Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=2)[CH2:16][CH2:15]1)[C:7](N)=[O:8].C(O)C[OH:35]>O>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:31])[F:32])=[N:19][N:18]=2)[CH2:15][CH2:16]1)[C:7]([OH:8])=[O:35]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C1(Oc2ccc(C(N)=O)cc2Br)CC1
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C1(Oc2ccc(C(=O)O)cc2Br)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (87 mg) was added to a mixture of 3-bromo-4-[(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}cyclopropyl)oxy]benzamide (250 mg) and ethyleneglycol (6 ml), followed by stirring at 130° C. for 3 hours. The reaction solution was cooled to room temperature, and water was added thereto, followed by washing with ethyl acetate. The aqueous layer was acidified with 1M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting product was solidified with diisopropylether and washed to obtain, as a colorless solid, 3-bromo-4-[(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}cyclopropyl)oxy]benzoic acid (71 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[CH2:21]([N:23]([CH2:29][CH3:30])[C:24](=[O:28])/[CH:25]=[CH:26]/[CH3:27])[CH3:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:21]([N:23]([CH2:29][CH3:30])[C:24](=[O:28])/[CH:25]=[C:26](/[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1)\[CH3:27])[CH3:22]
Reactant: OCCc1cc(Br)ccc1OCc1c(F)cccc1F
Reactant: C/C=C/C(=O)N(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(CCO)c1

Procedure:
A solution of 2-[5-bromo-2-[2,6-difluorobenzyloxy)phenyl]-1-ethanol (14.07 g, 41.02 mmol) and N,N-diethylcrotonamide (8.68 g, 61.53 mmol) in 60 mL triethylamine in a thick-walled pyrex tube is degassed wish nitrogen for 15 minutes. Pd(OAc)2 (0.46 g, 2.05 mmol) and tri-o-tolylphosphine (1.25 g, 4.10 mmol) are placed into the tube, which is then sealed, and the mixture is heated to 100° for 5 hours. The mixture is diluted with EtOAc (400 mL), and white precipitate is filtered out. The filtrate is then washed with 1 N HCl (2×400 mL), H20 (1×100 mL) and brine (1×100 ni), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 3:1 EtOAc/hexane) gives (E)-3-[4-(2,6-difluorobenzyloxy)-3-(2-hydroxyethyl)-phenyl]-2-butenoic acid diethy amide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[C:5][CH2:6][Cl:7].O.[OH-].[Na+].[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[C:11]([O:15][C:16]([NH:2][CH2:3][C:4]#[C:5][CH2:6][Cl:7])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCC#CCCl
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCC#CCCl
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Ex-8c) 14.1 g of 1-Amino-4-chloro-2-butyne hydrochloride was taken up in 70 mL of dioxane and :35 mL water. 4 g NaOH was added and the reaction mixture was stirred for 30 minutes followed by the addition of 21.8 g di-t-butylcarbonate at 20° C. The reaction mixture was stirred at 20° C. to 25° C. for 8 h and then the lower organic layer was separated. The upper aqueous layer was extracted with 100 mL of dichloromethane. Organic layers were combined and washed with 50% aqueous NaHCO3, dried over anhydrous MgSO4, treated with Darco, filtered over celite and concentrated to give a brown oil. This oil was chromatographed to give 9 g of 1-t-Butyloxycarbonylamino-4-chloro-2-butyne as a white solid.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:16])([CH3:15])[C:9]([CH2:19][OH:20])([CH2:17][OH:18])[C:8]2=O.Cl>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:16])([CH3:15])[C:9]([CH2:19][OH:20])([CH2:17][OH:18])[C:8]2=[CH2:1]
Reactant: C[Mg+]
Reactant: CC1(C)Oc2ccc(Br)cc2C(=O)C1(CO)CO
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2OC(C)(C)C1(CO)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
Under nitrogen, MeMgBr solution (2.9 M in 2-methyltetrahydrofuran solution, 3.06 L, 8.88 mol) was diluted by adding into THF (8 L) at 0-5° C. A solution of 6-bromo-3,3-bis(hydroxymethyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (700 g, 2.22 mol) in THF (5 L) was added dropwise via a dropping funnel to the diluted MeMgBr solution maintaining the temperature below 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Then the reaction mixture was heated under reflux overnight. The mixture was cooled to room temperature followed by cooling with an ice-water bath and 6 M hydrochloric acid (3.7 L, 22.2 mol) was added dropwise via a dropping funnel over 30 minutes maintaining the temperature below 10° C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 20 minutes. The mixture was extracted with toluene (5 L×2) and the combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was treated with a mixture of hexane/toluene (5:1, 2 L) and the resulting suspension was stirred for 30 minutes. The precipitate was collected by filtration, washed with hexane and dried under vacuum to give (6-bromo-2,2-dimethyl-4-methylene-3,4-dihydro-2H-chromene-3,3-diyl)dimethanol (500 g).
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]3[C:20](=[O:23])[NH:21][N:22]=[C:12]3[C:11]3[CH:24]=[CH:25][CH:26]=[N:27][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N:30]1([CH2:35][CH2:36]Cl)[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[N:30]1([CH2:35][CH2:36][N:21]2[C:20](=[O:23])[N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:9]([C:7](=[O:8])[CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:10]4[N:27]=[CH:26][CH:25]=[CH:24][C:11]=4[C:12]3=[N:22]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ClCCN1CCCC1
Reactant: O=C(CN1CCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1)N1c2ccccc2-n2c(nn(CCN3CCCC3)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-[(pyrrolidino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (2-pyrrolidinoethyl)chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-(2-pyrrolidinoethyl)-9-(pyrrolidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one.
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[NH2:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[C:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[CH2:23][NH:22][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using (R)-2-(aminomethyl)-1-N-BOC-pyrrolidine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 442 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.48 (1H, br. s.) 10.24 (1H, br. s.) 8.17 (1H, br. s.) 8.02 (1H, d, J=5.47 Hz) 7.79 (1H, d, J=5.27 Hz) 7.44-7.54 (1H, m) 7.31 (1H, d, J=2.73 Hz) 6.82 (1H, br. s.) 6.41 (1H, br. s.) 3.93 (1H, br. s.) 3.39 (1H, br. s.) 3.23 (2H, br.s.) 1.67-1.88 (4H, m) 1.39 (9H, s)
Reaction SMILES: CCN(CC)CC.C(OC([N:15]1[CH2:19][C:18]([F:21])([F:20])[C:17]([CH3:23])([CH3:22])[C@H:16]1[C:24]([OH:26])=O)=O)(C)(C)C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:24]([C@@H:16]1[C:17]([CH3:22])([CH3:23])[C:18]([F:20])([F:21])[CH2:19][NH:15]1)=[O:26]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C(C)(C)[C@H]1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)[C@@H](C(=O)NCC(F)(F)F)NCC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 107 %

Procedure:
NEt3 (75.2 g, 743 mmol) was slowly added to a 10° C. solution of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (98.3 g, 352 mmol), chlorodiphenylphosphate (101 g, 376 mmol), and ethyl acetate (1.0 L). The mixture was warmed to ambient temperature for 45 min., and was then cooled to 10° C. 2,2,2-Trifluoroethylamine (39.5 g, 399 mmol) was slowly added and the resultant mixture was stirred at ambient temperature for 2.75 h. 20% Aqueous citric acid (1.0 L) was added and the resulting layers were separated. The aqueous fraction was extracted with ethyl acetate (2×300 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (2×500 mL), and then with saturated aqueous NaCl (300 mL). The resulting organic fraction was concentrated to a weight of 900 g using a rotary evaporator. A 3 N HCl/ethyl acetate solution (500 mL) was added to the concentrate, and the mixture was stirred at ambient temperature for 24 h. The resulting solid was filtered, washed with ethyl acetate (100 mL), and was then dried in a vacuum oven at 55° C. to provide 98.0 g (93.9%) of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.46 (br s, 2H), 9.50 (t, J=6.2Hz, 1H), 4.17–4.33 (m, 2H), 3.68–4.02 (m, 3H), 1.23 (app d, J=2.1 Hz, 3H), 0.97 (app d, J=2.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 165.6, 127.9 (dd, JCF=250.2, 257.2 Hz), 125.6 (q, JCF=279.0 Hz), 64.8, 48.2 (t, JCF=33.4 Hz), 45.7 (t, JCF=21.2 Hz), 18.2 (d, JCF=7.5Hz), 17.2 (app dd, JCF=2.3, 5.8 Hz); MS (CI) m/z 261.1015 (261.1026 calcd for C9H14N2OF5, M−HCl+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].[CH3:14]O>OS(O)(=O)=O>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Br:1]
Reactant: CO
Reactant: COc1ccc(CC(=O)O)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)cc1Br
Reaction time: 18 h

Procedure:
To a solution of (2-bromo-4-methoxy-phenyl)-acetic acid (1.07 g, 4.37 mmol) in 25 mL MeOH was added two drops of concentrated H2SO4 and the reaction was heated to reflux. After 18 hours, the solvent was removed in vacuo to give 920 mg of (2-bromo-4-methoxy-phenyl)-acetic acid methyl ester. This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-4-piperidinol (2.5 g, 11.8 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.56 g, 13.0 mmol). The mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. This allowed the isolation of compound H, 2.83 g (72%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[F:12].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[F:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=[CH:11][C:2]=1[CH:21]=[O:22]
Reactant: Fc1c(Br)ccc2c1OCCO2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1F)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
A solution of 6-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin (146 mg, 0.627 mmol) in THF (5 ml) at −78° C. was treated with n-BuLi (0.551 ml, 1.378 mmol) under a nitrogen atmosphere and stirred at −78° C. for 15 min before treatment with a solution of DMF (0.243 ml, 3.13 mmol) in THF) (2.00 ml). The reaction was stirred for 10 min at −78° C. and then the reaction was allowed warm to rt over 10 min and stirred at rt for 0.5 h. Reaction was treated with 2M HCl (20 ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were evaporated, dried (MgSO4), filtered, evaporated, chromatographed (0-100% EtOAC:Cyclohexane) to give product as a white solid (25 mg, 22%).
Reaction SMILES: [CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[CH:5]=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH:7]=[C:8]([C:11](OC)=[O:12])[C:9]=1[CH3:10])[CH3:2].[NH2:40][CH2:41][C:42]1[C:43](=[O:53])[NH:44][C:45]([CH3:52])=[C:46]([F:51])[C:47]=1[CH:48]([CH3:50])[CH3:49]>>[CH2:1]([N:3]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:4]1[CH:5]=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)=[N:19][CH:20]=2)[CH:7]=[C:8]([C:11](=[O:12])[NH:40][CH2:41][C:42]2[C:43](=[O:53])[NH:44][C:45]([CH3:52])=[C:46]([F:51])[C:47]=2[CH:48]([CH3:50])[CH3:49])[C:9]=1[CH3:10])[CH3:2]
Reactant: Cc1[nH]c(=O)c(CN)c(C(C)C)c1F
Reactant: CCN(c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)OC)c1C)C1CCOCC1
Product: CCN(c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1

Procedure:
Hydrolysis of tert-Butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate following the similar methods for examples described earlier resulted in a crude corresponding carboxylic acid 5-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid. This acid was then coupled with 3-(aminomethyl)-5-fluoro-4-isopropyl-6-methylpyridin-2(1H)-one following similar methods described earlier. After purification by reverse phase HPLC (ACN-H2O containing 0.1% formic acid), the titled compound was obtained. 1H-NMR (400 MHz, CD3OD) δ ppm 8.33 (d, J=2.6 Hz, 1H), 7.81 (dd, J=2.6, 8.8 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.54 (s, 2H), 3.92 (m, 2H), 3.46-3.56 (m, 9H), 3.34 (m, 2H), 3.07-3.18 (m, 3H), 2.33 (s, 3H), 2.24 (d, J=3.2 Hz, 3H), 1.74-1.77 (m, 2H), 1.62-1.69 (m, 2H), 1.49 (s, 9H), 1.37 (dd, J=1.6, 6.8 Hz, 6H), 0.90 (t, J=6.8 Hz, 3H); MS (ES) (M+H) 705.7.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Br.Br.[C:22]1([CH2:28][N:29]2[CH2:34][CH:33]3[CH2:35][CH:30]2[CH2:31][NH:32]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:32]3[CH2:31][CH:30]4[CH2:35][CH:33]3[CH2:34][N:29]4[CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CC3CN4Cc3ccccc3)c(F)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.1 %

Procedure:
A solution of 0.54 g (2.0 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.77 g (2.2 mmol) of 5-(phenylmethyl)-2,5-diazabicyclo(2.2.1)heptane dihydrobromide, (P. S. Portoghese and A. A. Mikhail, J. Org. Chem. 31, 1059 (1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo(5.4.0)undec-7-ene, and 20 ml of acetonitrile was heated under reflux for two hours and stirred at room temperature for two days. The mixture was filtered and the solid was washed with methanol to give 0.44 g of the title compound, mp 195°-198° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1.I[CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Reactant: O=C(CCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)cc1
Yield: 80.6 %

Procedure:
tert-Butyl 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (0.274 g, 0.672 mmol), 4-iodobutyrophenone (0.18 g, 0.672 mmol), and potassium carbonate (0.14 g, 1.01 mmol) in N,N-dimethylformamide (5 mL) were heated at 65° C. for 3 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.30 g, 80%); MS for C34H39N3O4 m/z 554 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][NH:28][CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[CH3:13])[CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1
Reactant: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CNCC12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3F)(c3ccccc3F)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
N,N'-Carbonyldiimidazole (0.44 g) is added to a solution, cooled to +4° C., of (2-dimethylaminophenyl)acetic acid (0.49 g) in dry dichloromethane (20 cc). The mixture is stirred for 1 hour at 25° C. and a solution of 7,7-bis(2-fluorophenyl)perhydro-4-isoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 20 hours at 25° C. and washed with water (2×100 cc) and with saturated sodium chloride solution (100 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50:50) and collecting 10-cc fractions. Fractions 14 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(2 -fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (1 g), the hydrochloride of which is prepared by dissolution in ethyl acetate (2 cc) and the addition of a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(2-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone hydrochloride (0.87 g) is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](OC)=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:18])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Product: CC(C)(CO)NC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and 2-amino-2-methylpropanol were reacted to yield 5-fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.41 (s, 1H), 9.28 (s, 1H), 9.22 (s, 1H), 8.18 (t, 1H, J=2.4, Hz), 8.09 (d, 1H, J=3.6 Hz), 7.56 (dd, 1H, J=2.4 and 8.7 Hz), 7.47 (d, 1H, J=8.7 Hz), 7.32 (s, 1H), 7.26–7.21 (m, 1H), 7.13–7.07 (m, 2H), 6.53 (d, 1H, J=8.7 Hz), 5.05 (t, 1H, J=5.7 Hz), 3.46 (d, 2H, J=5.7 Hz), 1.32 (s, 6H); LCMS: ret. time: 17.93 min.; purity: 97%; MS (m/e): 452 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([C:11](=O)[CH3:12])[CH:10]=1.[CH3:25][NH2:26]>C(O)C>[CH3:25][N:26]=[C:11]([C:9]1[CH:10]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:12]
Reactant: CC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CN=C(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrophenyl ethanone (3.3 g., 0.0092 mole) in absolute ethanol (30 ml) was bubbled methylamine for 0.5 hour as the temperature rose to about 40° C. The solution was stirred for 12 hours at room temperature and then heated to reflux for 4 hours. The solvent was stripped to give 3.0 g of a brown oil. Recrystallization from methanol/water gave a brown solid (1.2 g., mp. 133°-7° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32](Cl)Cl)=[CH:27][CH:26]=1.O>ClCCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:32]([NH:31][C:28]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCCCCOc1ccc2nc(Nc3ccccc3)n(-c3ccccc3)c2c1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was dissolved in 1 ml of 1,2-dichloroethane, the solution was mixed with 85 μl of phenylisocyanide dichloride, and the mixture was heated for 6 hours to 65° C. After cooling, it was mixed with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 55 mg was obtained.