Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])([CH3:14])[CH3:13].C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]([CH:12]([CH3:14])[CH3:13])[C:21](=[O:22])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: NC(=O)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C1C(=O)NC(=O)N(Cc2ccccc2)C1=O

Procedure:
To a suspension of 22.53 g (150 mmol) of benzylurea and 30.34 g (150 mmol) of diethyl isopropylmalonate in 77 ml of methanol, 36.6 ml (150 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 34.96 g (89.5%, white crystal) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].O1CCCC1.[Li+].[OH-]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoate (100 mg, 0.22 mmol, 1.00 equiv), tetrahydrofuran (1 mL) and a solution of LiOH (100 mg, 4.18 mmol, 18.93 equiv) in water (1 mL). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was then concentrated under vacuum. The pH value of the solution was adjusted to pH5 with hydrogen chloride (2 mol/L). The resulting solution was extracted with ethyl acetate (3×5 mL) and the organic layers combined. The resulting residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O(0.05% CF3COOH)=1:1 increasing to ACN/H2O(0.05% CF3COOH)=9:1 within 10 min; Detector, UV 254 nm to yield 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoic acid as a white solid (22.5 mg, 23%).
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.I[C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][NH:29]2)=[CH:25][CH:24]=1>>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([C:2]3[C:10]4[S:9][C:8]([NH:11][C:12]([C:14]5[S:15][C:16]([CH3:19])=[CH:17][CH:18]=5)=[O:13])=[N:7][C:6]=4[C:5]([O:20][CH3:21])=[CH:4][CH:3]=3)[CH:31]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: Ic1ccc2c(c1)NCC2
Product: COc1ccc(-c2ccc3c(c2)NCC3)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
The title compound was prepared from 5-methyl-thiophene-2-carboxylic acid (7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and 6-iodo-2,3-dihydro-1H-indole using the general procedure B in Example 54 as light brown crystals (26%), MS: m/e=422(M+H+).
Reaction SMILES: C1(S([O:10][C:11]2[CH:12]=[N:13][C:14]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:21][S:18]([CH2:17][C:14]1[N:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cc1ccc(OS(=O)(=O)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc(O)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-[(methylsulfonyl)methyl]pyridin-3-yl benzenesulfonate (30 g) in ethanol (200 mL) and tetrahydrofuran (200 mL) was added 1N aqueous sodium hydroxide solution (190 mL), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, 1N hydrochloric acid (190 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (13.9 g, yield 79%) as white crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[NH:13])OC.[C:14](OCC)(=[O:17])[NH:15][NH2:16]>O1CCOCC1>[NH:13]1[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:16][NH:15][C:14]1=[O:17]
Reactant: COC(=N)c1nc2ccccc2o1
Reactant: CCOC(=O)NN
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2nc3ccccc3o2)[nH]1

Procedure:
Methyl benzoxazole-2-imidate, 8.0 g. and 5.2 g. of ethyl carbazate in 60 ml. of dioxane was heated at 110° overnight. After evaporation of solvent, the residue was suspended in 45 ml. of Dowtherm A and heated at 220° for 15 minutes. The precipitated product was filtered, washed with CH2Cl2, CH3OH, and dried to give 3.6 g. of solid, mp. >300°.
Reaction SMILES: ClCC1SC2C=CC(F)=CC=2[N:7]=1.FC1C=CC2SC(CSC3C=C(C=CC=3)CO)=NC=2C=1.S[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][OH:38].C([O:44][C:45]([CH:47]1[CH2:56][CH2:55][C:54]2[C:49](=[CH:50][C:51](OCC3SC4C=CC(F)=CC=4N=3)=[CH:52][CH:53]=2)O1)=O)C.C(OC(C1CCC2C(=CC(O)=CC=2)O1)=O)C>>[N:7]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:55]=[CH:56][C:47]=1[CH2:45][O:44][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][OH:38]
Reactant: CCOC(=O)C1CCc2ccc(OCc3nc4cc(F)ccc4s3)cc2O1
Reactant: Fc1ccc2sc(CCl)nc2c1
Reactant: OCc1cccc(S)c1
Agent: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: OCc1cccc(SCc2nc3cc(F)ccc3s2)c1
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
In a similar manner 4-(5-fluorobenzothiazol-2-ylmethoxy)-4'-hydroxydiphenyl, m.p. 210°-211° C. was prepared from 2-chloromethyl-5-fluorobenzothiazole and 4,4-dihydroxydiphenyl, 3-(5-fluorobenzothiazol-2-ylmethylthio)benzyl alcohol was prepared from 3-mercaptobenzyl alcohol and 2-chloromethyl-5-fluorobenzothiazole and 2-ethoxycarbonyl-7-(5-fluorobenzothiazol-2-ylmethoxy)chroman, m.p. 109°-112° C. was prepared from 2-chloromethyl-5-fluorobenzothiazole and 2-ethoxycarbonyl-7-hydroxychroman.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:7]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]2[C:7]=1[C:15](=[O:16])[CH:10]=[CH:9][NH:8]2
Reactant: CCCOc1ccc(F)cc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCCOc1ccc(F)c2c(=O)cc[nH]c12
Temperature: 25 °C
Yield: 60.6 %

Procedure:
5-[(5-Fluoro-2-propoxyphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (7.6 g, 23.5 mmol) was added to diphenyl ether (15 ml), and the mixture was heated using a mantle heater, and then kept under reflux for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (5 ml) and n-hexane (10 ml) were added. The resulting mixture was stirred and the resultant insoluble matter was collected by filtration. The filtrate was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 3.15 g of powdery dark brown 5-fluoro-8-propoxy-1H-quinolin-4-one (yield: 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[K+].[K+].Cl[CH:34]([CH3:38])[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:11]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:35](=[O:36])[CH:34]([CH3:38])[O:26][C:3]=3[CH:4]=2)(=[O:9])=[O:10])=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Reactant: CC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (INTERMEDIATE AD) (2.0 g, 5.12 mmol) in DMF (15 mL) was added K2CO3 (2.1 g, 15.3 mmol, Quaigens). To the above suspension was added 2-chloropropanoyl chloride (0.780 g, 6.15 mmol) at 0° C. and reaction mixture was stirred at 25° C. for 30 min, then heated 60° C. for 3 h. The reaction mixture was cooled to 25° C. The organic compound was extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in hexanes as the eluent to afford 1.45 g of N-(4-methoxybenzyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as off white solid in 63.6% yield. 1H-NMR (400 MHz, DMSO): δ 7.45-7.46 (m, 2H), 7.40-7.44 (m, 1H), 7.23-7.26 (m, 3H), 7.02 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 5.19 (s, 2H), 3.70 (s, 3H), 1.44 (t, J=6.8 Hz, 3H); m/z (ESI, positive ion) 445.9 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C([Sn](CCCC)(CCCC)[C:17]1[O:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:21]=1)CCC>O1CCOCC1>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:19]1[O:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])=[CH:21][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccc(-c2ccc([N+](=O)[O-])cc2C)o1
Temperature: 97.5 °C
Yield: 84.8 %

Procedure:
To a solution of 2-bromo-5-nitrotoluene (4.32 g, 20 mmol) and tetrakis (triphenylphospine) palladium (0) (0.40 g) in anhydrous 1,4-dioxane (50 ml) was added 2,5-bis (tri-n-butylstannyl)furan (6.46 g, 10 mmol) and the mixture was heated overnight under nitrogen at 95-100° C. The resulting orange suspension was diluted with hexanes (15 ml), cooled to room-temperature, and filtered to give, after rinsing with hexanes, an orange solid (3.10 g), mp 241-243° C. The product was recrystallized from DMF (100 ml) to give a bright orange fluffy solid (2.87 g, 85%), mp 242-243° C. 1H NMR (DMSO-d6): 2.69 (s, 6H), 7.31 (s, 2H), 8.12 (m, 4H), 8.23 (s, 2H). Anal. Calcd. for C18H14N2O5 (338.31): C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:5]([CH:4]=1)[NH2:6]
Reactant: COc1cccc(N)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])c(N)c1
Temperature: 5 °C

Procedure:
A solution of 3-methoxyaniline (2.21 g) in acetic acid (3 ml) and acetic anhydride (10 ml) was stirred at room temperature for 1 hour. The solution was cooled to 5° C. and 60% nitric acid (1 ml) was added dropwise with stirring. When the cooling bath was removed, whereupon the solution temperature rose to 60° C. The solution was allowed to cool down to room temperature, poured into ice-water (100 ml) and neutralized with sodium hydroxide. The separated crystals were collected by suction and washed with water. To the crystals was added 4N hydrochloric acid (45 ml) and the mixture was refluxed for 2 hours. The reaction mixture was alkalized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform) to give 0.67 g of 5-methoxy-2-nitroaniline.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([O-:7])(=O)[CH3:5].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:37])[C:19]([N:22]2[C:27](=[O:28])[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:25](C=O)OC2)([CH3:21])[CH3:20])[CH:13]=[C:14]([Cl:16])[CH:15]=1>C(O)C>[Cl:16][C:14]1[CH:13]=[C:12]([NH:17][C:18](=[O:37])[C:19]([N:22]2[C:27](=[O:28])[CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25](=[N:2][OH:3])[O:7][C:4]2=[CH2:5])([CH3:21])[CH3:20])[CH:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: CC(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)N1COC(C=O)=C(c2ccccc2)C1=O
Reactant: CC(=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=C1OC(=NO)C(c2ccccc2)C(=O)N1C(C)(C)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 34.1 %

Procedure:
Hydroxylamine hydrochloride (0.31 g) followed by sodium acetate (0.37 g) was added to a stirred solution of N-(3,5-dichlorophenyl)-2-(6-formyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.5 g) in ethanol at room temperature. After 10 minutes the precipitated solid was filtered, washed with ethanol and water, and dried to give N-(3,5-dichlorophenyl)-2-(2,3-dihydro-6-hydroxyiminomethylene-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 115, 0.53 g) m.p. 207.5-209.5° C.
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:7])[NH2:6])[CH2:4][CH2:3]1.CC[O-].[Na+].[C:12]([OH:20])(=[O:19])/[C:13](=[C:15](\[CH:17]=O)/[Br:16])/[Br:14]>CCO>[Br:14][C:13]1[CH:12]=[N:7][C:5]([CH:2]2[CH2:4][CH2:3]2)=[N:6][CH:15]=1.[Br:16][C:15]1[C:13]([C:12]([OH:20])=[O:19])=[N:7][C:5]([CH:2]2[CH2:4][CH2:3]2)=[N:6][CH:17]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: N=C(N)C1CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc(C2CC2)nc1
Product: O=C(O)c1nc(C2CC2)ncc1Br
Temperature: 56 °C
Reaction time: 0.25 h
Yield: 127.8 %

Procedure:
5-Bromo-2-cyclopropylpyrimidine was prepared by the method of Budesinsky, Z., Coll. Czech. Chem. Commun., 1949, 14, 223-235. Cyclopropanecarboximidamide hydrochloride (2.5 g, 20.7 mmol) was dissolved in EtOH (4 mL), freshly prepared 4.1M NaOEt in EtOH (4.8 mL) was added followed by mucobromic acid (2.7 g, 10.3 mmol). The mixture was heated to 56° C. for 30 minutes, more NaOEt in EtOH (4.1M, 3.2 mL) was added and the reaction was stirred at 56° C. for another 15 minutes and then at room temperature overnight. The solvent was evaporated off, aqueous HCl (2M, 10 mL) was added and the brown solid was filtered off. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried and concentrated to give a brown oil that together with the solid gave crude intermediate 5-bromo-2-cyclopropylpyrimidine-4-carboxylic acid (1.6 g). The crude intermediate was heated at 140° C. for 8 minutes to give a brown sticky oil that was then partly dissolved in dichloromethane. The solution was decanted from the mixture and concentrated to give the subtitle compound as an oil (673 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>CN(C)C(=O)C>[C:22]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)[CH:14]=1)=[O:19])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CSc1ccc(-c2cnc3ccc(C(=O)NN)cn23)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CSc1ccc(-c2cnc3ccc(C(=O)NNC(C)=O)cn23)cc1
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
To a solution of 3-[4-(methylthio)phenyl]imidazo[1,2-a]pyridine-6-carbohydrazide (505 mg, 1.69 mmol) in N,N-dimethylacetamide (4 mL) was added acetyl chloride (0.132 mL, 1.86 mmol) at room temperature, and the resulting mixture was stirred for 1.5 hr. Ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration to give N′-acetyl-3-[4-(methylthio)phenyl]imidazo[1,2-a]pyridine-6-carbohydrazide (425 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:6])[CH3:5])[CH3:2].C(N(CC)CC)C.[SH2:33]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH:8]([N:10]1[C:23]2[CH:22]=[C:21]([C:24](=[S:33])[NH2:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH:4]([CH3:5])[CH3:6])[CH3:2]
Reactant: CCN(CC(C)N1c2ccccc2Sc2ccc(C#N)cc21)C(C)C
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCN(CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21)C(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 10-{(2RS)-1-[N-ethyl-N-(1-methylethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (2.3 g) and triethylamine in anhydrous pyridine (46 cc) is treated with hydrogen sulphide and stirred for 16 hours at a temperature in the region of 20° C. The greenish solution obtained is purged with nitrogen, poured into distilled water (200 cc) and extracted with ethyl acetate (200 cc and then 100 cc). The combined organic phases are washed with distilled water (3×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (4 g) is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (750 cc) of ethyl acetate and cyclohexane and collecting 60-cc fractions. The combined fractions 6 to 10 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-((2RS)-1-[N-Ethyl-N-(1-methylethyl)-amino]-2-propyl}-2-phenothiazinecarbothioamide (2.5 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.4 %

Procedure:
To a solution of 355 mg of t-butyl 4-(2-ethoxy-2-oxoethylidene)tetrahydropyridine-1(2H)-carboxylate in 10 ml of methanol, 50 mg of 10% palladium-on-carbon catalyst was added and stirred for 13 hours in 3 atmospheres' hydrogen pressure. Filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 334 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])C=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][C:29]2[C:37]([O:36][CH3:35])=[CH:42][CH:41]=[CH:40][C:39]=2[O:43][CH3:44])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1cccc(OC)c1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4c(OC)cccc4OC)cc3)c2cc1OC
Yield: 99.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2,6-dimethoxyphenol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:4][CH:3]=1.[Br:25]Br.O>C(O)(=O)C>[Br:25][C:8]1[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[C:6]=2[O:10][C:9]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1Br
Reaction time: 6 h
Yield: 50 %

Procedure:
1.0 g (2.8 mmol) of 3-(4-chloro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 30 ml of acetic acid, and 0.9 g (5.6 mmol) of bromine was dropwise added thereto at room temperature. After completion of the dropwise addition, stirring was carried out at 40° C. for 6 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and 10% aqueous ammonia and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.6 g (yield: 50.0%) of a pale yellow glassy substance. Refractive index: 1.5632 (20° C.).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].BrBr.[NH2:8][C:9]([NH2:11])=[S:10].[CH3:12]O>>[CH3:12][O:5][CH:2]([C:3]1[N:8]=[C:9]([NH2:11])[S:10][CH:4]=1)[CH3:1]
Reactant: NC(N)=S
Reactant: CO
Reactant: CCC(C)=O
Agent: BrBr
Product: COC(C)c1csc(N)n1
Temperature: 20 °C
Yield: 50 %

Procedure:
Butan-2-one (20 g, 277 mmol) and 200 mL MeOH were charged into a 1 L round bottom flask. A small amount of Br2 (5 mL) was added to the flask to initiate the reaction. The reaction initiated, and the mixture was stirred at 20° C. until the orange color disappeared. The reaction flask was immersed in an ice-water bath and Br2 was slowly added through an addition funnel. A total of 6 to 8 g (554 mmol) of Br2 was added. Thiourea (21 g, 278 mmol) was then added in portions to the reaction flask. After addition, the reaction mixture was heated at reflux for 2 hours. After the solvent was evaporated, the remaining residue was mixed with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over sodium sulfate. The product 4-(1-methoxyethyl)-thiazol-2-amine (22 g, yield=50%) was obtained and used in the next step without further purification. LCMS (API-ES) m/z (%) 159.2 (100%, M++H).