Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].BrC1C=NN([C:23]2[CH:28]=CC=[CH:25][CH:24]=2)C=1>>[C:1]1([N:3]2[CH:7]=[C:6]([B:8]3[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]3)[CH:5]=[N:4]2)[CH:25]=[CH:24][CH:23]=[CH:28][CH:2]=1
Reactant: Brc1cnn(-c2ccccc2)c1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-phenyl-1H-pyrazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)C.C(OCC)(=O)C>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[S:14]
Reactant: NCCCCc1nccs1
Reactant: CN=C=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=S)NCCCCc1nccs1
Yield: 85.2 %

Procedure:
2-(4-Phthalimidobutyl)thiazole (5.0 g) is hydrolysed with hydrochloric acid in the usual way. The amine hydrochloride obtained is basified with potassium carbonate and extracted with ether-ethanol (3:1) to give 2-(4-amino-butyl)thiazole as a colourless oil. The reaction of the amine (2.0 g) and methyl isothiocyanate (0.98 g) in ethanol (10 ml) for 1 hour, followed by chromatography of the product on silica gel with ethyl acetate as eluent gives N-methyl-N'-(4-(2-thiazolyl)butyl) thiourea (2.5 g) as a colourless oil. Formation of the hydrobromide salt yields a crystalline solid, m.p. 130°-132° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=3)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1OC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(OC)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 58.2 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methoxybenzoate obtained in Example (258b) (about 0.08 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (14 mg, 0.08 mmol), WSC hydrochloride (52 mg, 0.27 mmol), HOBT (18 mg, 0.14 mmol), dichloromethane (1 mL) and DMA (1 mL), to obtain 21 mg of the title compound as a colorless oily substance (57%).
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=1[Br:25].[CH3:26][CH2:27][SH:28].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:25][C:14]1[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=1[CH2:12][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH2:11])=[N:10][C:2]=2[S:28][CH2:27][CH3:26]
Reactant: CCS
Reactant: COc1cc(Cn2cnc3c(Br)nc(N)nc32)c(Br)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCSc1nc(N)nc2c1ncn2Cc1cc(OC)c(OC)c(OC)c1Br
Temperature: 70 °C

Procedure:
A mixture of 6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see previous example), EtSH, K2CO3 and THF was placed in a pressure vessel and heated to 70° C. for 6 h. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 6.039 min. 1H-NMR (CDCl3): δ 7.72 (s, 1H), 6.62 (s, 1H), 5.30 (s, 2H), 4.98 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H), 3.35–3.29 (q, 2H), 1.44–1.41 (t, 3H).
Reaction SMILES: Cl[C:2](Cl)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([CH3:13])=[CH:10][C:11]=1[Cl:12])=[O:5].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[NH:16]([C:2]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([CH3:13])=[CH:10][C:11]=1[Cl:12])=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc(Cl)c(C(=O)C=C(Cl)Cl)c(Cl)n1
Solvent: C1COCCO1
Product: Cc1cc(Cl)c(C(=O)C=C(Nc2ccccc2)Nc2ccccc2)c(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 18.0 mmol) in 1,4-dioxane (25 mL) was cooled to 0° C. and aniline (5.1 mL, 55.0 mmol) and TEA (7.7 mL, 55.0 mmol) were added dropwise. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. The solvents were removed in vacuo. The residue was purified by passing it through a pad of silica gel with EtOAc:Hex (1:5) as the eluent to provide 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (7.1 g, 99%): LCMS RT: 3.06 min, MH+: 398.7.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[F:19][CH2:20][CH2:21][NH2:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[F:19][CH2:20][CH2:21][NH:22][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12][CH2:13]1
Reactant: NCCF
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: FCCNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 2-fluoroethylamine hydrochloride (50 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added to the reaction mixture, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (12 mg) and a syn-form compound (12 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[CH3:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[CH3:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) and triethylamine (0.31 mL, 2.2 mmol) in THF (15 mL) at 5˜10° C., was added 3,4-dimethyl phenyl isocyanate (0.29 mL, 2.1 mmol). Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3,4-dimethyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.14 min (96.6%); mp, 241-243° C.; 1HNMR (DMSO-d6)2.11-2.21 (m, 7H, CHH, 2ArCH3), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.71 (d, J=5 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.56 (t, J=5 Hz, 1H, CH2NH), 6.92-7.78 (m, 6H, Ar), 8.58 (s, 1H, NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.58, 19.59, 20.70, 23.24, 30.62, 42.26, 56.52, 115.18, 117.76, 118.99, 125.54, 126.28, 128.50, 129.46, 134.01, 136.03, 138.15, 141.69, 148.27, 154.87, 155.11, 160.94, 169.47, 172.65. LCMS MH=448; Anal Calcd For C24H25N5O4+2.0H2O: C, 59.62; H, 6.05; N, 14.48. Found: C, 59.36; H, 5.95; N, 14.24.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH2:21])[CH2:20]2)[CH:14]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cl)cc1C1(c2ccc(C)cc2)C=C(N)N=C(N)C1
Yield: 17 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-ethoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and p-tolylboronic acid provided the title compound (17% yield). 1H NMR (acetone-d6) δ1.35 (t, 3H, J=7.0 Hz, CH3), 2.27 (s, 3H, CH3), 4.08 (q, 2H, J=7.0 Hz, CH2), 5.24 (bs, 2H, NH2), 6.14 (d, 1H, J=1.0 Hz, Ar), 6.32 (t, 1H, J=0.9 Hz, Ar), 7.06-7.10 (m, 3H, Ar), 7.29-7.34 (m, 2H, Ar), 7.51-7.54(m, 2H, Ar), 7.67 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH2:18])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C>[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH2:18])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:3]=2)[CH2:30][CH2:29]1
Reactant: Nc1nc2c(Oc3cc(Cl)ncn3)cccc2s1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2c(Oc3cc(N4CCC(C(F)(F)F)CC4)ncn3)cccc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 133(a)), (300 mg, 1.1 mmol) in dry DMF (3.0 mL) stirred at room temperature was added K2CO3 (590 mg, 4.3 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (410 mg, 2.1 mmol, Matrix Scientific). The reaction mixture was stirred at 80° C. for 4 h. The resulting mixture was allowed to cool to room temperature and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water (2×), MeOH (1×), and EtOAc (3×), then dried in vacuum. The title compound was obtained as a white amorphous solid. MS (ESI, pos. ion) m/z: 396 (M+1). Anal. Calcd for C17H16F3N5OS: C, 51.64; H, 4.08; N, 17.71; F, 14.41. Found: C, 51.62; H, 4.09; N, 17.61; F, 14.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[S:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:33]1[CH2:34][CH2:35][S:30][CH2:31][CH:32]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(C3=CCSCC3)c(Cl)cc21
Temperature: 85 °C

Procedure:
Palladium tetrakistriphenylphosphine (41.7 mg, 0.036 mmol) was added to a stirred suspension of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-hexahydrofuro[3,2-b]furan-3-ol (Intermediate 3, 100.0 mg, 0.181 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 45, 61.2 mg, 0.270 mmol), and potassium phosphate tribasic (115.0 mg, 0.542 mmol) in degassed 20% water in dioxane (1.85 mL). The reaction mixture placed under N2 and heated at 85° C. for 10 h. The reaction mixture was cooled to room temperature. The lower aqueous layer drawn off and discarded. The remaining reaction mixture was evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C23H32ClN3O5SSi 525.15 observed m/e: 526.17 (M+H)+ (Rt 1.64/2.0 min)
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][NH:4][CH2:3]1.C(Cl)Cl.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH2:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:2][CH2:3][N:4]([C:16](=[O:18])[CH3:17])[CH2:5]1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2ccccc2CC1
Yield: 95 %

Procedure:
To a solution of 2,3,4,5-Tetrahydro-1H-benzo[d]azepine hydrochloride (7.0 g) in DCM (200 ml) Et3N (12.1 ml, 2.5 eq) was added followed by a dropwise addition of acetic anhydride (4 ml). After 2 h the mixture was washed in sequence with 1N HCl, 5% aqueous NaHCO3 and brine, then dried over Na2SO4 and concentrated to afford a white solid (6.9 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[N:7]2>C(O)C.[Ni]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[CH:9][C:10]=1[C:15]([OH:17])=[O:16])[N:7]=[C:6]([C:18]([F:21])([F:19])[F:20])[CH:5]=[CH:4]2
Reactant: Cc1c([N+](=O)[O-])c(C(=O)O)cc2nc(C(F)(F)F)ccc12
Agent: [Ni]
Solvent: CCO
Product: Cc1c(N)c(C(=O)O)cc2nc(C(F)(F)F)ccc12
Reaction time: 12 h
Yield: 71.4 %

Procedure:
A solution of 5-methyl-6-nitro-2-trifluoromethyl-quinoline-7-carboxylic acid (1.40 g) in ethanol (100 mL) is hydrogenated at atmosphere pressure and ambient temperature in the presence of Raney-nickel catalyst. TLC analysis after 12 h shows reaction completion. The mixture is filtered over hyflo and the filtrate concentrated in vacuum. The residue is recrystallized from hexane/ethyl acetate to give 0.90 g of the title compound of the formula
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Temperature: 150 °C
Yield: 67.5 %

Procedure:
tert-Butyl piperidin-4-ylcarbamate (2 g, 10 mmol), 3,6-dichloropyridazine (1.79 g, 12 mmol) and TEA (2.1 ml, 15 mmol) was dissolved in dry DMF (30 ml) and the reaction mixture was heated in a microwave reactor at 150° C. for 20 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (300 ml). The organic phase was dried (Na2SO4), filtrated and evaporated. The residue was purified by silica gel column chromatography using a 98:2 mixture of DCM:MeOH to give the title compound (2.11 g, 68%) as a solid. 1H-NMR (CDCl3, 500 MHz): δ 7.19 (d, 1H), 6.91 (d, 1H), 4.48 (bs, 1H), 4.29-4.20 (m, 2H), 3.73 (bs, 1H), 3.14-3.04 (m, 2H), 2.10-2.02 (m, 2H), 1.49-1.38 (m, 2H), 1.45 (s, 9H); 13C-NMR (CDCl3, 125 MHz): δ 158.9, 155.2, 146.7, 128.9, 115.5, 79.6, 47.9, 44.4, 31.9, 28.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:14][OH:15])[CH2:9][CH2:8]2
Reactant: NO
Reactant: COc1cccc2c1C(=O)CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1C(=NO)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a suspension of 7-methoxyindanone (5.0 g, 31 mmol) and hydroxylamine hydrochloride (12.9 g, 185 mmol) in 100 mL ethanol was added the solution of sodium acetate (11.4 g, 139 mmol) in 35 mL water at room temperature. The reaction mixture was heated at reflux for 4 h, then stirred at room temperature for 18 h. The suspension was filtered, the white solid was washed with water, ethanol and diethyl ether to give the title compound (5.4 g, 31 mmol, 98%). ESMS m/z 178 (M+H)+.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].CI.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:12][CH:11]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][N:19]([CH3:1])[C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.9 %

Procedure:
1.18 g of sodium bicarbonate and 0.876 ml of methyl iodide were added, whilst ice-cooling, to a solution of 3.3 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methoxycarbonylpyrrolidine [prepared as described in step (9) above] dissolved in 30 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography over silica gel (eluted with a 1:2 by volume mixture of ethyl acetate and benzene), to afford 968 mg of the title compound as an oil.
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.[Br:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) and 4-bromophenylboronic acid (80 mg) were dissolved in a mixed solution composed of dichloromethane (5 ml) and triethylamine (0.07 ml) to prepare a solution. Copper(II) acetate (50 mg) was added to the solution, and the mixture was stirred at room temperature for 16 hr. The stirred mixture was filtered, and the filtrate was then concentrated. The crude thus obtained was purified by chromatography on silica gel to give (4-bromophenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]amine (70 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:21][S:22][C:23]1[C:28]([N:29]=[C:30]=[O:31])=[C:27]([S:32][CH3:33])[CH:26]=[C:25]([CH3:34])[N:24]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:21][S:22][C:23]1[C:28]([NH:29][C:30]([N:9]([CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[CH2:8][C:7]2[CH:19]=[CH:20][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:31])=[C:27]([S:32][CH3:33])[CH:26]=[C:25]([CH3:34])[N:24]=1
Reactant: CC(C)c1ccc(CNC2Cc3ccccc3C2)cc1
Reactant: CSc1cc(C)nc(SC)c1N=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cc(C)nc(SC)c1NC(=O)N(Cc1ccc(C(C)C)cc1)C1Cc2ccccc2C1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A solution of 2-(4-isopropylbenzylamino)indane (159 mg, 0.6 mmol) and 2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (136 mg, 0.6 mmol) in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, diluted with 50 ml ethyl acetate and washed with 3×50 ml water, then 50 ml brine, dried (sodium sulfate), filtered and concentrated in vacuo. The solid residue (265 mg) was purified by column chromatography on silica gel (150 g), eluting with 7:3 hexane/ethyl acetate to yield the title compound as a white solid (195 mg, 66% yield).
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:18]([O:17][C:15]([NH:14][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of 1 g of (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate in 5 mL of THF were added 0.4 mL of ethyl piperidine-4-carboxylate and 1 mL of diisopropylethylamine, followed by stirring at 70° C. for 14 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 160 mg of ethyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}piperidine-4-carboxylate.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:23])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)CCl>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:15]1[CH3:23])[CH3:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 22.5 g (0.15 mole) of phthalic anhydride and 61.0 g (0.30 mole) of 77.5 percent active 1-ethyl-2-methylindole in 120 ml of ethylene dichloride chilled to 0° to 5° C. by means of an ice bath, there was added in small portions 32.0 g (0.24 mole) of aluminum chloride. The mixture was maintained at 0°-5° C. for an additional 15 minutes, allowed to warm to room temperature and stirred overnight. Then, 240 ml of water was added to the reaction mixture and the ethylene dichloride layer was separated from the acidic aqueous layer. The organic layer was extracted with 600 ml of 3.5 percent aqueous sodium hydroxide. The alkaline extract was acidified with dilute hydrochloric acid and the separated solid collected, washed with water and dried to obtain 24.0 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =CH2CH3), a slightly pink solid having a melting point of 184°-185° C.