Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:38])[C@H:27]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:38])[C@H:27]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:28][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccccc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1
Product: CC(=O)SCC(C(=O)N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1)C(C)c1ccccc1
Yield: 62 %

Procedure:
Using the procedure described in Example 60, starting with 2-acetylthiomethyl-3-phenylbutanoic acid and O-benzylserine benzyl ester, and after purification by chromatography, eluting with a hexane/ethyl acetate (8:2 by volume) mixture, N-(2-acetylthiomethyl-1-oxo-3-phenylbutyl)-O-benzylserine benzyl ester is obtained in a 62% yield, the characteristics of which are as follows: Rf =0.16 [hexane/ethyl acetate (8:2 by volume)].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]([CH3:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[CH3:14][N:15]=[C:16]=[O:17]>C(OCC)(=O)C>[CH3:13][C:8]1([CH3:12])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH:15][CH3:14])=[O:17])[S:3][C:4]=2[CH:10]([CH3:11])[CH2:9]1
Reactant: CC1CC(C)(C)Cc2nc(N)sc21
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1nc2c(s1)C(C)CC(C)(C)C2
Reaction time: 2 h

Procedure:
2-Amino-5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazole (0.1 mole) is dissolved in ethyl acetate (100 ml) and the solution is charged into a glass reaction vessel fitted with a stirrer and thermometer. Methyl isocyanate (0.11 mole) is added dropwise to this solution over a period of about 30 minutes. The temperature of the reactant is held at about 20° C. to 30° C. during the addition. At the end of the addition, stirring is continued at room temperature for a period of about 2 hours. The reaction mixture is then filtered and the filtered-off solids are air dried to yield the desired product N-(5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)-N'-methylurea.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:2]([C:7]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[C:27]4[C:28]5[C:20](=[CH:21][NH:22][C:23]=5[CH:24]=[CH:25][CH:26]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl[S:38]([OH:41])(=[O:40])=[O:39]>C(Cl)Cl>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:2]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:16]3[C:27]4[C:28]5[C:20](=[C:21]([S:38]([OH:41])(=[O:40])=[O:39])[NH:22][C:23]=5[CH:24]=[CH:25][CH:26]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:29][CH:30]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3c[nH]c4cccc2c34)cc1)c1ccccc1-c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCc3c(S(=O)(=O)O)[nH]c4cccc2c34)cc1)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 10 (0.20 g, 0.42 mmol) in CH2Cl2 (100 mL) at about 0° C. was treated with chlorosulfonic acid (0.056 g, 1.1 eq) and stirred for about 2 h. The reaction was Warmed to about rt, stirred for about 18 h and evaporated to a tan powder. The powder was purified by preparative HPLC (MeCN:water, 1:3) to give 18 (tan powder). 1H NMR (DMSO-d6) 2.1 (m, 4 H), 3.0 (m, 1 H), 3.2 (t, J=4, 1 H), 6.1 (m, 1 H), 6.7 (t, J=6, 1 H), 6.9 (d, J=5, 1 H), 7.1 (m, 4 H), 7.3-7.6 (m, 9 H), 10.3 (br. s, 2 H), 11.1 (s, 1 H). MS m/e 552.62 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1sccc1Cl
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1sccc1Cl

Procedure:
N-[(tert-Butoxy)carbonyl]3-chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate (107) is synthesised from 3-chlorothiophene-2-sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, DMSO-d6) 8.29 (1H, d, 5.3 Hz), 7.40 (1H, d, 5.2 Hz), 1.39 (9H, s), 1.28 (9H, s).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.ClC1C=CC(C2(O)CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1>>[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([C:10]2([OH:12])[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: OC1(c2ccc(Cl)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Product: OC1(c2ccc(C(F)(F)F)cc2)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
This compound was prepared from compound (3) and 4-(trifluoromethyl)phenylmagnesium bromide using the procedure described for compound (4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH2:8][Br:10])[CH:7]=1
Reactant: Cc1cc(Br)ccc1F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr
Reaction time: 0.5 h

Procedure:
To a refluxing solution of 5-bromo-2-fluorotoluene (3.8 g, 20 mmol) in CCl4 (30 mL) illuminated with a 275 W UV-sun lamp, a solution of Br2 (1.1 mL, 20 mmol) in CCl4 (30 mL) was added dropwise. Refluxing and irradiation were continued for an additional 0.5 h and then the clear pale amber solution was concentrated. Distillation of the residue provided the desired compound (1a) as a clear colorless oil; bp 126°-136° C. (15 mm); NMR 4.38 (2H, s), 6.6-7.7 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35]C2N=CC(C#N)=CC=2)[N:21]=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:35][CH2:34][CH2:33][NH:32][C:22]2[N:21]=[C:20]([C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[Cl:12])[C:25]([C:26]3[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=3)=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-(4-methyl imidazol-2-yl)pyrimidin-2-yl]amine was prepared from 2-amino-6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)-pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1

Procedure:
The N-tert-butyl-3-{4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-benzenesulfonamide was prepared from 2-chloro-4-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.97) (0.350 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.400 g, 76%). MS (ISP) 527.2 [(M+H)+]; mp 218° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]=[N+:27]=[N-:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[CH:40]=[C:39]([Si:36]([CH3:38])([CH3:37])[CH3:35])[N:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2cc([Si](C)(C)C)nn2)CC1

Procedure:
A solution of 3-[(trans-4-azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.0 g, 2.0 mmol) in trimethylsilylacetylene (1.4 ml, 10 mmol) is treated in microwave at 120° C. for 2 h. The mixture is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (5% ethyl acetate/hexane to 100% ethyl acetate) to afford 5-(3,3-dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(4-trimethylsilanyl-[1,2,3]triazol-1-yl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.[NH2:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)=[S:32]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:32][C:31]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[N:30][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[C:12]=2[F:29])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 60 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (4.80 g, 10.86 mmol) and 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperidinecarboxylate (3.19 g, 13.04 mmol) the title compound of Step A was obtained (4.31 g, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 7.36-7.68 (m, 5H), 7.32 (t, J=7.8 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 4.01 (d, J=11.4 Hz, 2H), 3.20-3.34 (m, 1H), 2.92 (d, J=12.6 Hz, 2H), 2.07 (d, J=11.3 Hz, 2H), 1.52-1.70 (m, 2H), 1.40 (s, 9H). m/z (ES+): 667 [M+H]+.
Reaction SMILES: Cl[S:2]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3].O.[NH3:18]>C1COCC1>[NH2:18][S:2]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3]
Reactant: N
Reactant: CCOC(=O)c1c(C)nn(C)c1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)nn(C)c1S(N)(=O)=O
Reaction time: 1 h

Procedure:
4.6 g of ethyl 5-chlorosulfonyl-1,3-dimethylpyrazole-4-carboxylate is dissolved in 8 ml of THF, and the solution is added dropwise to 25 ml of ammonia water at 5° C. to 7° C. The reaction mixture is stirred at the same temperature for 1 hour, and then concentrated to dryness under reduced pressure. To the residue is added ethyl acetate, followed by filtration to remove impurities, and the filtrate is concentrated under reduced pressure. The residue is diluted with n-hexane, and then cooled with ice to give crystals. The crystals are filtered and dried to yield 3.6 g of the title compound. mp. 112° to 113° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[NH:13])[CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]([C:21]([N:23]=[C:24]=[S:25])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:1]([O:8][C:9](=[NH:13])[C:10]([C:11]#[N:12])=[C:24]([SH:25])[NH:23][C:21]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: N#CCC(=N)OCc1ccccc1
Solvent: CC#N
Product: N#CC(C(=N)OCc1ccccc1)=C(S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a stirred 0° C. solution of 2-cyano-acetimidic acid benzyl ester (327 g, 1.88 mol) in acetonitrile (1 L) was added a 0° C. solution of phenoxycarbonylisothiocyanate (353 g, 1.97 mol) in acetonitrile (1 L). The reaction was allowed to warm to ambient temperature and was stirred overnight. The mixture was then placed in the refrigerator and kept still at 5° C. for 48 hours. The solid product was filtered, compressed, and washed with 20° C. acetonitrile (3×200 mL). Air was then drawn though the relatively stable solid followed by further drying under high vacuum to yield a yellow solid (282 g, 798 mmol, 42%). 1H NMR (400 MHz, DMSO) δ5.39 (s, 2H), 7.11-7.19 (m, 2H), 7.20-7.24 (m, 1H), 7.36-7.46 (m, 7H), 10.23 (broad s, 1H), 10.67 (s, 1H), 12.19 (broad s, 1H) ppm; MS (APCI, m/z): 354 [M+H]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>ClCCl>[O:31]=[C:27]1[N:26]([CH2:25][CH:24]=[O:23])[CH2:30][CH2:29][O:28]1
Reactant: O=C1OCCN1CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCN1CCOC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A Dess-Martin reagent (516 mg) was added to a solution of 3-(2-hydroxyethyl)oxazolidin-2-one (144 mg) in dichloromethane (5.0 ml), and the mixture was stirred for 1 hour at room temperature. The solvent was evaporated off to obtain crude crystals, (2-oxooxazolidin-3-yl)acetaldehyde without purification. A solution of ammonium acetate (771 mg) in methanol (5.0 ml) was added to a suspension of (2-oxooxazolidin-3-yl)acetaldehyde and Compound 204 (286 mg) in tetrahydrofuran (10 ml), and the mixture was stirred for 2 weeks at room temperature. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and then extracted twice with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by NH silica gel column chromatography (chloroform→chloroform:methanol=95:5) and then recrystallized (methanol-ethyl acetate-hexane) to yield the title compound (149 mg) as a colorless powder (mp: 232.0-233.0° C.)
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][N:12]([CH:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[C:31](Cl)[CH:30]=2)=[O:28])[CH2:23][CH2:22]1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH3:11][N:12]([CH:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[C:31]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:30]=2)=[O:28])[CH2:23][CH2:22]1)[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(Cl)nc3ccccc23)CC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(OCc3ccccc3)nc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of 0.4 g of benzyl alcohol in 2 ml of dimethylformamide was dropwise added to a suspension of 150 mg of sodium hydride in 5 ml of dimethylformamide with ice-cooling. The mixture was stirred at the same temperature for 30 minutes. Thereto was dropwise added 1.0 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl)carbonyl-2-chloroquinoline in 2 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. The reaction mixture was poured into ice water, followed by extraction with methylene chloride. The extract was washed with water and an aqueous sodium chloride solution in this order, then dried with magnesium sulfate and concentrated under reduced pressure to obtain 1.1 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl)carbonyl-2-benzyloxyquinoline.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=O)[C:15]([OH:17])=[O:16].[OH-].[K+]>O.NN>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 93.6 %

Procedure:
A suspension of fluorene-2-glyoxylic acid (33.7 g) in hydrazine hydrate (50 ml) is refluxed until solution is achieved, cooled and treated with potassium hydroxide (33.7 g) in portions. The mixture is then refluxed for 1 hour, and the excess hydrazine removed by distillation. The residue is dissolved in water and extracted with chloroform. The aqueous layer is acidified to pH 2.0 with 10% HCl and extracted with ether. The ether extracts are washed, dried (MgSO4) and evaporated to give the title compound (29.7 g, mp 184°-186°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.Cl.[CH3:30][C:31]1([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:34]2[CH2:35][CH2:36][C:31]([OH:37])([CH3:30])[CH2:32][CH2:33]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: CC1(O)CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCC(C)(O)CC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 32 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.500 mmol), 4-methylpiperidin-4-ol hydrochloride (91 mg, 0.60 mmol), sodium tert-butoxide (187 mg, 1.95 mmol), Xantphos (23 mg, 0.040 mmol), and tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.010 mmol) in 1,4-dioxane (2.5 mL) was stirred at 90° C. under Ar atmosphere. The reaction mixture was poured into 5% NaHCO3 aqueous solution (20 mL) and extracted with AcOEt (20 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was purified by basic silica gel column chromatography (MeOH/AcOEt=0%-20%). The residue was recrystallized from AcOEt/hexane to give the title compound (76.2 mg, 32% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 1.14 (3H, s), 1.39-1.60 (4H, m), 3.20 (2H, ddd, J=13.2, 8.7, 5.3 Hz), 3.40-3.52 (2H, m), 3.76 (3H, s), 4.36 (1H, s), 6.70 (1H, dd, J=9.0, 2.6 Hz), 6.91 (2H, d, J=1.9 Hz), 6.79-6.94 (1H, m), 7.32 (1H, d, J=1.9 Hz), 7.29 (1H, s), 7.35-7.47 (3H, m), 7.77 (1H, d, J=1.9 Hz), 8.37 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 476 [M+H]+. Anal. Calcd for C26H26FN5O3: C, 65.67; H, 5.51; N, 14.73. Found: C, 65.53; H, 5.50; N, 14.66.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=O)[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5].C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][N:2]([CH3:3])[CH3:1])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)cc12
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethylamine (5.6 M solution in EtOH, 4.2 ml, 23.20 mmol) is added under an atmosphere of argon to a solution of (2-Chloro-7-formyl-naphthalen-1-yl)-acetic acid ethyl ester (4.28 g, 15.46 mmol) in THF (80 ml). The mixture is stirred at RT for 18 h, before a solution of sodium cyanoborohydride (1.16 g, 18.56 mmol) in MeOH (20 ml) and glacial acetic acid (4.4 ml, 77.33 mmol) are added. After stirring at RT for 2 h, TLC analysis indicates complete consumption of starting material. The reaction mixture is diluted with water and adjusted to pH 8-9 by the addition of conc. aq. NaHCO3 solution. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent yields the crude reaction product. Purification by FCC (EtOAc, then EtOAc/MeOH 4:1) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=8.8 Hz, 3H), 2.28 (s, 6H), 3.62 (s, 3H), 4.18 (q, J=8.8 Hz, 2H), 4.32 (s, 3H), 7.48 (d, J=9.9 Hz, 1H), 7.52 (d, J=9.9 Hz, 1H), 7.73 (d, J=9.9 Hz, 1H), 7.80-7.84 (m, 2H). ES+−MS: 306.3, 308.2. [M+H]+.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1([C:19](OC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:1]1([NH:8][C:9]2[S:10][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:19](=[O:20])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(Br)CCCCC1
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)SC12CCCCC2

Procedure:
Synthesis was performed from N-cycloheptylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:7]([O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:8]
Reactant: BrCCCCBr
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl cyanoacetate (2.50 g, 22 mmol) and 1,4-dibromobutane (5.00 g, 23.0 mmol) were dissolved in anhydrous DMF (20 ml) under nitrogen and cesium carbonate (21.0 g, 64 mmoles) added with water bath cooling. After stirring at room temperature for 18 h the reaction was diluted with water and extracted with ethyl acetate (2×80 ml), the organic layers were combined and washed with water (40 ml) and saturated aqueous sodium chloride solution (25 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 1-cyano-cyclopentanecarboxylic acid ethyl ester as an almost colourless oil (3.64 g, 98%).
Reaction SMILES: C(C1C=CC(N)=CC=1)CC1C=CC(N)=CC=1.C[C:18]1[CH:23]=[C:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27](C)[CH:26]=2)[CH:21]=[CH:20][C:19]=1[NH2:33].CC1C=C(C2C=C(C)C(N)=C(C)C=2)C=C(C)C=1N.C1C(N)=CC=C(S(C2C=CC(N)=CC=2)(=O)=O)C=1.C1C(N)=CC=C(OC2C=CC(N)=CC=2)C=1.NC1C2C(=C(N)C=CC=2)C=CC=1.CC1C=C(C2C=CC(N)=C(C)C=2)C=CC=1N>>[CH2:24]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[C:22]1[CH:21]=[CH:20][C:19]([NH2:33])=[CH:18][CH:23]=1
Reactant: Cc1cc(Cc2ccc(N)c(C)c2)ccc1N
Agent: Cc1cc(-c2cc(C)c(N)c(C)c2)cc(C)c1N
Agent: Cc1cc(-c2ccc(N)c(C)c2)ccc1N
Agent: Nc1ccc(CCc2ccc(N)cc2)cc1
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
4,4′-ethylenedianiline; 4,4′-diamino-3,3′-dimethyldiphenylmethane; 3,3′,5,5′-tetramethylbenzidine; 4,4′-diaminodiphenyl sulfone; 4,4′-diaminodiphenyl ether; 1,5-diaminonaphthalene; 3,3′-dimethyl-4,4′-diaminobiphenyl;