Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:32])[CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:10][CH2:9]1)=[O:7])[CH3:4].[CH2:33](Br)[CH2:34][CH3:35]>CN(C)C=O>[CH2:3]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([O:32][CH2:33][CH2:34][CH3:35])[CH2:16][N:17]2[C:18]3[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=3[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=3)[CH2:12][CH2:13]1)=[O:7])[CH3:4]
Reactant: CCCBr
Reactant: CCOC(=O)C1CCN(CC(O)CN2c3ccccc3CCc3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC(CN1CCC(C(=O)OCC)CC1)CN1c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
Sodium hydride (60% oil suspension, 0.108 g, 2.7 mmol) was added to a stirred solution of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxy-propyl)-4-piperidinecarboxylic acid ethyl ester (1.1 g, 2.7 mmol) in dry N,N-dimethylformamide (7.5 ml). Propylbromide (0.7 g, 5.68 mmol) was added dropwise to the ice-cooled stirred solution and the reaction mixture was left at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in toluene (20 ml), washed with water (3×10 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of toluene, ethyl acetate and triethylamine (35:6:1) as eluent to give 0.11 g (9%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-propoxypropyl)-4-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 6.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and morpholine to afford an off-white solid. UPLC-MS (Condition 3) tR=1.20 min, m/z=445.9 [M+H]+, m/z=443.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.37-3.46 (m, 4H) 3.69-3.81 (m, 4H) 7.39 (d, J=8.78 Hz, 2H) 7.86 (d, J=9.16 Hz, 2H) 8.47 (d, J=2.13 Hz, 1H) 8.80 (d, J=2.13 Hz, 1H) 10.44 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>>[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:47][C:30]([CH:29]2[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]2[CH2:24][C:23]2[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:22]=2)=[O:31])=[CH:44][CH:43]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)NCc4ccc(Cl)cc4)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 37.1 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.085 g, 0.142 mmol) was reacted with 4-chlorobenzyl amine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 43 μL, 0.355 mmol) to form 2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid 4-chloro-benzylamide (0.038 g, 37%). m/z=721 (M+1); HRMS: calcd for C36H48Cl2FN4O4S. Calc [M+H+] 721.2752. found 721.2755.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][N:18]([C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: O=C=Nc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccccc4)CC3)c2cc1OC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
In 5 ml of ethanol was dissolved 278 mg (1.0 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 0.109 ml (1.0 mmol) of phenyl isocyanate was added thereto. The mixture was heated under reflux for 10 minutes and then allowed to cool to room temperature. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 174.3 mg of the desired compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCc1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(NCc3ccncc3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and pyridin-4-ylmethanamine according to general procedure 1 providing the intermediate (94 mg, 84%) as a yellow solid: Rf=0.28 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.45-8.46 (m, 2H), 7.60 (d, J=9.7 Hz, 1H), 7.51-7.50 (m, 2H), 7.39 (s, 1H), 6.79 (d, J=9.7 Hz, 1H), 4.61 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][O:32][CH3:33].Cl.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][O:32][CH3:33])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(/C=C/C(=O)NO)cc21
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A mixture of (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OCH3.HCl (63.5 mg, 0.76 mmol) and pyridine (61 μl, 0.70 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-methyloxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (150 mg) as a 90/10 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:22]=[C:23]=[O:24])[CH:20]=[CH2:21]>C1(C)C=CC=CC=1>[CH2:19]([NH:22][C:23]([NH:10][C:8](=[O:9])[C@@H:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:24])[CH:20]=[CH2:21]
Reactant: C=CCN=C=O
Reactant: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: C=CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (prepared in Example 13, 1.02 g, 3.55 mmol) in toluene (30 mL) was treated with allyl isocyanate (0.47 mL, 5.33 mmol). This solution was heated to reflux for 16 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea (1.06 g, 81%) as a colorless oil: [α]23589=25.2° (c=0.151, chloroform); EI-HRMS m/e calcd for C18H22Cl2N2O2 (M+) 368.1058, found 368.1054.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:22](=[O:24])[CH3:23])[N:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)n1ccc(-c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
A solution of 3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole (0.16 g, 0.57 mmol) in pyridine (12 mL) was treated with neat acetic anhydride (1.0 mL, 1.0 mmol) and allowed to stir at room temperature for 16 hours. The reaction was then diluted with ethyl acetate, washed several times with an aqueous 2N HCl solution, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography, affording 116 mg (63%) of the title compound. TLC Rf 0.78 (70:30 hexane/ethyl acetate). 1H NMR (CDCl3): δ8.31 (d, J=3.0 Hz, 1H), 8.22 (d, J=9.3 Hz, 2H), 7.94 (d, J=8.7 Hz, 2H), 7.17 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.3 Hz, 2H), 6.77 (d, J=3.0 Hz, 1H), 2.78 (s, 3H).
Reaction SMILES: FC(S(O[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[Cl:20])(=O)=O)(F)F.[CH3:21][N:22](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:20][C:10]1[CH:11]=[C:12]([O:15][C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][C:9]=1[C:21]#[N:22]
Reactant: CN(C)C=O
Reactant: O=S(=O)(Oc1ccc(OC(F)(F)F)cc1Cl)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC(F)(F)F)cc1Cl
Temperature: 120 °C

Procedure:
3.00 g of the compound of Example 2A are dissolved in 12 ml of degassed DMF with 2.04 g of zinc cyanide and 1.00 g of tetrakis(triphenylphosphine)palladium and the solution is heated under argon at 120° C. for 2 h. After cooling, the reaction mixture is diluted with ethyl acetate and extracted by shaking twice with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel chromatography (cyclohexane/ethyl acetate 10:1). 880 mg (44% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br>CS(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:21][C:20]2[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cccc(F)c1Cn1cnc2c(Cl)nc(Cl)nc21
Yield: 61 %

Procedure:
To a stirred solution of 2,6-dichloropurine (5.3 mmol) in 10 ml anhydrous DMSO at room temperature was added anhydrous potassium carbonate (6.34 mmol) and 2,6-difluorobenzylbromide (6.34 mmol). The reaction mixture was maintained at this temperature for 20 hrs. The reaction can be monitored using either TLC or LC/MS. The reaction mixture was poured in to a beaker containing ice-cold water. The aqueous layer was acidified to pH 5-6. Extraction of the aqueous layer, using 3×75 ml portions of ethyl acetate, afforded the crude product. This was purified on the silica gel column (10-70% ethyl acetate in petroleum ether, step-gradient), to give the desired compound in a yield of 61%.
Reaction SMILES: Br[C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].[CH2:14]([SH:17])[CH2:15][SH:16]>CO>[S:16]1[C:2]2([CH2:7][C:6](=[O:8])[NH:5][C:3]2=[O:4])[S:17][CH2:14][CH2:15]1
Reactant: O=C1C=C(Br)C(=O)N1
Reactant: SCCS
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2(SCCS2)C(=O)N1
Yield: 41.2 %

Procedure:
To bromomaleimide (30 mg, 0.17 mmol) and sodium acetate (14 mg, 0.17 mmol) in methanol (6 mL) was added 1,2-ethanedithiol (17 μl 0.17 mmol). After five minutes solvent removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded the desired compound as a pale yellow powder (13 mg, 0.07 mmol) in 41% yield. δH (500 MHz, CDCl3) 8.39 (s, 1H, NH), 3.75-3.69 (m, 2H, HH-2 and HH-3), 3.60-3.53 (m, 2H, HH-2 and HH-3), 3.30 (s, 2H, H2-9); δc (125 MHz, CDCl3) 177.93 (C═O), 172.76 (C═O), 61.23 (C5), 43.12 (C9), 41.05 (C2 and C3); IR (solid, cm−1) 3290 (m), 1703 (m), 1629 (s); MS (ES−) m/z (relative intensity): 188 ([M−H], 100); Exact Mass Calcd for [C6H7NO2S2]−H requires m/z 187.9840 Found 187.9839 (ES−); m.p. 112-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.OC1C=CC([N:16]2[C:20](=[O:21])[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:28])[NH:17]2)=CC=1>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N:16]1[C:20](=[O:21])[N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:28])[NH:17]1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Product: O=c1[nH]n(-c2cc(Cl)ccc2O)c(=O)n1-c1ccccc1

Procedure:
Compound 34 was prepared from 4-chlorophenol in the same manner of compound 27, and was obtained as white solids (56%). 1H NMR (300 MHz, Methanol-d4): δ 7.75 (d, J=3.0 Hz, 1H), 7.52-7.46 (m, 4H), 7.38 (m, 1H), 7.08 (dd, J=1.8, 8.7 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 153.70, 152.32, 132.28, 129.63, 128.93, 128.19, 127.12, 126.41, 126.23, 124.62, 123.70, 118.20. HRMS: calcd for C14H10ClN3O3 (MH+) 304.0483. found 304.0487.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][C:31]=1[OH:37].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][C:31]=1[O:37][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: Cc1cc(C)c(O)cn1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cnc(C)cc2C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 4,6-dimethylpyridin-3-ol (0.19 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.4 g, 80%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[CH2:16][C:15]([O:14][CH3:13])=[O:18])=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: COC(=O)CBr
Reactant: Cc1ccc2c(c1)CC(C)C2=O
Product: COC(=O)CC1=C(C)Cc2cc(C)ccc21

Procedure:
The above reactions of Example 1C are repeated except that the starting materials are 2,5-dimethylindanone and methylbromoacetate. With the same reaction conditions and techniques, methyl 2,6-dimethyl-3-indenylacetate is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:14](=[O:15])[NH:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: Cc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
p-Toluidine (11.00 g, 102.65 mmol) dissolved in nitromethane (50 mL) was added slowly over 20 minutes to a solution of chlorosulfonyl isocyanate (16.89 g, 119.40 mmol) in nitromethane (160 mL) at −5° C. The suspension was stirred at −5° C. for an additional 15 minutes and AlCl3 (17.00 g, 129.00 mmol) was added portionwise. The reaction mixture was then heated at 105° C. for 30 minutes. The hot solution was poured onto ice (1 L) and the resulting precipitate was filtered off and washed with water (300 mL). The solid was then dissolved in a hot aqueous sodium bicarbonate solution (10 g/200 mL), treated with charcoal, and filtered. The cooled solution was neutralized using 6N HCl and the resulting white precipitate was filtered off, washed with water and dried to afford the title compound (14 g, 64%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](Cl)=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([O:1][C:2]3[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1nc2ccccc2cc1O
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
(3-Hydroxy-quinolin-2-yl)-ethanone (878 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (7.03 g), and 4-dimethylaminopyridine (3.44 g) were suspended in o-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-acetone to give 1-[3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (758 mg, yield 36%).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[CH:4]([OH:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:19][CH:4]([C:3]([CH2:21][F:22])([CH2:2][F:1])[CH3:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CF)(CF)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(CF)CF
Temperature: 100 °C
Reaction time: 16 h

Procedure:
112 g (0.328 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-ol (as the diastereomeric mixture of the pure forms A and B) were dissolved in 500 ml of acetic anhydride. The solution was stirred at 100° C. for 16 hours, the excess acetic anhydride was distilled off in vacuo and the residue was taken up in 600 ml of methylene chloride. The organic phase was washed twice with 1.5 liters of water each time, dried over sodium sulphate and concentrated. The oily residue was subjected to fractional crystallization in diisopropyl ether. 48 g (38% of theory) of the A-form (Compound 1a) of 2-acetoxy-3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butane of melting point 130°-133° C. and 20.5 g (16% of theory) of the B-form (Compound 1b) of 2-acetoxy-3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butane of melting point 98° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[C:3]([F:11])([F:10])[C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[H-].[Na+].Cl[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.O>CN(C)C=O>[Cl:26][C:25]1[C:20]([N:7]2[C:8]([CH3:9])=[C:4]([C:3]([F:11])([F:10])[C:2]([F:1])([F:16])[C:12]([F:14])([F:15])[F:13])[N:5]=[CH:6]2)=[N:21][CH:22]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:24]=1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)C(F)(F)F
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)C(F)(F)C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
To a solution of 0.6 g (2.4 m mol) of 4-heptafluoropropyl-5-methylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 100 mg (2.4 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.52 g (2.4 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product was subjected to silica gel chromatography to give 0.4 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-heptafluoropropyl-5-methylimidazole.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:4](C(OC(C)(C)C)=O)[C:3]1=[O:24].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[NH:4][C:3]1=[O:24]
Reactant: CN1C[C@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of (R)-1-tert-butyl 5-benzyl 3-methyl-2-oxoimidazolidine-1,5-dicarboxylate (25b) (0.650 g, 1.95 mmol) in DCM (20 mL), cooled to 0° C., TFA (3 mL, 2.9 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for further 1 h. After completion (by TLC), the reaction mixture was neutralized with saturated NaHCO3 solution and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide the crude residue which was purified by column chromatography to furnish 25c (0.320 g, 70%) as off white solid.