Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:53][N:54]([CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]([F:64])([F:63])[F:62]>CN(C=O)C.O>[CH3:53][N:54]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]([F:64])([F:62])[F:63])[CH:65]1[CH2:70][CH2:69][N:68]([C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:20][CH:19]=2)[CH2:67][CH2:66]1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Reactant: CN(c1ccccc1C(F)(F)F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)CNC(=O)c2ccc(Nc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.051 g, 0.00019 mol) in DMF (5 mL) was added DIPEA (0.061 g, 0.00048 mol), HOBt (0.025 g, 0.00019 mol) and EDCI.HCl (0.076 g, 0.00040 mol) at ambient temperature. After 2 minutes methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride (0.047 g, 0.00016 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [(column-Zorbax SB C18-21.2×150 mm, mobile phase-0.1% TFA in water (A)/Acetonitrile (B), gradient: (Time): (% B)-0:30; 2:50; 8:80)]) to afford 0.031 (38%) of N-(2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-4-phenylamino-benzamide. LCMS: 511.22 (M+1)+, 99.08%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.7 (m, 3H), 7.4 (m, 3H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.4 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.1 (m, 3H), 2.6 (s, 4H), 1.8 (d, 2H), 1.4 (m, 1H).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].C(COC)OC.Cl.[CH2:13]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]2[O:35][CH2:3][CH2:4][N:5]=2)=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: NCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C2=NCCO2)cc1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of glyme was added simultaneously solutions of 31 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride in 60 ml. of glyme and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the "solution" was stirred at room temperature overnight. The solution was refluxed for one hour and filtered. The solid was oven dried and portitioned between CH2Cl and water. The layers were separated and the organic phase dried over MgSO4. The organic layer was concentrated to about 100 ml. and 4-(hexadecylamino)benzoyl chloride hydrochloride diluted with an equal volume of hexane. The combined product (4.15 g.) was preabsorbed on 40 g. of silica III and placed on a column of silica III (800 g.). Fractions were collected by U.V. (CH2Cl2 -EtOH 97-3) and samples with the same TLC combined giving 3.8 g. after recrystallization from cyclohexane. A 210 mg. sample was recrystallized from acetonitrile and CH2Cl2 /hexane giving 149 mg., m.p. 123°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(F)cc12
Yield: 45 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-fluoro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 14) (26 mg, 0.10 mmol) and 3-aminobenzoic acid (26 mg, 0.19 mmol). The title compound was obtained in 45% yield (16.5 mg). MS (ESI+) calcd mass for C16H12FNO4S2 365.019178, found 365.018988.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.Cl[CH:10]([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: CC(C)Cl
Reactant: Oc1cncc(Br)c1
Product: CC(C)Oc1cncc(Br)c1

Procedure:
Prepared according to the procedure described in Example 167, Step 1, using 5-bromo-pyridin-3-ol and 2-chloro-propane.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][C:19](=[O:32])[CH:20]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:21].[OH-].[Na+].Cl>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([NH:18][C:19](=[O:32])[CH:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH3:21])=[C:11]([CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:33])=[O:2])[CH:16]=1
Reactant: COC(=O)c1ccccc1Cc1cc(Cl)ccc1NC(=O)C(C)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)Nc1ccc(Cl)cc1Cc1ccccc1C(=O)O)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of 2-[5-chloro-2-[2-(1-naphthyl) propanoylamino]phenyl methyl]benzoic acid methyl ester (440 mg; prepared in Example 1.) in methanol-dioxane (1:1; 8 ml) was added 2 mol/L aqueous solution of sodium hydroxide (3 ml) and the mixture was stirred for 3 hours at 50° C. The solution was acidified with hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried and concentrated to give a crude crystal. It was washed with ethyl acetate-hexane to give the title compound (342 mg; white powder) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:24][CH3:25])=[C:9]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[O:26]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][O:24][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:39][C:36]3[CH:35]=[CH:34][C:33]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:38][CH:37]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:13]
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)NCCCN1CCOCC1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(Oc4ccccc4)cc3)c2cc1C(=O)NCCCN1CCOCC1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A mixture of 4-chloro-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide (0.154 g), 4-phenoxyphenol (0.11 g), potassium carbonate (0.207 g) and DMF (4 ml) was stirred and heated to 100° C. for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate and the combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g); NMR Spectrum: (CDCl3) 1.86 (m, 2H), 2.47 (m, 6H), 3.6 (m, 2H), 3.7 (m, 4H), 4.11 (s, 3H), 6.48 (d, 1H), 7.04-7.18 (m, 7H), 7.37 (m, 2H), 7.51 (s, 1H), 8.02 (t, 1H), 8.65 (d, 1H), 9.19 (s, 1H); Mass Spectrum M+H+ 514.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])[NH:11]1.II.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C-:13]([N+:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Reactant: c1ccncc1
Agent: II
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2nn(-c3c(Cl)cc(Cl)cc3Cl)c(=O)[c-]2-[n+]2ccccc2)c1
Temperature: 0 °C

Procedure:
A mixture of 7.1 g of 1-(2,4,6-trichlorophenyl)-3-[2-chloro-5-(n-tetradecanamido)anilino]-5-pyrazolone, 2.5 g of iodine and 100 ml of pyridine was heated on a steam bath for 5 hours. After cooling, the reaction mixture was poured into a large volume of ice water. The precipitate was collected by filtration and dried. The powder was recrystallized from a solvent mixture of hexane and ethyl acetate to give 4.8 g of Compound 18 as yellow crystals having a melting point of 124° to 128°C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:22])[NH:18][CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH:19]([NH:18][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH2:8])=[CH:15][CH:14]=1)=[O:22])([CH3:21])[CH3:20]
Reactant: CC(C)NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)NC(=O)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-(iso-propylcarbamoyl-methyl)-benzylamine (426 mg, 1.4 mmol) in DCM (5 mL). Add 4M hydrogen chloride in dioxane (3.5 mL, 14 mmol) and stir at room temperature for 1 h. Concentrate in vacuo and elute the compound through a SCX column to obtain the title compound as a white solid (281 mg, 98%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:25][C:26]([CH2:29][OH:30])=[N:27][N:28]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:25][C:26]([CH2:29][OH:30])=[N:27][N:28]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1nnc(CO)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (200 mg, 0.58 mmol) in pyridine (3 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (70 mg, 0.53 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (8 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×20 mL). The organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 138-139° C., in 65% yield (151 mg, 0.34 mmol); 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=6.6 Hz), 1.22 (m, 18H), 1.54-1.57 (m, 2H), 2.64 (t, 2H, J=7.8 Hz), 4.57 (s, 2H), 6.05 (br, 1H), 7.35 (d, 2H, J=8.1 Hz), 7.67 (d, 2H, J=7.8 Hz); 13C NMR (75 MHz, DMSO-d6) δ 13.9, 22.1, 28.6, 28.7, 28.8, 29.0, 30.6, 31.3, 34.9, 58.4, 125.8, 128.9, 139.2, 147.5, 161.1, 167.5; MS (LCQ, ESI+) Calcd for C21H34N3O3S2 440.2. found 440.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C21H34N3O3S2 440.2042. found 440.2029 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]1[CH2:23][CH:22]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH:21]1[CH2:23][CH:22]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)C1CC1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1c1cc2cc(OCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a suspension of NaH (0.355 g, 14.0 mmol) in 100 ml of dry N,N-dimethylformamide was added slowly 5-benzyloxyindole (3.0 g, 13.4 mmol). When the evolution of H2 ceased, ethyl 2-bromocyclopropanecarboxylate(2.85 g, 0.0148 mol), as prepared in the preceding step, was added to the mixture and the reaction was refluxed for a period of 17 h under argon. Then the reaction was cooled down at ambient temperature and quenched carefully with water. After evaporation of the solvent under vacuum, the crude product was purified by flash chromatography on silica gel to obtain the title compound (3.45 g, 77%). 1H NMR (400 MHz, CDCl3) δ 1.34 (t, 3H, J=7.1 Hz), 1.62 (m, 1H), 1.73 (m, 1H), 2.14 (m, 1H), 3.78 (m, 1H), 4.24 (c, 2H, J=7.1 Hz), 5.10 (s, 2H), 6.36 (dd, 1H, J=0.7, 3.2 Hz), 6.98 (dd, 1H, J=2.4, 8.8 Hz), 7.04 (d, 1H, J=3.2 Hz), 7.14 (d, 1H, J=2.4 Hz), 7.38 (m, 4H), 7.45 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[CH2:7][CH2:8][Cl:9].[BH4-].[Na+]>C(O)C>[Cl:9][CH2:8][CH2:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[OH:10]
Reactant: O=C(CCCl)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCCl)c1cccs1

Procedure:
For example, a method is known wherein 1-(2-thienyl)-3-chloropropan-1-one is reduced using sodium borohydride in ethanol to obtain 3-chloro-1-(2-thienyl)-1-propanol, halogen exchange is subsequently conducted in acetone using sodium iodide to obtain 3-iodo-1-(2-thienyl)-1-propanol, and then this is reacted with a monomethylamine aqueous solution in tetrahydrofuran (CHIRALITY, 12, 26-29 (2000)). However, since the raw material used in this method is 1-(2-thienyl)-3-chloropropan-1-one, which is a very unstable compound, this method is not industrially applicable.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH3:19])[CH2:4][CH2:3]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.NN1CCN(CCC2C3C(=CC=CC=3)NC=2CC)CC1.C(N=C=O)CCC.NN1CCN(CCC2C3C(=CC(OC)=C(OC)C=3)NC=2)CC1.COC1C=C(N=C=O)C=C(OC)C=1OC>>[CH3:19][C:11]1[NH:12][C:13]2[C:18]([C:10]=1[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][N:2]([NH:1][C:31]([NH:30][C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)=[O:32])[CH2:3][CH2:4]1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: COc1cc(N=C=O)cc(OC)c1
Reactant: Cc1[nH]c2ccccc2c1CCN1CCN(N)CC1
Agent: CCCCN=C=O
Agent: CCc1[nH]c2ccccc2c1CCN1CCN(N)CC1
Agent: COc1cc(N=C=O)cc(OC)c1OC
Product: COc1cc(NC(=O)NN2CCN(CCc3c(C)[nH]c4ccccc34)CC2)cc(OC)c1

Procedure:
By following essentially the same procedure but starting with (a) 3-[2-(4-aminopiperazin-1-yl)ethyl]-2-methylindole and 3,5-dimethoxyphenylisocyanate; (b) 3-[2-(4-aminopiperazin-1-yl)ethyl]-2-ethylindole and butylisocyanate; and (c) 3-[2-(4-aminopiperazin-1-yl)ethyl]-5,6-dimethoxyindole and 3,4,5-trimethoxyphenylisocyanate, it is possible to obtain (a) 1-[1-(2-methylindol-3-ylethyl)piperazin-4-yl]-3-(3,5-dimethoxyphenyl)urea; (b) 1-[1-(2-ethylindol-3-ylethyl)piperazin-4-yl]-3-butylurea; and (c) 1-[1-(5,6-dimethoxyindol-3-ylethyl)piperazin-4-yl]-3-(3,4,5-trimethoxyphenyl)urea, respectively.
Reaction SMILES: Cl[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:3][N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:4][N:3]=[C:2]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1
Reactant: ClC(=NN=C(Cl)c1ccccc1)c1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2c(-c3ccccc3)nnc2-c2ccccc2)cc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
4.5 g (16 mmol) of 1,2-bis(chloro(phenyl)methylene)hydrazine, 2.0 g (16 mmol) of 4-bromoaniline, and 30 mL of N,N-dimethylaniline were put into a 100 mL three-neck flask, and nitrogen substitution was performed on the contents of the flask. The mixture was stirred at 135° C. for 5 hours. After the reaction, a solid was precipitated out with the reactive solution being added to approximately 100 mL of 1 N diluted hydrochloric acid and the mixture being stirred for 30 minutes. Suction filtration was performed on the precipitated solid, and a solid was obtained. The obtained solid was dissolved in toluene and washed with water and a saturated sodium carbonate solution, in the order given. Magnesium sulfate was added to an organic layer, and the mixture was dried. Suction filtration was performed on the mixture to remove the magnesium sulfate, and thus a filtrate was obtained. The solid, which was obtained by condensation of the obtained filtrate, was recrystallized with a mixed solvent of ethanol and hexane, so that 2.3 g of a powdery white solid, which was the object of the synthesis, was obtained at a yield of 38%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[C:6]1(=[O:13])C[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(OCC)=O>C(OCC)C>[OH:5]/[CH:3]=[C:4]1\[C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]\1
Reactant: CCO
Reactant: O=C1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC=O
Product: O=C1CCCCC/C1=C/O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 976.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 535 mg, 13.4 mmol) in diethyl ether (25 mL) at 0° C. was added ethanol (0.06 ml, 1.03 mmol) dropwise. The grey suspension was stirred at 0° C. for 20 min. A solution of cycloheptanone (1.58 ml, 13.4 mmol) and ethyl formate (1.63 ml, 20.1 mmol) in diethyl ether (3 mL) was added dropwise over 10 min. The pale yellow heterogeneous reaction mixture was stirred at 0° C. for 1 h then warmed to room temperature for 4 h. The reaction was carefully quenched with ethanol (2 mL) then water (25 mL) was added. The layers were separated and the aqueous phase was washed with diethyl ether. The organic layers were set aside and later discarded. The aqueous layer was acidified with 1M HCl until pH=2 and then extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 and concentrated to afford 1.41 g (75%) of 2-[1-hydroxy-meth-(Z)-ylidene]-cycloheptanone as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 14.69 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 2.52-2.61 (m, 2H), 2.23-2.32 (m, 2H), 1.67-1.82 (m, 4H), 1.58-1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1.[BH4-].[Na+]>CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[N:21][CH:22]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: O=Cc1ccc(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)nc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and 5-chloro-2-formylpyridine (60 mg, 424 μmol) in MeOH (3 ml) was stirred at room temperature for one day and then at 45° C. for two days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (163 mg, 4.3 mmol) was added in a few portions and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated. Crystallization from DCM afforded a white solid as desired product (96.6 mg, 90% yield). MS +m/z: 369 (M+H)+
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([NH2:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:29][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NC(Cc1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NC(Cc1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 1,2-diphenylethylamine (0.69 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(1,2-diphenylethyl)-3 pyridinecarboximidamide (0.60 g, 1.8 mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride solution in methanol (2.5 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=3[N:7]=2)[CH:19]=[CH:20][N:21]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccnc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2oc(-c3ccnc(Cl)c3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
To a mixture of 0.77 g of 2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 20 ml of tetrahydrofuran and 0.80 g of triphenylphosphine, 1.32 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the mixture solution was stirred for 1.5 hours at room temperature and then 1.5 hours at 60° C. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.60 g of 2-(2-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 21”).