Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C(CC)C)(CO)[CH2:3][OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[C:23]1[CH2:24][CH:25]([CH:30]=O)[CH2:26][CH:27]([CH3:29])[CH:28]=1>C1CCCCC1>[CH3:29][CH:27]1[CH:28]([CH:3]=[O:4])[CH2:23][CH2:24][C:25]([CH3:30])=[CH:26]1
Reactant: CCC(C)C(C)(CO)CO
Reactant: CC1=CC(C)CC(C=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC1=CC(C)C(C=O)CC1

Procedure:
A 3-necked round bottom flask (250 ml capacity) was fitted with a mechanical stirrer, thermometer and Dean and Stark apparatus, the latter was equipped with a double surface water condenser. Privetal (0.1 mole, 14.6 g) and 2-methyl-2-sec.butylpropane-1,3 diol (0.1 mole 14.6 g) were charged into the flask together with cyclohexane (50 ml) as solvent and a catalytic amount of p-toluenesulphonic acid (0.35 g). Privetal was a mixture of 2,4-dimethyl-and 3,5-dimethyl-cyclohex-3-ene-1-carboxaldehyde obtained from PPF International, Ashford, England; now obtained under the trade name Ligustral from Quest International, Ashford, Kent the successor company to PPF International. (The 1,3-diol was obtained from Hoechst GmbH of West Germany.)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].IC.[C:15](OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: CCOC(C)=O
Reactant: Clc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 0.794 mL (6.60 mmol) of 4-chloroindole in 10 mL of dry dimethylformamide is reacted with 0.260 g (6.60 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.411 mL (6.60 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature 15 h. TLC (2:1 hexanes:ethyl acetate) indicates the starting material is gone and new less polar spot. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 0.785 g of the title compound, 72% yield. MS, ES=166.1 (M+1); 1H NMR (DMSO-d6) δ 7.431-7.413 (m, 2H); 7.145-7.064 (m, 2H); 6.442-6.432 (m, 1H); 3.795 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11]Br>Br>[CH3:9][C:7]1[NH:8][C:4]([C:1](=[O:3])[CH2:2][Br:11])=[C:5]([CH3:10])[N:6]=1
Reactant: BrBr
Reactant: CC(=O)c1[nH]c(C)nc1C
Agent: Br
Product: Cc1nc(C)c(C(=O)CBr)[nH]1
Yield: 71.3 %

Procedure:
A solution of 1.0 g (7.24 mmol) of 5-acetyl-2,4-dimethylimidazole in 15 ml of concentrated hydrobromic acid was warmed to 50° and 1.16 g (7.25 mmol) of bromine was added dropwise over 1 minute. The mixture was then heated at 50°-60° for 1 hour. The mixture was concentrated and the solid residue was triturated with 30 ml of saturated sodium bicarbonate solution. The insoluble material was collected by filtration, washed with water, and dried in vacuo to give 1.12 g (71%) of 1-(2,4-dimethyl-5-imidazolyl)-2-bromoethanone as a white solid, mp 128°-132°. nmr (D6DMSO) (δ): 4.40 (s, 2H); 2.27 (s, 3H); 2.13 (s, 3H).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[Na+].[Cl-]>CN(C)C=O>[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OCCOCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOCCCl
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Imidazole (17.8 g, 261 mmol) was dissolved in dimethylformamide (100 ml) and t-butyldimethylsilyl chloride (36.3 g, 241 mmol) was added and stirred. 2-(2-chloroethoxy)ethanol (25.0 g, 200 mmol) was added dropwise over 1 hour under cooling with ice, and the mixture was stirred for 1 further hour, left standing overnight at room temperature, and then poured into saturated aqueous NaCl (500 ml). The resulting mixture was extracted twice with ether. The extract was washed twice with saturated aqueous NaCl, and dried over MgSO4. Then the solvent was removed in vacuo, giving 1-chloro-2-(2-t-butyldimethylsilyloxyethoxy)ethane (47.8 g, 100% yield). IR (CHCl3) [cm-1 ]; 2920, 2850, 1460, 1100, 930. NMR (CDCl3) [δ ppm]; 3.94-3.90 (4 H, m) 3.79-3.72 (4 H, m), 1.05 (9 H, s), 0.22 (6 H, s).
Reaction SMILES: [Na].[C:2](OCC)(=O)[CH2:3][C:4](OCC)=O.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:4][CH2:3][CH3:2])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: O
Product: CCCc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
Sodium metal (6.9 g, 300 mmol) was added in small pieces to a refluxing solution of diethyl malonate (90 ml, 480 mmol). When the sodium was completely dissolved, 2-chloro-5-nitropyridine (45 g, 285 mmol) was added in small portions. Reflux was continued for 20 hours. Water (500 ml) was added and the organic material was extracted into 4×200 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude malonate intermediate was then dissolved in 100 ml of water and 100 ml of concentrated sulphuric acid, and the mixture was refluxed at 110° C. for 18 hours. The mixture was then poured into 1200 ml of concentrated sodium hydroxide solution, and the organic material was extracted into 5×350 ml of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was evaporated. This gave 42.60 g (90%) of 5-nitro-2-n-propylpyridine as an orange oil. 1H-NMR (MeOD, 200 MHz) δ: 0.98 (t, 3H); 1.79 (sext, 2H); 2.89 (t, 2H); 7.51 (d, 1H); 8.48 (dd, 1H); 9.25 (d, 1H).
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:14](=[O:25])[CH:15]([CH2:18][C:19]3[N:20]=[CH:21][NH:22][C:23]=3[CH3:24])[CH2:16][CH2:17][C:6]=12)C.C([O-])=O.[NH4+]>[Pd].C(O)C.O.O1CCCC1>[CH3:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:14](=[O:25])[CH:15]([CH2:18][C:19]3[N:20]=[CH:21][NH:22][C:23]=3[CH3:24])[CH2:16][CH2:17][C:6]=12
Reactant: Cc1[nH]cnc1CC1CCc2c(CN(C)C)c3ccccc3n2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Temperature: 75 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A mixture of 8,9-dihydro-10-[(dimethylamino)methyl]-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (224 mg), ammonium formate (500 mg), 10% palladium on carbon (210 mg), water (1 ml), ethanol (2 ml) and tetrahydrofuran (1 ml) was heated at 75° C. for 45 minutes and then cooled. Ammonium formate (300 mg), 10% palladium on carbon (100 mg), water (1 ml), and ethanol (2 ml) were added successively to the reaction mixture. Heating at 75° C. was continued for further 1 hour. After cooling, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was diluted with water and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Silica gel column chromatography of the residue (5% methanol-chloroform) gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl] pyrido[1,2-a]indol-6(7H)-one (118 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.ClC1C=C(OC)C=C(F)C=1C[N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:16]1=[O:37]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:16]1=[O:37]
Reactant: OCc1c(Cl)cncc1Cl
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3ccccc32)c(Cl)c1
Product: COc1ccc(N2C(=O)N(Cc3c(Cl)cncc3Cl)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (217 mg, 0.44 mmol) was prepared from (IntA1) (167 mg, 0.50 mmol), and 3,5-dichloro-4-hydroxymethylpyridine (133 mg, 0.75 mmol) using the methods of (113).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.[OH-].[K+]>C(O)C>[CH3:26][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[C:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10]
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=C1CCc2ccccc2C1=O
Yield: 110.9 %

Procedure:
α-Tetralone (26.4 g) and 40 g of 2-[3-(dimethylamino)propoxy]benzaldehyde are reacted in 180 ml of ethanol in the presence of 1.2 g of potassium hydroxide following the procedure in Example 1A. The product is extracted with ether and the solvent is evaporated to give a viscous residue (67.2 g), which begins to solidify on standing. It is crystallized from a mixture of 120 ml of warm diisopropylether and 120 ml of hexane to give 45.7 g of crystals, melting point 67-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:33])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.COC1C=CC(B(O)O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]([NH2:33])([CH2:23][C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:19]([OH:21])=[O:20])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(N)(CC#CCN1CCOCC1)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)C(N)(CC#CCN3CCOCC3)C(=O)O)cc2)cc1

Procedure:
Methyl 2-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-6-morpholinohex-4-ynoate: The starting sulfonamide 34a (500 mg, 1.02 mmol) is coupled to 4-methoxyphenyl-boronic acid (233 mg, 1.53 mmol) as described for compound 32a to give the title compound as a light brown solid.
Reaction SMILES: P(=O)(O)(O)O.[CH2:6]([O:8][C:9]([C:11]1[C:21]([CH2:22][CH2:23][CH:24](O)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:20]([OH:32])[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=1)=[O:10])[CH3:7].[OH-].[Na+]>>[CH2:6]([O:8][C:9]([C:11]1[C:21]2[CH2:22][CH2:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:32][C:20]=2[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c(O)c1CCC(O)c1ccccc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Temperature: 25 °C
Yield: 85.1 %

Procedure:
42 ml Phosphoric acid (85%) and 4.2 g (11.4 mmol) 7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-di-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester were heated at 80° C. for 2 h. After cooling to room temperature the reaction mixture was poured into ice-water and neutralized with 10 N sodium hydroxide solution. The precipitate was filtered off and dried in vacuo at 40° C. to afford 3.4 g (86%) of the title compound as a white solid. m. p. 172°-173° C.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4].[CH3:19][NH:20][C:21](=S)[NH:22][NH2:23]>C(O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:21]([NH:20][CH3:19])=[N:22][N:23]=3)[N:13]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: CNC(=S)NN
Reactant: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CNc1nnc2ccc(-c3cccc(N(C)C(C)=O)c3)nn12
Yield: 30.9 %

Procedure:
A solution of 6.0 g N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 4.8 g 4-methylthiosemicarbazide in 200 ml ethanol was refluxed for 5 hours and treated in similar fashion to Example 67. Chromatography on silica gel with dichloromethane-methanol (96:4) and recrystalization from dichloromethane-hexane afforded 2.1 g yellow crystals, mp 213°-215° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39](Cl)=[CH:38][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:49]C[C@@H](OC(C)(C)C)C1C(C)=CC2N=C(C3C=CC=C(C4C=C5C(=CC=4)N(C)N=C5)C=3)SC=2C=1C1C=CC2OC(C)OC=2C=1)(=[O:48])[C:44](C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]2[O:48][CH:43]([CH3:44])[O:49][C:38]=2[CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc3c(c2)OC(C)O3)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc3c(c2)OC(C)O3)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)acetic acid in Method G, except using (2S)-2-tert-butoxy-2-(5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)-7-(2-methylbenzo[d][1,3]dioxol-5-yl)benzo[d]thiazol-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calcd for C36H34N3O5S: 620.2; Found: 620.3; 1H-NMR: 400 MHz, (CD3OD) δ 8.34-8.32 (m, 1H), 8.08 (s, 2H), 8.00-7.94 (m, 1H), 7.85-7.84 (m, 3H), 7.66 (d, J=8.8 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.17-7.11 (m, 1H), 7.06-7.00 (m, 1H), 6.97-6.94 (m, 1H), 6.43-6.37 (m, 1H), 5.46-5.36 (m, 1H), 4.10 (s, 3H), 2.60 (s, 3H), 1.74-1.68 (m, 3H), 0.99 (s, 9H).
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([CH3:26])[NH:11][CH:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:14][C:13]1=[O:25])C1C=CC=CC=1>CO.[Pd]>[O:25]=[C:13]1[CH:12]([NH:11][C@H:10]([C:9]([OH:27])=[O:8])[CH3:26])[CH2:16][CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:14]1
Reactant: CCCCCCCCC1CC(N[C@@H](C)C(=O)OCc2ccccc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCC1CC(N[C@@H](C)C(=O)O)C(=O)O1
Reaction time: 2 h

Procedure:
Dissolved in 100 ml of methanol was 3.75 g of Isomer BCD of N-(2-oxo-5-octyl-3-tetrahydrofuranyl)-L-alanine benzyl ester. Thereafer, 0.70 g of 10% palladium-charcoal was added and the reaction mixture was hydrogenated at room temperature and normal pressure for 2 hours. The palladium-charcoal was then filtered off and the filtrate was distilled under reduced pressure to obtain crystals. The crystals were recrystallized from methanol, thereby obtaining 2.41 g of Isomer BCD of N-(2-oxo-5-octyl-3-tetrahydrofuranyl)-L-alanine as colorless crystals.
Reaction SMILES: Cl[CH:2]([CH3:18])[C:3]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:18][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1=[O:4]
Reactant: CC(Cl)C(=O)N(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1C(=O)N(c2ccccc2)c2ccccc21
Temperature: 190 °C
Reaction time: 0.17 h
Yield: 832.9 %

Procedure:
A mixture of 13.3 g (0.00513 mole) of N-(2-chloropropanoyl)-diphenylamine and 14.7 g (0.011 mole) of anhydrous aluminum chloride was stirred for 10 minutes while heating over an oil bath of 190° C. The reaction mixture was poured into 10% hydrochloric acid-ice, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% hydrochloric acid, water, a sodium hydrogen carbonate aqueous solution and then water, and dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:ethyl acetate:hexane (1:5 (v.v))) and then recrystallized from hexane to obtain 9.54 g of the title compound as pale yellow crystals. Melting point: 77° to 78° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[C:12](O)=[N:11][C:10]([NH:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)=[CH:9]2.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=2)[CH:9]=[C:10]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1OCCOC
Product: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OCCOC
Temperature: 170 °C
Yield: 37.6 %

Procedure:
A mixture of 6,7-Bis-(2-methoxy-ethoxy)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol (1.8 g, 4.64 mmol) in POCl3 (15 ml) was sealed in microwave process vial (20 ml). The mixture was heated at 170° C. for 30 minutes under microwave irradiation. After removal of solvent, the ice water was added to the residue, and the mixture was neutralized by 2M NaOH, extracted by EtOAc. The organic layer was concentrated and the residue was purified by flash column chromatography to give product as a solid (0.7 g, 37.6%). LC-MS: m/e 408 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:29](CC2C=CC=CC=2)[C:28](=[O:37])[C:27]2=[CH:38][CH:39]=[CH:40][N:26]2[N:25]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC(C(Cl)=O)=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH:21]([C:24]1[NH:29][C:28](=[O:37])[C:27]2=[CH:38][CH:39]=[CH:40][N:26]2[N:25]=1)[CH2:22][CH3:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: [Pd+2]
Agent: O=C(Cl)c1ccc(Cl)cc1
Agent: [OH-]
Solvent: CCO
Product: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 65 %

Procedure:
A mixture of {3-[[1-(3-benzyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-propyl]-(4-methylbenzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (115 mg, 0.21 mmol, prepared using an identical synthetic sequence to that outlined for Example 12 A–F, except substituting p-toluoyl chloride for 4-chlorobenzoyl chloride in F) and Pd(OH)2 (20 wt. % Pd on carbon, 66 mg) in ethanol (6 mL) was stirred at 50° C., under 60 psi of hydrogen, for 22 h. The catalyst was filtered off and the residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 62–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove the methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (63 mg, 65%): 1H NMR (CDCl3) δ 10.52 (s, 1H), 7.37–7.35 (m, 3H), 7.27–7.23 (m, 2H), 7.07 (m, 1H), 6.54 (m, 1H), 4.60 (m, 1H), 4.21 (m, 1H), 3.40 (m, 2H), 2.89 (m, 2H), 2.40 (s, 3H), 2.29 (m, 2H), 1.64 (m, 2H), 1.37 (s, 9H), 1.08 (t, 3H, J=7.15 Hz); MS (ESI+) 468.21 (M++H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH2:12])=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[S:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=S)COCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2csc(COCc3ccccc3)n2)cc1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
To the solution of 2-Benzyloxy-thioacetamide (3.0 g, 16.57 mmol) in 3 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (3.0 g, 12.87 mmol). The reaction mixture was heated at 130° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (2.0 g, 49%). The corresponding cyano derivative was also prepared by the same general method.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.B(O)O>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[C:10]=1[N:9]([C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:21]([F:20])[CH:22]=1)[CH:8]=[CH:7]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)c(F)cc(Br)c32)ccc1OCc1ccccc1
Reaction time: 20 h
Yield: 30 %

Procedure:
A mixture of 7-bromo-5-fluoro-4-[(phenylmethyl)oxy]-1H-indole (D5) (3 g, 9.37 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (3.46 g, 14.06 mmol), copper (II) acetate (2.55 g, 14.06 mmol) and pyridine (0.834 mL, 0.815 g, 10.31 mmol) in dichloromethane (50 mL) were stirred together vigorously under an air atmosphere with powdered 4A molecular sieves (˜10 g). After stirring for 20 hours, another 0.5 g of boronic acid were added and the mixture was stirred for a further 24 hours. Then another 1.73 g boronic acid (0.75 eq), copper acetate (1.28 g, 0.75 eq) and pyridine (1.52 mL, 2 eq) were added and stirring was continued at room temperature. After a further 24 hours, the reaction was diluted with ethyl acetate and filtered through celite. The celite was washed with ethyl acetate and the combined filtrates were washed with water (2×), dried (Na2SO4) and concentrated. Chromatography SP4 (0-30% ethyl acetate in hexane) gave the title compound as a white solid (D6), (1.463 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[C:6]=2[CH:7]=1
Reactant: O=C(O)c1ccccc1CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2ccccc2CCc2ccc(F)cc21
Yield: 99.7 %

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]benzoic acid (4.00 g, 16.4 mmol, 1 equiv) and oxalyl chloride (2.0 mL, 2.9 g, 23 mmol, 1.4 equiv) in CH2Cl2 (50 mL) was refluxed for 30 min. The resulting solution was then added to a stirring suspension of aluminum chloride (3.0 g, 2.2 mmol, 1.4 equiv) in CH2Cl2 (50 mL). This mixture was refluxed for 1 h. The reaction mixture was then washed with 1N HCl (3×50 mL), aq. satd. NaCl (1×50 mL), and H2O (1×50 mL). The organic layer was dried (anh. Na2SO4) and rotary evaporated (75° C.) to provide 3.7 g of a dark-brown oil. This oil was flash chromatographed (20:1 hexane/EtOAc) through flash silica gel (250 mm×25 mm). Evaporation of the combined fractions of interest provided 1.58 g (42.6%) of the desired product as a yellow oil.