[ClH:66].[F:22][C:21]([F:23])([F:24])[C:20]1[CH:15]=[CH:16][C:17]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidine carboxylate (1.0 g, 5.0 mmol) in anhydrous THF (5 mL) was added 4-[(4-trifluoromethyl)phenoxy]phenol (1.65 g, 6.5 mmol) in THF (5 mL) and triphenyl phosphine (1.57 g, 6 mmol) in THF (5mL). The resulting mixture was cooled to 0° C. using ice-water bath and purged with nitrogen. Diisopropyl azodicarboxylate (1.21 g, 6 mmol) was dissolved in 5 mL of THF and added to above solution drop wise over a period of 30 min under nitrogen. Reaction then was stirred at 0° C. for 0.5 h heated at 70° C. for 16 h. THF was removed in vacuo and crude mixture was purified by silica gel flash chromatography (10% EtOAc/Hexane) to obtain the product. To a solution of the product in dioxane (4 mL) was added 4M HCl in dioxane (10 mL) at rt and the resulting mixture was stirred for 2 h at that temperature. The solvent was removed in vacuo and residue was triturated with ether to obtain a white solid (1.21 g, 65%): MS; m/z 338.4 (M+H), 1H NMR (400 MHz, DMSO-d6); δ 1.83-1.90 (m, 2H), 2.09-2.14 (m, 2H), 3.03-3.09 (m, 2H), 3.20-3.26 (m, 2H), 3.32 (s, 1H), 4.62-4.66 (m, 1H), 7.06-7.10 (m, 7H), 7.70 (d, 2H, J=8.8 Hz), 9.08 (s, 2H); HPLC (UV); 97%.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1([CH2:17][CH3:18])[CH2:10][O:9][C:8]2([CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[O:7][CH2:6]1)[CH3:4]>C(O)C>[CH2:17]([C:5]1([CH2:3][CH3:4])[CH2:6][O:7][C:8]2([CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[O:9][CH2:10]1)[CH3:18]
Reactant: CCC1(CC)COC2(CCC(=O)CC2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(CC)COC2(CCC(O)CC2)OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
820 mg (21.5 mmol) of sodium borohydride were added to a solution of 13 g (57.4 nmol) of 3,3-diethyl-1,5-dioxaspiro[5.5]undecan-9-one in 200 ml of ethanol and the mixture was stirred at room temperature for 1 hour. To complete the reaction, the mixture was heated at 40° C. for a further 15 hours. To destroy excess sodium borohydride, approximately 5 ml of acetone were added to the reaction solution and stirring was continued at 40° C. for a further 30 minutes. The reaction solution was subsequently concentrated in vacuo and the product taken up in ether and washed using ammonium chloride solution and water. The organic phase was dried carefully over magnesium sulfate and subsequently evaporated to dryness. This gave 11.8 g (90.0%) of the desired cyclohexanol. The crude product was further reacted without further purification.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13](=[O:18])[NH:12][C:11]1=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:20]([N:16]([CH3:17])[C:14]1[C:13](=[O:18])[NH:12][C:11](=[O:19])[N:10]([C:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:9])[CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCNC(=O)n1cc(NC)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCCCCCNC(=O)n1cc(N(C)C(=O)c2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
N-hexyl-5-methylamino-2,4-dioxo-pyrimidine-1-carboxamide (0.08 g, 0.30 mmol) was dissolved in dry pyridine (4 mL). To the resulting solution, benzoyl chloride (0.04 mL, 0.39 mmol) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 18 hrs, then concentrated under reduced pressure. The crude was purified by column chromatography using SI (5 g) cartridge (cyclohexane:EtOAc 84:16) to afford the title compound (0.05 g, 45%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.89 (t, J=6.9 Hz, 3H), 1.28-1.33 (m, 6H), 1.53-1.59 (m, 2H), 3.29 (s, 3H), 3.34 (dt, J=5.7, 7.0 Hz, 2H), 7.33-7.43 (m, 5H), 8.22 (br s, 1H), 8.31 (br s, 1H) 8.88 (t, J=5.7 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 13.96, 22.48, 26.44, 29.04, 31.31, 37.17, 41.41, 121.47, 127.17, 128.43, 130.27, 135.29, 137.63, 149.03, 150.05, 159.01, 171.78. MS (ESI) m/z: 371 [M-H]−.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:2]1[O:4][CH2:3]1.[SH-:10].[Na+].[NH4+].[Cl-]>C(O)(C)C.O>[S:10]([CH2:3][CH:2]([OH:4])[CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH:2]([OH:4])[CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCC1CO1
Reactant: [SH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCCOCC(O)CSCC(O)COCCCC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of butyl glycidyl ether (2.91 g, 22.39 mmol) in isopropanol (5 mL) and H2O (1 mL) was added to sodium bisulfide (0.628 g, 11.20 mmol) under nitrogen in a 100 mL 3-neck round bottom flask equipped with a N2 inlet, a rubber septum, glass stopper and a magnetic stir bar. The mixture was heated at 90° C. and monitored for completion by gas chromatography/mass spectrometry for disappearance of starting materials and formation of the product. After 3 h, the reaction was judged to be complete. The mixture was cooled to ambient temperature and treated with saturated NH4Cl (5.0 mL) and extracted into ethyl acetate (50 mL). The solvent was dried (MgSO4), filtered, and evaporated in-vacuo to give the product, 1,1′-thiobis(3-butoxypropan-2-ol), which was identified by mass spectrometry as well as 1H and 13C NMR.