Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O[CH2:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>FC(F)(F)C(O)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([NH:10][CH2:9][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:18])[CH:13]=1
Reactant: Sc1ccncc1
Reactant: O=C(NCO)c1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCSc1ccncc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a mixture of 1.11 g (10 mmol) of 4-mercaptopyridine and 1.52 g (10 mmol) of N-(hydroxymethyl)nicotinamide, 30 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and 30 ml of ethanol was added to the residue. The solvent was distilled off and water was added to the residue. The mixture was neutralized with saturated aqueous sodium bicarbonate, followed by extraction with chloroform. After washing with saturated saline, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol =5:1) to give 390 mg of the desired compound (15.9% yield, yellow solid).
Reaction SMILES: N[S:2]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:6]=1[C:7]([N:9](CC)CC)=[O:8])(=[O:4])=[O:3]>C(O)(=O)C>[CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:5]2[C:6]=1[C:7](=[O:8])[NH:9][S:2]2(=[O:4])=[O:3])([CH3:20])[CH3:19]
Reactant: CCN(CC)C(=O)c1c(C(C)C)cccc1S(N)(=O)=O
Solvent: CC(=O)O
Product: CC(C)c1cccc2c1C(=O)NS2(=O)=O
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of 2-aminosulfonyl-6-isopropyl-N,N-diethylbenzamide (60 g) in acetic acid (400 mL) was refluxed for 24 hours, then cooled to room temperature. The solvent was removed under vacuum. The oily residue was dissolved in water (500 mL) and the pH was adjusted to 1 with hydrochloric acid (2N). The crude product was collected by filtration, washed with water (300 mL), dried at 60° C. under vacuum for 18 hours and recrystallized from ether-hexane to give 4-isopropylsaccharin (40 g, 90% yield, m.p. 177° C.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:18])[S:12][CH2:13][C:14](=O)[CH2:15][Cl:16].Cl.S(=O)(=O)(O)O>C(O)C>[Cl:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:18])[S:12][CH:13]=1
Reactant: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F

Procedure:
That is, first the known compound (XIV)(see European patent publication No. 286089) is reacted with 1,3-dichloroacetone in an organic solvent such as chloroform, methylene chloride or a lower alcohol to produce 3-chloro-2-oxopropyl N-(2,3,4-trifluorophenyl)dithiocarbamate (XV). The compound (XV) is then heated with an inorganic acid such as hydrochloric acid or sulfuric acid in a lower alcohol such as ethanol to give 4-chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-1,3-thiazolethione (XVI). The compound (XVI) is then reacted with methylamine in an aprotic organic solvent such as N,N-dimethylformamide or acetonitrile to give 1H,4H-thiazolo[3,4-a]quinoxaline-1-thione derivative (XVII). The compound (XVII) is then reacted with a lower alkyl iodide in a polar solvent such as N,N-dimethylformamide, acetonitrile or ethanol to give a 1-(lower alkyl)thioquinoxalino[1,2-c]thiazolium iodide (XVIII). Then the compound (XVIII) is reacted with a di(lower alkyl) malonate sodium, which is prepared from di(lower alkyl) malonate and sodium hydride, in an organic solvent such as tetrahydrofuran or dioxane to give di(lower alkyl) (1H,4H-thiazolo[3,4-a]quinoxalin-1-ylidene)malonate (X).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:8]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1cc(C(=O)O)cc2c1OCCO2
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3-methoxy-4,5-ethylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3]>C1COCC1.[Rh]>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1Cc1ccccc1
Agent: [Rh]
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC1CCCCC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 102.2 %

Procedure:
To a 50 mL high pressure reactor with a magnetic stir bar was added (3S,6S,7R,8R)-8-benzyl-3-(tert-butoxycarbonylamino)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (400 mg, 0.863 mmol) in THF (3 mL) to give a colorless solution. To the solution was added 5% Rh/C (50 mg, 0.024 mmol). After the reactor was sealed, it was purged with hydrogen gas (4 times). The reactor was charged to approximately 600 psi of H2 at room temperature (about 22° C.) and then the reaction was warmed to 70° C. and stirred at for 6 h. The reaction mixture was cooled, filtered, and concentrated. The residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (414 mg, 92%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 5.32 (dd, J=39.3, 12.3 Hz, 2H), 5.01 (t, J=9.9 Hz, 1H), 4.94-4.72 (m, 2H), 3.58 (s, J=51.8 Hz, 1H), 2.72-2.51 (m, 2H), 1.78-1.52 (m, 6H), 1.45 (s, J=6.0 Hz, 9H), 1.26 (d, J=6.3 Hz, 3H), 1.20 (dd, J=7.0, 3.0 Hz, 6H), 1.19-1.04 (m, 4H), 1.02-0.68 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 175.50, 172.74, 154.78, 133.68, 123.39, 80.39, 75.22, 74.50, 67.85, 65.49, 51.47, 47.36, 35.85, 35.40, 34.05, 34.01, 32.09, 28.19, 26.28, 26.00, 25.87, 18.95, 18.82, 17.77; ESIMS m/z 492 ([M+Na]+).
Reaction SMILES: C([Li])CCC.CCCCCC.P(=O)(O)O.C([C:18]([CH2:23][CH3:24])([C:20]([OH:22])=[O:21])[F:19])C.[CH3:25][O:26][C:27]([CH2:29][CH2:30]CC=O)=[O:28]>C1COCC1>[F:19][C:18](=[CH:23][CH2:24][CH2:30][CH2:29][C:27]([O:26][CH3:25])=[O:28])[C:20]([OH:22])=[O:21]
Reactant: CCC(F)(CC)C(=O)O
Reactant: COC(=O)CCCC=O
Agent: O=[PH](O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCCC=C(F)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
n-Butyl lithium (a hexane solution with f=1.69, 20.7 ml) was dissolved in THF (57 ml), and the solution was cooled to -78° C. To this solution, a solution of diethylcarboxyfluoromethane phosphonate (3.48 g, 16.3 mmol) in THF (25 ml) was dropwise added at -78° C. The mixture was stirred at the same temperature for 30 minutes. To this reaction solution, a solution of 4-methoxycarbonylbutanal (2.11 g, 16.3 mmol) in THF (16 ml) was dropwise added at -78° C., and the mixture was stirred at the same temperature. One hour later, the cooling bath was removed, and the mixture was stirred at room temperature for further one hour. Then, the reaction solution was cooled to 0° C., and water (40 ml) was added thereto. The mixture was vigorously stirred. The separated organic layer was extracted with a saturated sodium hydrogencarbonate aqueous solution (20 ml×2), and the extract solutions were combined with the previous aqueous layer, and the mixture was washed with ethyl ether (40 ml×2). The aqueous layer was adjusted to pH 4 by using hydrochloric acid under cooling with ice, and then sodium chloride was added to saturation. Then, the mixture was extracted with ethyl ether (40 ml×3), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/acetone=4/1 (containing 0.1% of acetic acid)) to obtain 2-fluoro-6-methoxycarbonyl-2-hexenoic acid (2.34 g, a mixture of E- and Z-isomers, yield: 76%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=[CH:5]2.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=S(=O)(Oc1cccc2cc(F)c(F)cc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(F)c(F)cc23)CC1
Temperature: 80 °C

Procedure:
A third intermediate compound, 1-(6,7-Difluoro-naphthalen-1-yl)-piperazine, was produced as follows: Nitrogen gas was bubbled through a solution of trifluoro-methanesulfonic acid 6,7-difluoro-naphthalen-1-yl ester (4.38 g, 14.04 mmol), 1-Boc-piperazine (3.18 g, 16.85 mmol), Pd(OAc)2 (0.31 g, 1.4 mmol) and 2-dicyclohexylphosphino biphenyl (0.49 g, 1.4 mmol) in toluene (40 mL) for 10 min. NaOtBu (1.89 g, 19.66 mmol) was added. The resulting mixture was heated at 80° C. for 2 h, cooled to RT, diluted with EtOAC (40 mL) and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by chromatography on silica gel to give 4-(6,7-difluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+:11].[Cl-]>ClCCl>[C:1]1([CH2:7][C:8]([NH2:11])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: S=C(Cl)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: NC(=S)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of secondary amine I and TEA in anhydrous dichloromethane, are added dropwise a solution of phenylthioacetyl chloride (prepared from phenylthioacetic acid and thionyl chloride) in anhydrous dichloromethane at 0° C. The reaction mixture is warmed to room temperature, stirred for 2 hours, then sat'd NH4Cl solution and dichloromethane are added. The organic layer is washed with brine, dried over Na2SO4, and concentrated to afford α-phenylthioacetamide II, which is used for the next reaction without purification.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1)=[O:16]>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:17]2[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1cncn1C
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1cncn1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (1.2 g, 7.45 mmol) in DCM (10 mL) was added ethyl magnesium bromide (2.5 mL, 7.45 mmol, 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting pale yellow solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and then N-methoxy-N,1-dimethyl-1H-imidazole-5-carboxamide (1.0 g, 6.21 mmol, Intermediate 55: step a) dissolved in DCM (3 mL) was added dropwise. The cold bath was removed and the reaction mixture stirred at room temperature for 48 hours. To the resulting yellow suspension was added water followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM (2×). The combined DCM extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The product was precipitated with Et2O, filtered and dried to provide the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[C:26]([C:28]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35])([CH3:30])[CH3:29])#[N:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:26]([C:28]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=3)[N:13]=2)[CH:23]=1)=[O:35])([CH3:30])[CH3:29])#[N:27]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 71.2 %

Procedure:
Using N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (88 mg, 0.46 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (87 mg, 0.46 mmol), 1-hydroxybenzotriazole (62 mg, 0.46 mmol) and N,N-dimethylformamide (10 mL) as starting materials and in the same manner as in Example 318, the title compound (160 mg, 71%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][OH:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a 250 mL round bottom flask was added 4-bromophenol (16.5 g, 95.3 mmol), 3-bromopropanol (15.9 g, 114.4 mmol), N,N-dimethylformamide (50 mL) and potassium carbonate (22.4 g, 162.0 mmol). The reaction was allowed to stir at room temperature while being monitored by TLC(CH2Cl2). Upon the disappearance of 4-bromophenol the mixture was poured into a separatory funnel containing 50 mL of water. The product was extracted in diethyl ether and the organic layer was washed with 3×25-mL portions of cold water. The solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel eluting with dichloromethane. The solvent was removed under reduced pressure. Residual solvent and remaining 3-bromopropanol were removed in vacuo (14.2 g, 64.4%). 1H NMR (300 MHz, CDCl3) δ 7.35 (d, 9.0 Hz), 6.77 (d, J=9.0 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.10 (q, J=6.0 Hz, 2H), 1.65 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])OC4C=CC=CC=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH2:30]([NH2:32])[CH3:31]>C(O)(C)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])[NH:32][CH2:30][CH3:31])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN
Reactant: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: Cl
Solvent: CC(C)O
Product: CCNC(=NC#N)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-[4-(cyanimino(phenoxy)methyl)piperazin-1-yl]quinoline (0.39 g, 1.0 mmol), ethylamine hydrochloride (1.68 g, 20.6 mmol), and diaza[2.2.2]bicyclooctane (2.24 g, 20.0 mmol) in isopropanol (20 mL) are heated in a sealed tube for 4 h at 110° C. The reaction mixture is concentrated, and the residue is suspended in EtOAc. Washing with water, drying (MgSO4), and removing the solvent leads to a colorless solid, which is washed with hot ether to yield the title product.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][S:4][CH:3]1[C:8]([O:10]CC)=O.[OH-].[K+].Br.[CH3:16][S:17][C:18](=[NH:20])[NH2:19]>C(O)(=O)C>[OH:10][C:8]1[C:3]2[S:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:19]=[C:18]([S:17][CH3:16])[N:20]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)C1SCCCC1=O
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1nc(O)c2c(n1)CCCS2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
20 g of ethyl 3-oxotetrahydrothiopyran-2-carboxylate was added to 120 ml of a methanolic solution containing 9 g of potassium hydroxide at room temperature while stirring. Then, a small amount of S-methylisothiourea hydrobromide was added to the mixture and the stirring was continued for 2 hours. The reaction solution was then poured into ice-water, and the mixture was made acidic with acetic acid. The precipitated crystals were separated by filtration and recrystallized from acetic acid to obtain 4-hydroxy-2-methylthio-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point of 248° C.
Reaction SMILES: CC1C=CC(S(OC[C@@H]2COC(C)(C)O2)(=O)=O)=CC=1.C([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N+:33]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:32]2)([O-:35])=[O:34]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 134.7 %

Procedure:
To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under nitrogen gas was added 2-tert-butyl-5-nitro-1H-indole (1.00 g, 4.58 mmol) followed by Cs2CO3 (2.99 g, 9.16 mol). The mixture was stirred and heated at 80° C. under nitrogen gas. After 20 hours, 50% conversion was observed by LCMS. The reaction mixture was re-treated with Cs2CO3 (2.99 g, 9.16 mol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) and heated at 80° C. for 24 hours. The reaction mixture was cooled to room temperature. The solids were filtered and washed with ethyl acetate and hexane (1:1). The layers were separated and the organic layer was washed with water (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/hexane=1.5/1) to give (R)-2-tert-butyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitro-1H-indole (1.0 g, 66%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.2 Hz, 1H), 8.08 (dd, J=2.2, 9.1 Hz, 1H), 7.49 (d, J=9.1 Hz, 1H), 6.00 (s, 1H), 4.52-4.45 (m, 3H), 4.12 (dd, J=6.0, 8.6 Hz, 1H), 3.78 (dd, J=6.0, 8.6 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 9H), 1.33 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>CO.CCOCC>[NH2:7][CH:8]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2OCCN2CCOCC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2OCCN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of (1-(4-chloro-benzyl)-2-{4-[2-(2-morpholin-4-yl-ethoxy)-phenyl]-piperazine-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (23.57 g, 41.1 mmol) in MeOH (225 mL) was added 1.0 M HCl in Et2O. The mixture is stirred at r.t. overnight. The solid was filtered, washed with Et2O and dried under vacuum overnight to afford 2-amino-3-(4-chloro-phenyl)-1-{4-[2-(2-morpholin-4-yl-ethoxy)-phenyl]-piperazine-1-yl}-propan-1-one (19.6 g, 36 mmol, 88%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][N:41]1[CH2:45][CH3:46]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:45]([N:41]1[CH2:42][CH2:43][CH2:44][CH:40]1[CH2:39][NH:38][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:46]
Reactant: CCN1CCCC1CN
Reactant: COc1ccc(C(=O)O)cc1OC/C=C(\C)CCC=C(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1ccc(OC)c(OC/C=C(\C)CCC=C(C)C)c1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
3-geranyloxy-4-methoxybenzoic acid(1.52 g) was dissolved in chloroform (50 ml) and triethylamine (1.4 ml), and then diphenylphosphinic chloride(1.0 ml) was added thereto while being cooled with ice. After being stirred for 15 minutes, the mixture, with 2-aminomethyl-1-ethylpyrrolidine(0.7 ml) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1), thereby yielding 1.47 g(71%) of the aimed compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[N:14]([CH2:29][CH3:30])[C:15]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)=[N:16][C:17]=3[CH3:18])=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:13]3[N:14]([CH2:29][CH3:30])[C:15]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)=[N:16][C:17]=3[CH3:18])[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCn1c(-c2cccc3ccccc23)nc(C)c1C(=O)N1CCN(C2CCC2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CCn1c(-c2cccc3ccccc23)nc(C)c1CN1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-cyclobutyl-piperazin-1-yl)-(3-ethyl-5-methyl-2-naphthalen-1-yl-3H-imidazol-4-yl)-methanone (40 mg) in THF (1 ml) is added DIBAL-H (0.25 ml, 1.5 M in toluene) at 0° C. The resulting solution is stirred at rt for 2 hr, and then quenched with brine. The THF layer is separated, evaporated and purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound. LCMS 389.5 (M+1). NMR (CDCl3) δ ppm 1.05 (t, 3H), 1.63-2.05 (m, 9H), 2.29 (s, 3H), 2.35-2.56 (m, 5H), 2.74 (m, 1H), 3.52 (s, 2H), 3.82 (q, 2H), 7.42-7.60 (m, 5H), 7.87-7.94 (m, 2H).