Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:40])[N:9]([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH2:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:3]=1[C:41]1[CH:46]=[CH:45][C:44]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:40])[N:9]([CH2:10][CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH2:26][CH:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[N:4][C:3]=1[C:41]1[CH:42]=[CH:43][C:44]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)c(Cl)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccc(-c2nc(NC(=O)N(CCC3CCNCC3)CCC(c3ccccc3)c3ccccc3)sc2Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)ethyl)piperidine-1-carboxylate (0.29 g, 0.4 mmol) dissolved in DCM (2 ml) was added TFA (0.5 ml, 7 mmol). The resulting mixture was stirred at room temperature for 2 hours. After this time the mixture was concentrated under reduced pressure and the residue triturated with diethyl ether. The pale yellow solid was filtered, washed with ether and dried under vacuum. This solid TFA salt was partitioned between DCM and saturated aqueous NaHCO3. The aqueous was re-extracted with DCM (×2). The combined organic extracts were dried over MgSO4 and concentrated up. The residue was taken up in dry DCM and HCl (2M in diethyl ether) was added. The cloudy solution was conc under reduced pressure and dried under high vac to give 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-(piperidin-4-yl)ethyl)urea HCl salt 51 as a pale yellow solid.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.Cl>C(OCC)C.CCCCCC.O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20](=[NH:3])[NH2:21])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of hexamethyldisilazane (19.4 g, 120 mmol) in diethyl ether (200 ml) was added dropwise a 1.6 N solution (75.0 ml, 120 mmol) of n-butyllithium in hexane under ice-cooling. Thereto 4-fluorobenzonitrile (7.01 g, 57.9 mmol) was added, followed by stirring at room temperature for 2 hours. Thereto 3 N hydrochloric acid (80 ml) was added dropwise under ice-cooling, and the reaction mixture was stirred under ice-cooling for 0.5 hour. Water (200 ml) was added thereto, and the diethyl ether layer was removed. The aqueous layer was basified with an aqueous 3 N sodium hydroxide solution, and then extracted with chloroform. The extracts were dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.90 g (61.3%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)[NH:8]2)=[C:4]([O:22][CH2:23][C:24]2[CH:37]=[CH:36][C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[N:3]=1.FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH2:13][NH2:14])[NH:8]2)=[C:4]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([F:32])([F:34])[F:33])=[CH:36][CH:37]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCCc1nc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc2[nH]1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1nc2c(OCc3ccc(CNC(=O)C(F)(F)F)cc3)nc(N)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
The tert-butoxycarbonyl derivative 11 (Example 23, 100 mg, 0.19 mmol) is suspended in 10 mL dichloromethane, and 2 mL trifluoroacetic acid are added. The mixture is stirred at room temperature for 30 min and poured into 70 mL of diethyl ether. The precipitate is collected by filtration and purified by flash column chromatography (CH2Cl2/MeOH 5:1) yielding 74 mg (0.17 mmol, 92%) of the title compound. MS (ESI) m/z 424.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:20](Cl)(=[O:24])[O:21][CH2:22][CH3:23]>C(OCC)(=O)C>[C:20](=[O:24])([O:21][CH2:22][CH3:23])[O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.71 mL) and ethyl chlorocarbonate (2.55 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 ml), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.92 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)N1CCCCC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCCCC4)nc3cc21

Procedure:
Piperidine-1-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and 1-piperidinecarbonyl chloride. The title compound was obtained as light brown powder (101 mg).
Reaction SMILES: C([N:8]1[C:12]([NH:13][C:14]2C=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2CCC(O)=O)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].C(O)(=O)[CH2:31][C:32]([CH2:37][C:38](O)=O)([C:34]([OH:36])=[O:35])O.[C:43]1(C)C=CC=CC=1>O.CCOC(C)=O>[N:10]1[NH:9][N:8]=[C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][C:38]=2[CH2:37][C:32]([CH3:31])([CH3:43])[C:34]([OH:36])=[O:35])[CH:11]=1
Reactant: O=C(O)CCc1cc(Cl)ccc1Nc1cnnn1Cc1ccccc1
Reactant: Cc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(Cc1cc(Cl)ccc1Nc1cn[nH]n1)C(=O)O
Temperature: 100 °C

Procedure:
To a solution of 3-(2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorophenyl)propanoic acid 7h (85 mg, 0.22 mmol) in toluene (3.5 mL) was added aluminium trichloride (165 mg, 1.24 mmol) and the mixture heated at 100° C. for 1 h. The mixture was allowed to cool to room temperature and diluted with water and EtOAc followed by 5% citric acid solution. The aqueous was further extracted with EtOAc and the combined organics washed with brine, dried (MgSO4), and concentrated. Material was purified by ISCO (0-60% EtOAc/hexanes) to afford the title compound I-33 as an off white solid (36 mg, 38%). 1H NMR (500 MHz, d6-DMSO) δ 14.14 (1H, brs), 12.37 (1H, brs), 7.84 (1H, brs), 7.60-7.63 (1H, m), 7.38-7.41 (1H, m), 7.14 (1H, d), 7.08 (1H, d), 2.77 (1H, d), 2.67 (1H, d), 1.12 (6H, s). MS m/z: 295.1 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[O:27][CH:31]=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: c1ccoc1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and furane
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:34]=[CH:35][C:36]=1[CH:37]=O.CCOC(C)=O.CCCCCC>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:34]=[CH:35][C:36]=1[CH:37]=[CH:8][O:9][CH3:10]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a an ambient temperature suspension of potassium tert-butoxide (419 mg, 3.73 mmol) in THF (20 mL) is added (methoxymethyl)triphenylphosphonium chloride (1.28 g, 3.73 mmol) and is stirred at room temperature for 30 min. 3-Fluoro-4′-trifluoromethyl-biphenyl-4-carbaldehyde (500 mg, 1.87 mmol) is added and the reaction mixture continues to stir at room temperature. After 2 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction is quenched with saturated aqueous NH4Cl and concentrated. The residue is partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer is extracted with EtOAc (50 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (120 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (474 mg, 85%).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])O1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:17]([NH:19][CH:20]1[CH2:22][CH2:21]1)=[O:18]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[N:13]1[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:17]([NH:19][CH:20]1[CH2:21][CH2:22]1)=[O:18]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccccc2C1=O
Temperature: 150 °C
Yield: 56.3 %

Procedure:
A suspension of 1H-isochromene-1,3(4H)-dione (400 mg) and 3-amino-N-cyclopropyl-4-methylbenzamide (514 mg) in toluene (3 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate and washed with 2N HCl, water, brine, dried (magnesium sulfate) and concentrated to a foam which was purified by column chromatography with a gradient of iso-hexane to 70% ethyl acetate/iso-hexane to yield 3-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a solid (464 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.09 (s, 3H), 2.85 (m, 1H), 4.33 (d, 1H), 4.41 (d, 1H), 7.42 (d, 1H), 7.49-7.55 (m, 2H), 7.65 (s, 1H), 7.74 (t, 1H), 7.80 (d, 1H), 8.09 (d, 1H), 8.39 (d, 1H); Mass Spectrum: M+H+ 335.
Reaction SMILES: C([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])C.[CH3:10][N:11]([CH3:13])[NH2:12].C(N(CC)CC)C.C(O)(=O)[CH2:22][C:23](CC(O)=O)(C(O)=O)[OH:24]>C(#N)C>[CH2:23]([O:24][C:7](=[O:8])[CH2:3][C:4](=[O:5])[NH:12][N:11]([CH3:13])[CH3:10])[CH3:22]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN(C)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)NN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Ethyl malonyl chloride (5.0 g, 33 mmol) was added to a mixed solution of N,N-dimethylhydrazine (4.0 g, 67 mmol), triethylamine (6.7 g, 66 mmol) and acetonitrile (30 mL) at 10° C. or below. The mixture was stirred overnight at room temperature. The reaction mixture was added with an aqueous solution of citric acid, and extracted with chloroform. The organic layer was washed with water, dried, and concentrated, to obtain 4.6 g of a desired product (yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[C:52]1(B(O)O)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccccc5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:13](O)[CH3:14])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:13][CH2:14][Cl:18])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCN(Cc1ccc(Cl)nc1)C(C)O
Solvent: ClC(Cl)Cl
Product: CCCN(CCCl)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 1.0 gram (0.0044 mole) of 2 {[(6-chloro(3-pyridyl))methyl]propylamino}ethan-1-ol in two mL of chloroform was cooled to 0° C., and 2 mL (excess) of thionyl chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature, and then it was heated to reflux where it was stirred for one hour. After this time the reaction mixture was concentrated and made basic with aqueous 10% sodium hydroxide. The mixture was then extracted multiple times with ethyl acetate. The combined extracts were then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 1.0 gram of the subject compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].O1CCCC1.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25]>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To a 20 mL volume two-necked flask, 0.50 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 10 ml of tetrahydrofuran (anhydrous), 0.27 g of acetophenone and 130 mg of acetic acid were added under a nitrogen atmosphere, and the mixture was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (60 ml) was added to the residue and the resultant was extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure and subjected to silica gel column, chromatography (ethyl acetate:chloroform=3:1) to give 0.32 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-phenyl-1-ethylidene)hydrazine ((40-b)-(15)-6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][N:18]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH:24]=[CH:23][CH:22]=[C:21]3[NH:20][C:19]1=[O:31].C(=O)(O)[O-].[Na+].O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:29]4=[C:30]5[C:25](=[CH:26][CH:27]=[CH:28]4)[CH:24]=[CH:23][CH:22]=[C:21]5[NH:20][C:19]3=[O:31])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2cccc3cccc(c23)N1CCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 22.8 %

Procedure:
1.35 g of 4-(4-fluorophenyl)piperazine, 1.84 g of 1-(3-chloropropyl)-2-perimidinone and 0.66 g of sodium bicarbonate, in 25 cm3 of dry N,N-dimethylformamide are stirred at the reflux temperature of the solvent for 2 hours. The reaction mixture is cooled and poured into a mixture of 20 cm3 of water and 25 cm3 of dichloro-methane. The organic phase is decanted, washed with water (3×15 cm3), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column under a pressure of 0.7 bar of nitrogen, eluting with ethyl acetate. 0.65 g of 1-{3-[4-(4-fluorophenyl)-1-piperazinyl]-propyl }-2-perimidinone is thus obtained; melting point =206° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.ClS([N:19]=[C:20]=[O:21])(=O)=O.O>C(#N)C>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[N:9]2[C:20]([NH2:19])=[O:21])=[CH:5][CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Solvent: CC#N
Solvent: O
Product: NC(=O)N1C(=O)Cc2ccc(C(F)(F)F)cc21
Reaction time: 0.75 h
Yield: 9.4 %

Procedure:
To a slurry of 6-trifluoromethyl-2-oxindole (8.0 g, 0.04 mole) in acetonitrile (80 ml) was added chlorosulfonyl isocyanate (6.65 g, 0.047 mole) and the mixture was stirred for 45 minutes. Water (100 ml) was then added and the aqueous mixture was stirred for one hour. The precipitate which formed was filtered off and recrystallized from acetonitrile to give 0.92 g of the title product. Extraction of the filtrate from the aqueous reaction mixture with ethyl acetate (300 ml) followed by drying the extract over MgSO4 and then evaporating it under reduced pressure gave additional product. Recrystallization from acetonitrile gave an additional 2.2 g of product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:37])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([O:34]CC)=[O:33])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:37])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([OH:34])=[O:33])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxylate (1.338 g, 2.396 mmol) in tetrahydrofuran (48 mL) and methanol (16 mL) at room temperature was added a solution of lithium hydroxide hydrate (0.402 g, 9.58 mmol) in water (10 mL). The resulting solution was stirred at room temperature for 1.5 hr, and then concentrated under vacuum to a volume of about 10 mL. The residue was diluted with water (5 mL) and neutralized with 1 N HCl solution to pH 5-6. The precipitating product (1.177 g, 2.219 mmol, 93% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [Br:1][C:2]1[C:11](Br)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.C[N:16](C=O)C>>[Br:1][C:2]1[C:11]([NH2:16])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cc2nc(Br)c(Br)nc2cc1Cl
Product: Nc1nc2cc(Cl)c(Cl)cc2nc1Br
Reaction time: 2 h
Yield: 89 %

Procedure:
2,3-Dibromo-6,7-dichloro-quinoxaline (2.75 g, 7.7 mmol) was dissolved in DMF (50 mL). Anhydrous ammonia was bubbled into the solution. After 2 hours, DMF was removed in vacuo at 70° C. The residue was filtered through a pad of silica gel (one inch thick) eluted with ethyl acetate. After removal of the solvent in vacuo, the residue was recrystallized from acetone to give the desired 2-bromo-3-amino-6,7-dichloroquinoxaline as a white solid. (7.84 g, 89% yield): mp 232-4° C.; Rf=0.41, EtOAc:Hex (1:1); IR (KBr, cm−1) 3488, 3348, 1617, 1588, 1443, 1406, 1338, 1114, 1036, 965, 893, 867, 577, 557; 1H NMR (DMSO) δ 8.02 (s, 1H), 7.76 (s, 1H), 7.51 (broad s, 2H, NH2), 7.18 (s, 2H); 13C NMR (DMSO) δ 147.7, 136.7, 131.4, 129.0, 128.8, 124.4, 122.3, 121.9; MS (ACPI), m/z 291.8 (M−1)−; Anal. Calcd for C8H4N3BrCl2: C, 32.80; H, 1.38; N, 14.34. Found: C, 32.98; H, 1.43; N, 14.34.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=O)[C:7](OCC)=[O:8])[CH2:3][CH2:2]1.Cl[Si](C)(C)C.Cl.N>O1CCCC1.ClCCl.CO>[NH3:5].[CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)NCC1CC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: OCCNCC1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 150.1 %

Procedure:
A solution of ethyl [(cyclopropylmethyl)amino](oxo)acetate (5.9 g, 34.6 mmol) in tetrahydrofuran (30 ml) was added at ambient temperature to a mixture of borane-tetrahydrofuran complex (130 ml of a 1.0 N solution in THF, 130 mmol) and chlorotrimethylsilane (34 ml, 268 mmol). The reaction mixture was stirred at ambient temperature for 48 hours. Methanol (20 ml) was added and the reaction stirred for a further 30 minutes before dilution with dichloromethane followed by addition of a concentrated solution of hydrochloric acid (4 ml). The mixture was stirred for 30 minutes, basified with methanolic ammonia (7 N) and the resultant solid filtered and washed with dichloromethane. The organic phases were recovered, concentrated and purified by chromatography on silica gel. Elution with dichloromethane followed by increased polarity to dichloromethane:methanol (95:5), dichloromethane:methanolic ammonia (9:1) yielded 2-((cyclopropylmethyl)amino)ethanol as a pale yellow liquid (2.99 g, 75% yield):