Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[C@@H:12]2[CH2:13][C@@H:9]([CH:10]=[CH:11]2)[C@H:8]1[C:14](O)=[O:15])=[O:6])#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH:8]([CH2:14][OH:15])[CH:9]2[CH2:13][CH:12]1[CH:11]=[CH:10]2)=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@H]1[C@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Product: N#CCNC(=O)C1C2C=CC(C2)C1CO
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(1S,2R,3R,4R)-3-{[(Cyanomethyl)amino]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (840 mg, 3.81 mmol) was placed in a 25 mL round bottom flask and the flask was fitted with a rubber septum. After flushing the flask with nitrogen, tetrahydrofuran (8.0 mL) was added and the solution was cooled to −78° C. 4-Methylmorpholine (0.46 mL, 4.0 mmol) and isobutyl chloroformate (0.52 mL, 4.0 mmol) were added and the reaction mixture was stirred at −78° C. for 10 min., and then warmed to ambient temperature over 1 h. After stirring for an additional 1 h, the reaction mixture was recooled to −78° C. and sodium borohydride (0.25 g, 6.5 mmol) and methanol (6.0 mL) were added. After stirring for 1 h, the reaction mixture was allowed to warm to ambient temperature over 1 hour and then quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with saturated aqueous sodium chloride solution (100 mL) and the product was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. Chromatography of the residue on a silica gel using a mixture ethyl acetate:hexanes (gradient elution 5:2 to 3:1) provided (1R/S,2R/S,3R/S,4S/R)-N-(cyanomethyl)-3-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH:18]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[O:20][C:19]2=O>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:19](=[O:20])[CH:18]3[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]3)[C:21]2=[O:27])[CH2:11][CH2:10]1
Reactant: O=C1OC(=O)C2CCC1CC2
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Product: O=C1C2CCC(CC2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
An intimate mixture of 0.5 g (2.14 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine and 0.22 g (1.42 mmol) of 3-oxabicyclo[3.2.2]nonan-2,4-dione was heated in an oil bath at 220°-230° C. for 15 minutes. An additional 0.22 g (1.42 mmol) of 3-oxabicyclo[3.2.2]nonan-2,4-dione was added. Heating in an oil bath at 220°-230° C. was continued for 15 minutes and then an additional 0.22 g (1.42 mmol) of 3-oxabicyclo[3.2.2]-nonan-2,4-dione was added. Heating was continued for 30 minutes at 220°-230° C. and then the reaction mixture was cooled. The resulting product was chromatographed on silica gel, eluting with dichloromethane/methanol (96:4 followed by 94:6), to give 46 mg of the title compound (6% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH:11]=O)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C
Reaction time: 4 h

Procedure:
A solution of (3S*,4S*)-4-formyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.87 g, 10.56 mmol) and isopropylamine (2.72 mL, 31.68 mmol) in 1,2-dichloroethane (150 mL) is stirred 25 min, before addition of NaBH(OAc)3 (3.12 g, 14.78 mmol) follows. The solution is stirred for 4 h, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The combined organic extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 80:20) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.1.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O.C1C=CC=CC=1>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.COCCOC>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3ccc(Cl)cc3Cl)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (70 mg, 0.208 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (210 μL, 0.420 mmol), (Ph3P)4Pd (10 mg, 0.009 mmol) (Aldrich), and 2,4-dichlorophenylboronic acid (44 mg, 0.231 mmol) (Lancaster) in 6 mL of a 5:1 mixture of benzene:1,2-dimethoxyethane was heated at reflux under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 60% ethyl acetate-hexanes elution) to yield pure (Z)-4-(2,4-dichlorophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield 52 mg, 69%) as a yellow-brown solid (mp 185-187° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:19][CH2:18][CH2:17][Br:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCOc1ccc(OCc2ccccc2)cc1
Yield: 41.6 %

Procedure:
A mixture of 4-benzyloxyphenol (50 g), 1,3-dibromopropane (101 g) and powdered anhydrous potassium carbonate (17.3 g) in acetone (500 ml) was stirred under reflux for 30 hours. The solids were removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 300 ml of dichloromethane and the resulting solution was washed with 10% sodium hydroxide solution to remove unreacted p-benzyloxyphenol. The dichloromethane extract was dried over potassium carbonate, concentrated in vacuo and distilled giving 33.4 g of 1-benzyloxy-4-(3-bromopropoxy)benzene; bp 180°-195° (0.6 mm) (41% yield, 98% pure by gas chromatography). The structure was confirmed by mass spectrum analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24]CC)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:29]1([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:27])[NH:20][C:19](=[O:28])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[CH:40][CH:39]=2)[CH:3]=1)=[O:15]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)cc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (80 mg, 0.192 mmol) and [4-(1-piperazinyl)phenyl]boronic acid (59 mg, 0.288 mmol). The product was collected as a white solid (34 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1H) 8.66 (br. s., 1H) 8.33 (s, 1H) 8.00 (s, 1H) 7.82 (s, 1H) 7.73-7.76 (m, 1H) 7.72 (s, 1H) 7.01-7.09 (m, 2H) 5.89 (s, 1H) 5.14 (dt, J=13.33, 6.60 Hz, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.38-3.52 (m, 4H) 3.09-3.14 (m, 1H) 3.00-3.09 (m, 3H) 2.81-2.90 (m, 1H) 2.21 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.48 (s, 3H). LC-MS (ES) m/z=499.4 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[ClH:24]>O1CCOCC1>[ClH:24].[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCNCC2)cn1

Procedure:
Prepared in analogy to example 4.4(b) from 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl ester and 1,4-dioxane saturated with gaseous HCl. MS (m/e): 223.1 (MH+, 100%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH3:5].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>O1CCCC1>[CH3:5][S:4][CH2:3][CH2:2][O:1][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CSCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCCOc1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
16.3 g of 2-hydroxyethylmethyl sulfide are added dropwise at 20°-25° C. to 8.5 g of a 55% NaH suspension in 150 ml of absolute tetrahydrofuran. The mixture is stirred for 1 hour at 20° C. and for 20 minutes at 40° C., and 25 g of 1-fluoro-2-nitrobenzene are subsequently added at 20° C. After the suspension has been stirred for 10 hours at 20° C., the tetrahydrofuran is distilled off in vacuo. Water is added to the residue, and extraction is repeatedly performed with ether. There is thus obtained an oil which can be used without further purification for the following hydrogenation stage.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@H:8]2[NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C:3]1=[O:26].Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=2)[N:31]=[CH:30][N:29]=1.C(N(CC)CC)C>C(O)(C)C>[O:26]=[C:3]1[C@@H:2]([NH:1][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH2:6][CH2:5][N:4]1[C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:9][C@H:8]1[NH:21][C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-propionamidocyclohexylcarbamate (650 mg, 1.764 mmol) in 5 mL of isopropanol was added 4-chloro-6-(trifluoromethyl)quinazoline (492 mg, 2.117 mmol) and triethylamine (0.492 mL, 3.53 mmol). The mixture was stirred at 50° C. for 4 h. The solvent was removed under reduced pressure and the residue was diluted with 30 mL of 20% AcOH in water before being extracted with diethyl ether (2×20 mL). The ethereal layer was extracted with 20% AcOH solution in water (3×30 mL). The aqueous layers were combined and basified with Na2CO3 and extracted with methylene chloride (3×50 mL). The organic extracts were combined, washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give tert-butyl (1R,3R,4S)-4-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)-3-propionamidocyclohexylcarbamate, LC/MS found [M+H]+=565. The entirety of this crude product was dissolved in 5 mL of methylene chloride. The resultant solution was charged with TFA (3 mL), stirred at room temperature for 30 min, and then concentrated in vacuo. The residue was purified with preparative reverse-phase HPLC to give the title compound as its TFA salt in aqueous methanol solution. This solution was concentrated in vacuo to remove the methanol and the residue solution was basified with saturated NaHCO3 and extracted with methylene chloride (3×50 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound as its free base (550 mg, 1.184 mmol, 67% yield). LC/MS found [M+H]+=465. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.77 (1H, s), 8.57 (1H, s), 8.03 (1H, dd, J=9.16, 2.03 Hz), 7.88 (1H, d, J=8.65 Hz), 5.24 (1H, t, J=8.65 Hz), 4.55 (1H, d, J=3.56 Hz), 3.97-4.05 (1H, m), 3.52-3.67 (2H, m), 3.35-3.41 (1H, m), 2.47-2.58 (1H, m), 2.20-2.34 (3H, m), 1.62-2.04 (6H, m), 1.14 (3H, t, J=7.63 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:26])=[C:8]([C:10]2[NH:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[N:11]=2)[CH:9]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])=[CH:9][C:8]=1[C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[N:11]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1
Yield: 93.7 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using methyl 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate hydrochloride (0.250 g, 0.5 mmol), cyclopropane carbonyl chloride (0.108 g, 1.0 mmol), DIPEA (2.0 mL), THF (10 mL) to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.05 (s, 2H), 1.60 (m, 2H), 3.14 (m, 1H), 3.87 (s, 3H), 4.33 (d, J=5.7 Hz, 2H), 7.41-7.61 (m, 4H), 8.11-8.17 (m, 3H), 8.69 (m, 1H), 12.65 (br s, 1H); MS (m/z): 427.14 (M+H)+.
Reaction SMILES: [Br:1]Br.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe].C(OCC)(=O)C>[Br:1][C:8]1[CH:7]=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:13]
Reactant: BrBr
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a suspension of iron powder (0.0669 g, 1.20 mmol) in bromine (2.05 mL, 39.9 mmol) at 0° C. was added methyl p-tolyl sulfone (0.340 g, 2.00 mmol). The reaction was warmed up to RT and stirred for 2 h. The mixture was poured into an ice-cold 1 M solution of sodium thiosulfate and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 545 mg of crude material. The crude material was purified by column chromatography (3/1 Hex/ethyl acetate to 1/1 ethyl acetate/hexanes) to give 374 mg of 2-bromo-1-methyl-4-(methylsulfonyl)benzene as a white solid. ES+=251.0 (M+H)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([OH:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(C=O)cc1O
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1O

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-hydroxy-4-methoxy-benzaldehyde. MS (ESI) m/z 515.
Reaction SMILES: [C:1]1(=[O:37])[N:5]([CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][N:14]2[C:23]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:31])[CH:21]=3)[N:16]=[CH:15]2)=O)=[O:8])[C:4](=[O:32])[C:3]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:2]12>C(O)(=O)C>[Cl:31][C:20]1[CH:19]=[CH:18][C:17]([N:16]2[CH:15]=[N:14][N:13]=[C:11]2[CH2:10][NH:9][C:7](=[O:8])[CH2:6][N:5]2[C:4](=[O:32])[C:3]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:2]3[C:1]2=[O:37])=[C:22]([CH:21]=1)[C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NCC(=O)NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CN1C(=O)c2ccccc2C1=O)NCc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A solution of 3-[Nα -(2-phthalimidoacetyl)-glycylamino]-4-hydroxy-4-phenyl-6-chloro-3,4-dihydroquinazoline (0.7 g) in acetic acid (5 ml) is refluxed with heating for 2.5 hours. The reaction mixture is evaporated under reduced pressure, and the residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with saturated aqueous sodium bicarbonate and water in order, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate-methanol (20:1) to give 5-chloro-2-[3-(2-phthalimidoacetamidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone as crystals melting at 214° to 215° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[CH:36]=[N:37][CH:38]=[C:33]([F:32])[CH:34]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cncc(F)c1
Product: Cn1ncc(NC(=O)c2csc(-c3cncc(F)c3)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (5-fluoropyridin-3-yl)boronic acid gave 239. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.15 (t, J=1.7 Hz, 1H), 8.74 (d, J=2.7 Hz, 1H), 8.55 (s, 1H), 8.37 (dt, J=9.5, 2.3 Hz, 1H), 7.84 (s, 1H), 4.87 (dd, J=10.5, 3.9 Hz, 1H), 4.58-4.36 (m, 1H), 4.34-4.20 (m, 1H), 4.16-3.92 (m, 1H), 3.79 (s, 3H), 3.37-3.23 (m, 2H), 2.15-2.05 (m, 1H), 1.91-1.67 (m, 5H). LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:33])=[C:29]([CH:32]=1)[CH2:30]Br>O1CCCC1.C(Cl)Cl>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:33])=[C:29]([CH:32]=1)[CH2:30][O:17][CH2:16][CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CCCOCc1cc(Br)ccc1F
Temperature: -40 °C
Reaction time: 0.58 h
Yield: 49.9 %

Procedure:
3-[1-(t-Butoxycarbonyl)piperidin-2-yl]propanol (800 mg, 3.29 mmol) was taken up in tetrahydrofuran (17 ml), cooled to −40° C., and treated with potassium t-butoxide (1 M in tetrahydrofuran, 3.62 ml, 3.62 mmol). The resulting mixture was stirred at −40° C. for about 35 minutes, then cooled to −78° C. To this mixture was then added 5-bromo-2-fluorobenzyl bromide (881 mg, 3.29 mmol) as a solution in tetrahydrofuran (5 ml). The resultant yellow reaction mixture was slowly warmed to 0° C. and stirred for about four hours. The reaction mixture was diluted with methylene chloride and washed with 1 M potassium carbonate and brine. The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by high performance liquid chromatography, yielding 707 mg (50%) of the title intermediate as a clear oil.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C)CC=C(C(C)=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1(C)CCC(C(C)=O)CC1
Yield: 99 %

Procedure:
0.1 g of 10% palladium-carbon was added to a solution of 2.1 g of methyl 4-acetyl-1-methyl-3-cyclohexene-1-carboxylate (Example 34) in 50 ml of ethanol. The solution was reacted for 18 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. The oily substance obtained was refined by vacuum distillation (Kugelrohl), yielding 2.1 g of methyl 4-acetyl-1-methyl-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:13]2[C:5](=[CH:6][C:7]3[NH:8][C:9]([S:14][CH2:15][C:16]4[C:21]([CH3:22])=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=4)=[N:10][C:11]=3[CH:12]=2)[C:4]([CH3:27])([CH3:26])[C:3]1=[O:28].[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:15][S:14][C:9]2[NH:8][C:7]3[CH:6]=[C:5]4[C:13](=[CH:12][C:11]=3[N:10]=2)[C:2]([CH3:29])([CH3:1])[C:3](=[O:28])[C:4]4([CH3:27])[CH3:26])[C:21]=1[CH3:22]
Reactant: C[O-]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
A solution of 4.4 g (0.011 mol) of 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl -4-nitro-2-pyridyl)methyl)thio]indeno[5,6-d]imidazol-6(1H)-one in 100 ml of abs. methanol is treated with 3 g of sodium methylate, whereupon the mixture is boiled at reflux for 18 houre under argon. After concentrating the reaction mixture in vacuo the residue is treated with methylene chloride, whereupon the mixture is buffered by means of glacial acetic acid; the methylene chloride phase is extracted several times with a sodium bicarbonate solution, dried and evaporated. By recrystallisation from ethyl acetate there is obtained 5,7-dihydro-2-[[(4-methoxy-3 -methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 222°-226°.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]([C:7]([F:10])([F:9])[F:8])([OH:5])[CH2:6][NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1ccccc1
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Yield: 58.8 %

Procedure:
Analogously to Example 1, 500 mg (2.05 mmol) of 2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 650 mg (4.10 mmol) of 5-amino-2-methylquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0–70%), 485 mg of product is obtained.