Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].O>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ccccc2Cl)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (5 g) and 2-chloroaniline (2.5 mL) in toluene (60 mL) is heated at reflux under a Dean and Stark water trap for 3 hours. After concentration, the residue is dissolved in methanol (60 mL) and the stirred solution is treated at 0° C. with sodium cyanoborohydride (2.1 g). The temperature is allowed to rise to room temperature, and the stirring is continued for 2 hours, before dilution with ethyl acetate (100 mL) and washing with saline (100 mL). The organic layer is dried and concentrated, to give a brown oil. This oil is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1:4 v/v), to give N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine (0.64 g), in the form of an oil. [Elemental analysis: C, 69.5; H, 6.8; N, 4.1; Cl, 10.6%; calculated: C, 68.8; H, 6.7; N, 3.2; Cl, 10.7%].
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:23]([O-:25])=[O:24])=[C:12]([CH:22]=1)[O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[N:20]([C@H:17]1[CH2:16][CH2:15][C@H:14]([O:13][C:12]2[CH:22]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[N+:23]([O-:25])=[O:24])[CH2:19][CH2:18]1)[CH3:21]
Reactant: COC(=O)Cl
Reactant: CN[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(C)[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
129 μl methyl chloroformate were added to an ice-cooled mixture of 0.305 g [trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexyl]-methyl-amine hydrochloride and 417 μl triethylamine in 5 ml methylene chloride. After 10 minutes the coolant was removed and the mixture was stirred at rt overnight. Then the reaction mixture was diluted with methylene chloride and washed with 10% aq. potassium hydrogen sulfate solution and 10% aq.potassium carbonate solution. The organic phase was passed through a hydrophobic frit.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:27])=[CH:22][CH:23]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)CCc1ccc(O)cc1
Product: O=C(CCc1ccc(O)cc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 55 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3-(4-hydroxyphenyl) propionic acid in 55% yield following procedure 1. The product was chromatographed on silica and crystallized from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=357, 1H NMR (MeOH-d4): 2.61 t, 7.4 Hz (1H), 2.89 t, 7.4 Hz (1H), 6.37 s (1H), 6.72 d, 8 Hz (2H), 7.00–7.06 m (3H), 7.11 t, 7 Hz (1H), 7.27–7.35 m (2H), 7.38 d, 8 Hz (1H), 7.54 d, 7 Hz (1H), 7.58 dd, 7.1 Hz (1H), 7.67 d, 8 Hz (1H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3]1.[N:13]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:28]([O:27][C:25]([N:13]([C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:1])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)C1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(N(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of ethyl 2,5-dioxopyrrolidine-3-carboxylate (3.92 g) in ethyl acetate (60 ml) was added dibenzyl azodicarboxylate (7.27 g), followed by potassium carbonate (317 mg) at room temperature. After this mixture was stirred at room temperature for 1 hour, the mixture was filtered through a Celite pad. The filtrate was concentrated and the resulting residue was purified by a flash column chromatography (hexane:ethyl acetate=2:1) to give the desired product (10.1 g, 94%) as amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:41])([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32]O.[K+].[Br-].Cl>>[CH3:30][C:31]([CH3:41])([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:41])([CH3:32])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)(CO)Cc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)Cc1ccccc1)(C(=O)OCC(C)(C)Cc1ccccc1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2 -[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethyl-3-phenylpropanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.82 (s, 12H, 4×CH3), 1.08 (d, J=6.37 Hz, 3H, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 3.96 (s, 4H, OCH2, OCH2), 5.04 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.89 (dd, J=8.13, 1.53 Hz, 1H, Ar--H), 7.05 (m, 4H, Ar--H), 7.14 (m, 8H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.81 (brs, 1H, NH), 9.38 (brs, 1H, NH); IR (KBr, cm-) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 714 (M+H)+ ; Analysis for: C42H48ClNO7 ×HCl: Calc'd: C, 67.19; H, 6.58; N, 1.87; Found: C, 66.69; H, 6.53; N, 1.83.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[O:12][C:13]([CH:15]=O)=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[NH:3]1.[NH3:23]>C(O)(C)C.O=[Mn]=O>[O:1]=[C:2]1[C:11]2[O:12][C:13]([C:15]#[N:23])=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[NH:3]1
Reactant: N
Reactant: O=Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Agent: O=[Mn]=O
Solvent: CC(C)O
Product: N#Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Reaction time: 1.5 h

Procedure:
A solution of 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbaldehyde (v) in isopropanol (“iPrOH”) is treated with ammonia gas at room temperature. After 90 min, the reaction is treated with MnO2 and stirred for an additional 16 h. The reaction is filtered and evaporated onto celite. Chromatography on silica gel affords 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbonitrile. IV. Results
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(OCC)C>[N:21]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][CH:18]=[C:12]3[C:13]([NH:15][C:16](=[O:17])[C:11]=23)=[O:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21
Reactant: C1CCNC1
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCCCCN3CCCC3)cccc21

Procedure:
8-Bromooctylphthalimide (517 mg; 2.0 mmoles) and pyrrolidine (0.33 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.[CH2:30]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:42]4[CH:41]=[CH:40][C:39]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:44][CH:43]=4)[CH:29]=[CH:28][C:5]=3[N:6]=2)=[CH:10][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCOc1ccc(-c2nc3ccc(Br)cc3s2)cc1
Reactant: CCCCCCCCCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCOc1ccc(-c2nc3ccc(-c4ccc(CCCCCCCCC)cc4)cc3s2)cc1
Yield: 74.6 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26×10−3 mol), 6-bromo-2-(4-dodecyloxyphenyl)benzothiazole (2.50 g, 5.27×10−3 mol), 4-nonylbenzene boronic acid (1.57 g, 6.33×10−3 mol), 2M sodium carbonate solution (25 cm3) and 1,2-dimethoxyethane (100 cm3). The reaction mixture was heated under reflux overnight. The cooled reaction mixture was extracted with dichloromethane (2×100 cm3) and the combined organic layers were washed with brine (2×100 cm3) and dried (MgSO4). After filtration the solvent was removed under reduced pressure and the residue was purified by column chromatography [silica gel, dichloromethane: hexane 1:1] followed by recrystallisation from ethanol to yield 2.35 g (74.5%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].Cl.Cl[CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:21][CH2:22][NH2:23])[C:7]=1[CH2:13][CH3:14]
Reactant: NCCCl
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CCc1nn(CCN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 54.3 %

Procedure:
A mixture of the pyrazole (390 mg, 1.37 mmol) of Example 3 and chloroethylamine hydrochloride (238 mg, 2.05 mmol) was stirred and heated at 150° C. for 24 hours. After cooling, the mixture was partitioned between saturated aqueous sodium bicarbonate solution (100 ml) and dichloromethane (2×50 ml). The combined organic layers were washed with brine (30 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (90:10, by volume) to afford the title compound (244 mg) as a brown oil.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[N:8][C:9]=1[Cl:10].[OH:14]S([O-])=O.[Na+]>FC(F)(F)C(O)=O>[Cl:3][C:4]1[C:9]([Cl:10])=[N+:8]([O-:14])[C:7]([C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=S([O-])O
Reactant: O=C(O)c1ccc(Cl)c(Cl)n1
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cl)c(Cl)[n+]1[O-]
Reaction time: 1 h

Procedure:
50% Hydrogen peroxide (38 g, 0.35 mol) was carefully added to a mechanically stirred mixture of trifluoroacetic acid (350 mL) and 5,6-dichloropyridine-2-carboxylic acid (56.4 g, 0.29 mol) at 79° C. After one hour, the reaction mixture was poured into 1 L of saturated aqueous NaHSO3, stirring vigorously and cooling in an ice bath. The precipitate was collected and dried to provide 5,6-dichloropyridine-2-carboxylic acid-N-oxide (62.9 g, 0.30 mol), mp 160° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](F)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])CC1.CNC(C1C2C=C(C3C([Br:52])=CN=C(Cl)N=3)SC=2C=CC=1)=O>>[CH3:1][NH:4][C:5]([C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([Br:52])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3F)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Br)cc12

Procedure:
Using the method of 2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 488 (79Br) and 490 (81Br) [M+H].
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:1]([NH:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cccc(-c2ccccc2)c1N
Solvent: ClCCl
Product: Cc1cccc(-c2ccccc2)c1NC(=S)NC(=O)c1ccccc1

Procedure:
A mixture of benzoylisothiocyanate (8.78 g), 2-amino-3-methylbiphenyl (9.85 g) and dichloromethane (75 ml) at ambient temperature for two hours gave N-benzoyl-N'-(3-methyl-2-biphenylyl)thiourea (m.p. 172°-173° C.).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:15]/[CH:13]=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCC#Cc1ccccc1
Solvent: ClCCl
Product: O=C/C=C/CCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
5-Phenylpent-4-ynal (0.5 g) in CH2Cl2 (5 ml) was added to a solution of formylmethylenetriphenyl phosphorane (1.8 g) in CH2Cl2 (10 ml) and the mixture was stirred at room temperature under a dry nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was slurried with ether (50 m), filtered, and the residue washed with ether. The ethereal solutions were combined and the product was purified by chromatography on silica eluting with ether:hexane (1:9) to yield 7-phenylhept-2E-en-6-ynal (0.25 g) as a yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30])=O)C1C=CC=CC=1.[N:33]1[C:42]2[C:37](=[N:38][C:39]([CH:43]=O)=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.N1CCCCC1>CC(O)C>[F:32][C:29]([F:30])([F:31])[C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:43][C:39]2[CH:40]=[CH:41][C:42]3[C:37](=[CH:36][CH:35]=[CH:34][N:33]=3)[N:38]=2)[C:14](=[O:16])[N:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
To a mixture of 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (94.5 mg, 0.20 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.7 mg, 0.20 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4.5 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, ether and dried in vacuum at 100° C. for 3 h to give 2-(2,4-bis-trifluoromethyl-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-1,5-dihydro-imidazol-4-one as a light yellow solid (21.6 mg, 23.2%). HR-ES (+) m/e calcd. for C21H13F6N5O: (M+H)+ 466.1097. Found: 466.1098.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[CH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][C:15]#[C:16][C:21]3[CH:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Brc1cccnc1
Reactant: C#CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CC#Cc2ccccn2)CCN(C)C1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(prop-2-ynyl)-1H-pyrido[4,3-b]indole (150 mg, 0.6 mmol), 3-bromopyridine (0.6 ml, 0.6 mmol), dichlorobis(triphenyl-phosphine) palladium (8 mg, 0.012 mmol), CuI (1 mg, 0.006 mmol), and triethylamine (0.01 ml 0.071 mmol) in acetonitrile (5 ml) was heated at 80° C. to obtain 108 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(3-(pyridin-2-yl)prop-2-ynyl)-1H-pyrido[4,3-b]indole after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.O.[CH3:13][N:14]1CCCC1=O>S([O-])([O-])(=O)=O.[Cu+2]>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([C:13]#[N:14])=[CH:11][C:6]=2[N:7]=1
Reactant: CN1CCCC1=O
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1nc2cc(C#N)ccc2s1

Procedure:
28.0 g of 5-bromo-2-methylbenzothiazole was dissolved in 200 ml of N-methyl-2-pyrrolidone, the solution thus prepared was mixed with 13.8 g of cuprous cyanide and a catalytically effective amount of copper sulfate, and the mixture was stirred for 4 hours with heating at a temperature of 180° to 190° C. in a stream of nitrogen. The resulting reaction solution was poured into water, and insoluble materials thus formed were collected by filtration. The thus collected insoluble materials were mixed with a mixture consisting of 22 ml of ethylenediamine and 50 ml of water, and the resulting mixture was stirred thoroughly. After extraction with benzene, the resulting organic layer was washed with water, and dried to distill of benzene. Thereafter, the residue thus formed was washed with ethanol to obtain 10.22 g of 2-methyl-5-benzothiazolecarbonitrile in the form of light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2[NH:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[NH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:24]([O:26][CH:27]=[CH:28][CH2:29][CH3:30])=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:16][C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:18][C:24]([O:26][CH2:27][CH2:28][CH:29]=[CH2:30])=[O:25])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)NC(=N)NC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: CCC=COC(=O)Cl
Product: C=CCCOC(=O)N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)NC(C)C

Procedure:
Compound 4g was prepared by the same method for preparation of 4b, using pure compound 4 (0.200 g, 585 mmol) and butenyl chloroformate as starting materials to yield compound 4g as a white color solid (98 mg, 38%). 1H NMR (300 MHz, CDCl3) δ 12.46 (s, 1H), 9.22 (s, 1H), 7.56–7.53 (m, 2H), 7.30–7.26 (dd, J=8.6 and 2.4 Hz, 1H), 5.85–5.72 (m, 1H), 5.20–5.13 (m, 2H), 4.29 (t, J=6.9 Hz, 2H), 4.16 (m, 1H), 2.47 (q, J=6.8 Hz, 2H), 1.24 (d, J=6.6 Hz, 6H); 13C NMR: δ170.76, 168.08, 159.19, 155.88, 153.96, 132.63, 132.53, 131.26, 130.40, 128.61, 125.65, 118.32, 66.60, 45.23, 32.74, 22.27; MS m/z 440 (M+), 388, 338, 269, 245, 180, 159.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]=O)=[C:12]([O:19][CH:20]([CH3:22])[CH3:21])[CH:11]=2)[CH2:6][CH2:5]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:34]3[N:35]=C(S(C)(=O)=O)[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([NH2:45])=[O:44])=[CH:26][CH:25]=1>CN(C)C=O.CO>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:34]3[N:35]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([N:7]5[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]5)=[CH:11][C:12]=4[O:19][CH:20]([CH3:22])[CH3:21])[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([NH2:45])=[O:44])=[CH:28][CH:29]=1
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(N2CCN(C)CC2)ccc1Nc1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27 mg of sodium hydride (at 60%) are added to a solution of 126 mg of N-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 2 ml of dimethylformamide. The suspension is stirred at ambient temperature for 30 min, and is then diluted with 1 ml of dimethylformamide, and a solution of 80 mg of 7-(4-fluorophenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxamide in 2 ml of dimethylformamide is added. The mixture is stirred at ambient temperature for 30 min, and then diluted with 50 ml of methanol. The mixture is stirred at ambient temperature for 1 h, and then concentrated under vacuum. The residue is purified on 40 g of silica, elution being carried out with 0-20% of methanol in dichloromethane, and then by high performance liquid chromatography (Macherey-Nagel 250×40 mm reverse phase C18 Nucleodur 10μ column. Eluent: MeCN containing 0.07% TFA and H2O containing 0.07% TFA. 10% MeCN hold: 3 min, gradient up to 95% MeCN in 37 min and then 95% MeCN hold of 8 min. Flow rate: 70 ml/min). The fractions containing the expected material are loaded on to a 2 g Varian Bond Elut SCX cartraige (preconditioned with MeOH). Washing the cartridge four times with methanol, followed by elution of the expected material with 2N ammonia in methanol gives, after drying, 10 mg of 7-(4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](OS(C)(=O)=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.375 g, 1.93 mmol), (R)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (0.513 g, 1.93 mmol), C2CO3 (0.943 g, 2.90 mmol) in anhydrous DMF (5.13 mL) was heated to 100° C. for 6 h. The reaction mixture was partitioned between EtOAc and H2O and separated and the aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude brown oil. The crude was purified by chromatography on silica gel [eluting with 12% EtOAc in CHCl3] resulting in the title compound as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 12H), 1.47 (s, 9H), 2.36 (q, J=7.0 Hz, 2H), 3.46-3.79 (m, 3H), 3.81-3.92 (m, 1H), 4.90 (quint, J=6.1 Hz, 1H), 7.73 (s, 1H), 7.81 (s, 1H).