Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56].I([O-])(=O)=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][C:25]([O:28][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:29]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCCBr
Reactant: Oc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A mixture of 200 mg 4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}phenol (compound in Example 14), 232 mg ethyl 7-bromoheptanoate, 6 mg sodium iodate, 68 mg potassium carbonate, and 15 mL N,N-dimethylformamide was stirred overnight at 80° C. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, then washed with water, an aqueous saturated sodium thiosulfate, an aqueous solution of sodium chloride (×2) and brine, and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 157 mg of the title compound as a pale brown amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:36])[C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:33]4[CH2:34][CH2:35][C@@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CN(C)[C@@H]1CCNC1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(N3CC[C@@H](N(C)C)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 83.9 %

Procedure:
To a stirred suspension of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (49 mg, 0.1 mmol) (prepared according to Example 7, step B) and (R)—N,N-dimethylpyrrolidin-3-amine (23 mg, 0.2 mmol) in 300 μL THF at ambient temperature in a capped reaction vial was added racemic Binap (9 mg, 0.015 mmol) followed by NaOtBu (14 mg, 0.15 mmol) and 18-crown-6 (40 mg, 0.1499 mmol). The reaction purged with nitrogen gas and then held under a balloon of nitrogen. Pd(dba)2 (6 mg, 0.01 mmol) was then added and the reaction was sealed and heated to 40° C. After stirring for 72 hours, the reaction was cooled to ambient temperature, diluted to 30 mL with dichloromethane and washed with 10% sodium carbonate solution. The organics were dried (MgSO4), filtered and concentrated. The brown residue was dissolved in a minimum of dichloromethane and loaded onto a Biotage 12S column. The column was eluted with 95/5 dichloromethane/MeOH to provide the product as a tan foam (40 mg, 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[Cl:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[CH2:25][C:26]([NH:28][CH3:29])=[O:27]>>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=4)[S:10][C:3]=23)[CH:21]=[CH:20][C:19]=1[CH2:25][C:26]([NH:28][CH3:29])=[O:27]
Reactant: CNC(=O)Cc1ccc(O)cc1Cl
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Product: CNC(=O)Cc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)cc1Cl

Procedure:
was prepared from coupling of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine and intermediate 63a following Method C. 1H NMR (300 MHz, CD3OD) δ 8.38 (d, 1H, J=5.65 Hz), 7.67 (s, 1H), 7.38 (d, 1H, J=8.48 Hz), 7.27 (d, 1H, J=2.44 Hz), 7.20 (s, 1H), 7.12–7.06 (m, 1H), 6.99 (s, 1H), 6.67 (d, 1H, J=5.47 Hz), 3.91 (s, 3H), 3.61(s, 2H), 2.66 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 413, found 413. Anal. (C20H17N4O2SCl.0.25CH2Cl2), C, H, N.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.O.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>O1CCCC1>[CH3:7][O:6][CH:3]([O:2][CH3:1])[CH:4]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(C)=O
Reactant: COC(C=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC(OC)OC

Procedure:
Dissolve dimethoxyacetaldehyde (97 g, 0.635 mol, 60% in water) and triethylphosphonoacetate (142 g, 0.633 mmol) in 7:1 tetrahydrofuran:water. Add potassium carbonate (100 g, 0.723 mole) and stir for 4 hours at room temperature. Pour the reaction into ethyl acetate (500 ml) and wash with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. Concentrate under reduced pressure to provide the desired compound as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][C:13](=[O:15])[CH3:14])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 125 ml of dry methylene chloride was cooled to 0° C. and mixed with 1.25 ml of acetic anhydride and 2.1 g of 4-N,N-dimethylaminopyridine. The reaction mixture was warmed to room temperature and stirred for 1 hour. Additional amounts of 4-N,N-dimethylaminopyridine (809 mg) and acetic anhydride (1.25 ml) were added to the reaction mixture and stirring was continued overnight. The reaction mixture was diluted with 300 ml of methylene chloride and was washed with 60 ml of 5% citric acid solution. The organic extracts were dried, concentrated in vacuo, and the residue was chromatographed on silica gel (chloroform-methanol, 97:3 v/v) to yield 500 mg of the title compound in pure form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]CCCC)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
Into a 50-mL round-bottom flask, was placed butyl 2-(4-fluorophenyl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.37 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (74 mg, 1.85 mmol, 5.02 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Gilson Pre-HPLC (Max. pressure: 8 MPa)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (70% CH3CN up to 77.5% in 6 min, up to 100% in 0.1 min, hold 100% in 1.9 min); Detector, UV 220 NMnm. This resulted in 70 mg (52%) of 2-(4-fluorophenyl)-3-(piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])[CH:15]=2)[NH:10][CH:9]=1.CO>[Pd].C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:15]=2)[NH:10][CH:9]=1
Reactant: CC(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1

Procedure:
Obtained from the title compound of Example 49 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. [α]D25 +83° (c=0.1, CH3OH). Found: C,71.61; H,8.36; N,9.02. C18H24N2O; 0.20 CH2Cl2 requires C,71.84; H,8.16; N,9.30%. LRMS: m/z 285.3 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH2:25][C:26]([CH3:36])([CH3:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([CH3:36])([CH3:35])[CH2:25][OH:24])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: CC(C)(CO)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(CO)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (23.5 g) and 4-[(3-hydroxy-2,2-dimethylpropyl)amino]-1,3-thiazol-2(5H)-one (7.00 g) in 2-propanol (200 mL) was added piperidinium acetate (10.1 g). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (8.83 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].CCOCC>O1CCOCC1>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccncc3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1cc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a 20 mL vial which contained a solution of (R)-2-[4-(4-Pyridin-4-yl-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 0.15 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. the resulting solid was filtered out and dried in vacuo to yield the title product (35 mg, 80%); LCMS; 97%, APCI+, Calcd: 344.5; Found m/z: 345.8 (M+1); 1H NMR (500 MHz, DMSO-d6); δ 1.66-1.76 (m, 1H), 1.84-2.02 (m, 2H), 2.06-2.15 (m, 1H), 3.14-3.26 (m, 2H), 3.87 (br, 1H), 4.00 (s, 2H), 4.09-4.19 (m, 1H), 4.21 (dd, J1=11.0, J2=4.0, 1H), 6.93 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 8.27 (d, J=6.0 Hz, 2H), 8.89 (d, J=6.0 Hz, 2H):
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:13][CH:12]=1)(=[O:9])=[O:8].C([Li])CCC.[CH3:36][C:37]([CH3:39])=[O:38].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[OH:38][C:37]([CH3:39])([CH3:36])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:15][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CCN3CCOCC3)cc2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccc(CCN2CCOCC2)cc1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-C-[4-(2-morpholin-4-ylethyl)phenyl]methanesulfonamide (50 mg) in THF (1 ml) was initially charged and then, at −78° C., 1.6 N butyllithium solution in hexane (0.3 ml) was added dropwise. The reaction mixture was stirred for 10 minutes, and then acetone (50 μl) was added dropwise. The mixture was stirred at constant temperature for 30 minutes, trifluoroacetic acid (40 μl) was added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 2 ml of dichloromethane, and 250 μl of trifluoroacetic acid were added. After stirring at room temperature for 2 h, the mixture was diluted with dichloromethane and extracted with 1 M hydrochloric acid. The aqueous phase was concentrated and the residue was coevaporated with toluene. This gave the crude product with a molecular weight of 378.9 g/mol (C16H26N2O4S), which was used without further purification.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.[CH3:21][OH:22].O>C1(C)C=CC=CC=1>[OH:2][CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:22][CH3:21])[C:5]=2[CH2:4][O:3]1
Reactant: O=C1OCc2ccccc21
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1COC2O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The phthalide (346 mg) prepared in reference example 33 was dissolved in toluene (20 ml). The solution was cooled to -78° C. A 1.76N solution of diisobutylaluminum hydride (DIBAL) in toluene (1.43 ml) was added dropwise to the cooled solution. The mixture was stirred for 30 min. at -78° C. Methanol (0.2 ml) was added to the reaction solution to decompose the excess DIBAL. Water was added to the reaction solution. A temperature of the solution was up to room temperature. The solution was stirred for 30 min. at room temperature. The reaction solution was dried over anhydrous sodium sulfate, washed with ethyl acetate and evaporated to give the residue contained the title compound having the following physical data. The residue was used in next reaction without purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[Na].[Na].[C:35]([C:37]1[C:41](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[NH:40][C:39](=[O:47])[C:38]=1O)#[N:36].O=P(Cl)(Cl)Cl>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:13]=[CH:14][C:15]([C:38]2[C:39](=[O:47])[NH:40][C:41](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[C:37]=2[C:35]#[N:36])=[CH:16][CH:17]=1)[CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2]
Reactant: N#CC(C#N)=C1NC(=O)C(O)=C1C#N
Reactant: CCCCC(CC)CN(CCCCCCOC(C)=O)c1ccccc1
Agent: [Na]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC(CC)CN(CCCCCCOC(C)=O)c1ccc(C2=C(C#N)C(=C(C#N)C#N)NC2=O)cc1
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
In a three-neck flask, 6-((2-ethylhexyl)(phenyl)amino)hexyl acetate (7.0 g, 0.020 mol) was dissolved in dimethylformamide (100 ml), stirred, and added with acetic anhydride (2.9 g, 0.028 mol) and 4-cyano-5-dicyanomethylene-3-hydroxy-2-oxo-3-pyrroline disodium salt (5.6 g, 0.024 mol). The temperature was decreased to 0° C., after which POCl3 was slowly added thereto for 30 min, and the mixture was allowed to react at room temperature for 6 hours with stirring. A solid product was precipitated with water, filtered, and then dried, thus obtaining 4.0 g of a dark blue solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH2:8][NH2:9])[CH:7]=1.CCN(C(C)C)C(C)C.[Br:24][CH2:25][C:26](Br)=[O:27]>C1COCC1.CCOC(C)=O>[Br:24][CH2:25][C:26]([NH:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[N:13][N:12]=[N:11]1)=[O:27]
Reactant: O=C(Br)CBr
Reactant: NCc1cc(Cl)ccc1-n1cnnn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-[5-chloro-2-(1H-tetraazol-1-yl)phenyl]methanamine (150 mg, 0.72 mmol) and Hünig's base (137 μL, 0.79 mmol) in anhydrous THF (3.3 mL) at 0° C. was added dropwise bromoacetyl bromide (69 μL, 0.79 mmol). The resulting orange-yellow suspension was stirred under N2 atmosphere at 0° C. for 20 min. The mixture was diluted with EtOAc and washed twice with H2O, twice with saturated aqueous NaHCO3 and once with brine. The organic layer was dried (anhydrous Na2SO4), filtered and concentrated to a brown oil. Silica gel chromatography (70% EtOAc-hexanes) afforded the title compound as a yellow oil which slowly formed a tan foam after drying in vacuo. 1H NMR (400 MHz, CDCl3): δ 8.95 (s, 1 H), 7.70 (d, J=2.2 Hz, 1 H), 7.50 (dd, J=2.0, 8.4 Hz, 1 H), 7.30 (d, J=8.4 Hz, 1 H), 7.21 (br s, 1 H), 4.29 (d, J=6.4 Hz, 2 H), 3.88 (s, 2 H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15][CH2:14]2.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15][CH2:14]2
Reactant: CCOC(=O)CC1CCCc2cc(OC3Cc4ccccc4C3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCCc2cc(OC3Cc4ccccc4C3)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (R/S)-ethyl 2-(6-(2,3-dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetate 52 (85 mg, 0.24 mmol) and LiOH (40 mg) in THF-H2O (1/1, 4 mL) was stirred at room temperature for 6 hours. 2N HCl was added to acidify the mixture to pH 2-3. The mixture was then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water and brine, and dried over Na2SO4. The residue obtained after filtration and concentration was purified with flash chromatography (0-60% EtOAc in hexane). (R/S)-2-(6-(2,3-Dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid (53) was obtained as colorless oil (79 mg, 96%). MS ESI (neg.) m/e: 321 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.11-7.28 (m, 5H); 6.65-6.75 (m, 2H); 5.16 (m, 1H); 3.36-3.40 (m, 3H); 3.19 (dd, J=16.6, 3.0 Hz, 2H); 2.62-2.80 (m, 3H), 2.59 (q, J=9.9 Hz, 1H), 1.99 (m, 1H), 1.78-1.87 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH3:9])[C:5]2[CH2:18][CH2:19][CH2:20][C:4]=2[N:3]=1.[CH2:21]([N:23](C(C)C)C(C)C)C.CN>C(O)(C)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]([CH3:9])[C:6]2[C:5]3[CH2:18][CH2:19][CH2:20][C:4]=3[N:3]=[C:2]([NH:23][CH3:21])[N:7]=2)=[CH:11][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(N(C)c2nc(Cl)nc3c2CCC3)cc1
Agent: CN
Solvent: CC(C)O
Product: CNc1nc2c(c(N(C)c3ccc(OC)cc3)n1)CCC2
Temperature: 110 °C
Reaction time: 72 h

Procedure:
Crude (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-(4-methoxyphenyl)-methylamine (100 mg, 0.32 mmol) was dissolved in isopropanol (10 mL) followed by the addition of ethyl-diisopropyl-amine (83 mg, 0.64 mmol) and alcoholic methylamine (excess, 800 μL). The mixture was stirred for 3 days at 110° C. The mixtures were evaporated and the residue was dissolved in CH2Cl2 and extracted with HCl (1 N). The organic layer was dried with MgSO4 and concentrated. The title compound was purified by preparative RPLC. 1H NMR (CDCl3) δ 7.18 (d, 2H), 6.95 (d, 2H), 3.85 (S, 3H), 3.50 (s, 3H), 3.03 (d, 3H), 2.79 (m, 2H), 1.80-1.70 (m, 4H); LC-MS (ESI+; 285 ([M+H]+)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[S:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:13]=3[S:14][C:15]=2[N:17]([CH3:18])[CH3:19])=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(F)c(C(F)(F)F)c1
Yield: 93 %

Procedure:
The title compound was prepared in 93% yield from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene and 4-fluoro-3-(trifluoromethyl)benzoyl chloride by essentially following the procedure outlined in Example 81, Part C, and Example 85, Part B.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH:7]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:19][C:5]1[CH:4]=[C:3]([CH3:22])[C:2]([OH:1])=[CH:7][C:6]=1[S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Sc2cc(O)c(C)cc2N)cc1
Yield: 91.4 %

Procedure:
A solution of the product of Example 34a (2.5 g, 6.45 mmol), iron powder (1.79 g, 32 mmol) and ammonium chloride (0.514 g, 9.6 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.7 g, 91%).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[CH:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][CH:21]=1>CC(C)=O>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=3)[CH2:23][CH2:24]2)=[CH:6][CH:7]=1)[C:12](=[O:14])[CH3:13]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc(OCC(O)CN2CCN(c3ccccc3)CC2)cc1
Yield: 92.5 %

Procedure:
10.0 g of 4-(2,3-epoxypropoxy)phenylacetone are dissolved in 60 ml of acetone and the solution is heated under reflux with 7.64 g of phenylpiperazine for 3 hours. The mixture is allowed to cool and the product which has crystallised out is filtered off with suction. 16.05 g of 1-[4-(propan-2-on-yl)-phenoxy]-3-(4-phenylpiperazin-1-yl)-propan-2-ol are obtained.