Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.O.[CH:10]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])CC=C[CH2:11]1.S(=O)(O)[O-].[Na+].[CH3:25][C:26]([CH3:28])=[O:27]>[Os](=O)(=O)(=O)=O.C(OCC)(=O)C.CCCCCC>[CH2:18]([O:17][C:15]([CH:10]1[CH2:28][CH:26]([OH:27])[CH:25]([OH:5])[CH2:11]1)=[O:16])[CH3:19]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOC(=O)C1CC=CC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(O)C(O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 84.6 g of N-methylmorpholine N-oxide, 1 g of osmium tetroxide, 230 ml of water and 115 ml of acetone was allowed to stir for 30 minutes at room temperature. To this stirred mixture was added very slowly over at least 8 hours, a solution of 80 g of ethyl 3-cyclopentene-1-carboxylate in 115 ml of acetone. The stirred mixture was heated at 50° C. for 2 hours to complete the reaction (verified by TLC examination using ethyl acetate/hexane 70/30). Sodium bisulfite (~10 g) was added, the stirring continued for a further 15 minutes, and the mixture filtered through Celite. The pH of the filtrate was adjusted to 7 by the addition of 12 N sulfuric acid (37 ml), the acetone evaporated, the pH of the residual solution adjusted to 2 with 12 N sulfuric acid (13 ml) and the solution extracted with ethyl acetate (4×250 ml). Evaporation of the dried ethyl acetate solution gave 4-ethoxycarbonyl-1,2-cyclopentanediol.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:11]([C:10]([F:20])([F:19])[F:9])[CH:12]=[C:13]2[OH:14]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: c1ccccc1
Product: Oc1cc(C(F)(F)F)nc2c(F)cccc12
Temperature: 110 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
2-Fluoroaniline (10.0 g), ethyl trifluoroacetoacetate (16.6 g) and concentrated hydrochloric acid (0.1 mL) were dissolved in benzene (40 mL), and the mixture was refluxed in a reaction vessel equipped with Dean-Stark trap for 7 hr. The reaction mixture was concentrated under reduced pressure and 75% phosphoric acid (40 mL) was added thereto. The mixture was stirred at 110° C. for 5 hr. The reaction mixture was added to water, neutralized with sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was concentrated under reduced pressure to give 8-fluoro-4-hydroxy-2-trifluoromethylquinoline (1.77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[OH:42][C:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: O=C=Nc1ccc(O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(O)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.1 g, 0.27 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethyl amine (67.5 mg, 0.68 mmol) (Aldrich), followed by the addition of solution of 4-isocyanato-phenol (1.8 mL, 0.32 mmol) in toluene (from Example 78a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-hydroxy-phenyl)-amide as a white solid. (Yield 15 mg, 11%).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13][C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20].O>ClCCl>[Br:13][C:14]1[C:18]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20]
Reactant: Cc1cc(Br)c(C)s1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Under a nitrogen atmosphere, ethyl chlorooxoacetate (1.04 mL, 9.27 mmol) and aluminum chloride (per 3 portions) (2.47 g, 18.54 mmol) was added successively at −5° C. to a solution of 3-bromo-2,5-dimethylthiophene (28b) (886 mg, 4.64 mmol) in dichloromethane (20 mL). After 3 hours at −5° C., the reaction mixture was slowly hydrolyzed at 0° C. with water. The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to give the desired keto-ester (28c) (725 mg, 2.50 mmol, 50%).
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([C:9]1[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].S(=O)(=O)(O)[OH:17].N(O)=O>O>[CH3:8][CH2:7][CH2:6][CH2:5][C:9]1[CH:15]=[CH:14][C:12]([OH:17])=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: CCCCc1ccc(N)cc1
Agent: O=NO
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(O)cc1
Yield: 73.3 %

Procedure:
A cold solution of sodium nitrite (28.95g, 0.419m) in water (90ml) was added in drops to a mixture of 4-n-butylaniline (60g, 0.402m), concentrated sulfuric acid (135g) and water (300ml) at 0°-5° C with stirring. After completion of addition the excess nitrous acid was tested with potassium iodide starch paper, and destroyed by the addition of urea. The resulting cold diazonium salt solution was slowly added to a boiling solution of water (210ml), sulfuric acid (375g) and anhydrous sodium sulfate (285g). The resulting reaction mixture was steam distilled. The distillate was collected until it became clear and saturated by adding sodium chloride. The resulting solution was extracted with ether and the combined ether extract were dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was vacuum distilled to yield 4-n-butylphenol (44g, 73.3%), bp 106° C at 4.6 mm.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:20][CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](C(O)=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.S(=O)(=O)(O)O.[N+:27]([O-:30])(O)=[O:28].[C:31]([OH:34])(=[O:33])C>>[CH3:1][CH:2]([CH2:20][CH3:21])[CH2:3][O:4][C@:5]1([C:31]([OH:34])=[O:33])[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:27]([O-:30])=[O:28])[CH:16]=2)=[CH:9][CH2:10]1
Reactant: CC[C@H](C)COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CCC(C)CO[C@]1(C(=O)O)C=CC(c2cccc([N+](=O)[O-])c2)=CC1

Procedure:
Quantities: compound 26 (3.00 g, 0.01 mol), concentrated sulphuric acid (18 ml), concentrated nitric acid (9 ml), glacial acetic acid (40 ml).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1)=[N+:24]=[N-:25]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4-phenyl-1H-imidazole (1.1 g, 3.4 mmol) and KI (566 mg, 3.4 mmol) in DMF (7 mL) was added sodium azide (443 mg, 6.8 mmol), and then the resulting mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 960 mg (89%) of the title compound as pale yellow amorphous: MS (ESI) m/z 318 [M+H]+, 1H-NMR (CDCl3)δ1.26 (2H, t, J=7.5 Hz), 2.72 (3H, q, J=7.7 Hz), 2.98 (2H, t, J=6.6 Hz), 3.59 (2H, t, J=6.6 Hz), 7.20-7.41 (9H, m), 7.79 (2H, dd, J=7.1, 1.3 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([O:26]C)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([OH:26])=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(NC(=O)c2cc(NC(=O)OC(C)(C)C)cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)Nc1cn(C)c(C(=O)O)n1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Methyl 4-(4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxylate (2.0 g, 5.30 mmol) in 50 ml of DMA was added 2 g of LiOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 with vacuum to afford 1.44 g (75%) of the title product. 1H NMR (DMSO) 10.41 (br, 1H), 9.07 (s, 1H), 7.48 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 3.92 (s, 1H), 3.81 (s, 1H), 1.47 (s, 9H); 13C NMR 160.46, 158.42, 152.85, 145.21, 135.81, 129.11, 127.77, 122.39, 121.57, 113.58, 79.81, 36.06, 35.25, 28.17; MS m/z−362.1 (M−H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C1COCC1.C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C>[C:25]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCC1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CCO)CC1

Procedure:
To a stirred solution of 4-piperidineethanol 8 (15 g, 0.12 mol), THF (500 mL), and diisopropylethylamine (40.5 mL, 0.23 mol) at 0° C. was added benzyl chloroformate (16.5 mL, 0.12 mmol). After 1 h at 0° C. the reaction mixture was diluted with ethyl acetate and then washed with H2O (2×), 10% KHSO4, and brine, dried (MgSO4), and concentrated to give 112 as a colorless oil. TLC Rf=0.60 (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 4.18 (m, 2H), 3.70 (q, J=7 Hz, 2H), 2.80 (m, 2H), 1.80-1.50 (m, 5H), 1.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:4]
Reactant: COC(C)C1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C1CCCN1
Reaction time: 16 h

Procedure:
To tert-butyl 2-(1-methoxyethyl)pyrrolidine-1-carboxylate (827 mg, 3.61 mmol) dissolved in DCM (15 mL) was added TFA (0.83 mL). The mixture was stirred for 16 hours. The reaction was concentrated, diluted with DCM, and washed with HCl (1N). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-(1-methoxyethyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12].[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([C:21]#[C:20][C:22]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(I)nc21
Reactant: C#CC1(O)CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(C#CC3(O)CCCC3)nc21
Reaction time: 4 h
Yield: 87.7 %

Procedure:
6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine (1076 g) was dissolved in 10 liters of tetrahydrofuran and 97.2 g of bistriphenylphosphine palladium dichloride, 26.4 g of cuprous iodide and 248 g of 1-ethynylcyclopentanol were added thereto. Into this mixture were added dropwise 331 ml of triethylamine within 15 minutes keeping the bulk temperature at not higher than 26° C. in a nitrogen atmosphere. After reacting at room temperature for 4 hours, the reaction solution was diluted with 10 liters of ethyl acetate and washed with 4 liters of a saturated ammonium chloride solution and 1 liter of brine. The organic layer was dried over 2 kg of anhydrous sodium sulfate and filtered followed by concentrating to an extent of 3 liters. The resulting residue was diluted with 4 liters of hexane-ethyl acetate (1:1), filtered and washed with 1 liter of hexane to give 732 g of 1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol. The yield was 88%.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]([CH3:8])=[N:3]1.[F-].[K+].Cl[CH2:12][N:13]1[C:17](=[O:18])[C:16]2[C:19]([CH:25]([CH3:27])[CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[S:14]1(=[O:29])=[O:28]>CN(C=O)C>[CH:25]([C:19]1[C:16]2[C:17](=[O:18])[N:13]([CH2:12][O:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH:5]=3)[S:14](=[O:29])(=[O:28])[C:15]=2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=1)([CH3:27])[CH3:26]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: CC1=NN(C)C(=O)C1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C)nn1C)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
To a solution of 2,4-dihydro-2,5-dimethyl-3H-pyrazol-3-one (475 mg; 4.24 mmol) in DMF (25 ml) was added 280 mg (4.83 mmol) of KF followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g, 3.3 mmol), and the resulting mixture was stirred at room temperature for 24 hours and then was poured into ice/water. The above mixture was extracted with ethyl acetate and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.46 g (37%) of 4-isopropyl-6-methoxy-2-(1,3-dimethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 146°-147° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11]>C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: NO
Solvent: CCO
Product: ON=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a stirred suspension of 4-iodobenzaldehyde (2000 mg, 8.620 mmol) in ethanol (9.000 mL) cooled in an ice bath, hydroxylamine (569.4 μL of 50% w/v, 8.620 mmol) was added and the reaction was removed from ice bath and stirred at rt for 1 h. After this time the reaction mixture was heated at 50° C. for 1 h and then cooled to rt and concentrated in vacuo to leave the title compound as a white solid (2.03 g, 95% yield); 1H NMR (400 MHz, DMSO) d 7.38 (m, 2H), 7.76 (m, 2H), 8.11 (s, 1H) and 11.37 (s, 1H) ppm; MS (ES+) 248.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH:24][C:29]([CH:25]4[CH2:28][CH2:27][CH2:26]4)=[O:30])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(N)ccc3o2)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(NC(=O)C4CCC4)ccc3o2)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-(5-amino-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.40 g, 4.21 mmol, 1.0 equiv) in anhydrous DMF (5 mL) was added cyclobutanecarbonyl chloride (0.55 g, 4.63 mmol, 1.1 equiv; commercially available) and diisopropylethylamine (1.03 mL, 1.14 g, 8.84 mmol, 2.1 equiv) and the reaction mixture stirred at rt. After 1 h, water was added (50 mL) and the water phase extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, the organic solvent removed under reduced pressure and the crude oil purified with column chromatography on silica eluting with ethyl acetate/heptane (2:1) to afford 1.1 g (64%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.46-1.50 (m, 2H), 1.47 (s, 9H), 1.94-2.02 (m, 2H), 2.10-2.13 (m, 2H), 2.20-2.26 (m, 2H), 2.34-2.47 (m, 2H), 2.95-2.97 (m, 2H), 3.10-3.22 (m, 1H), 3.90 (br s, 1H), 4.05 (br s, 2H), 5.24 (brs, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.28 (brs, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.41 (brs, 1H). 13C NMR (75 MHz, CDCl3): δ 18.05, 25.33, 28.41, 32.30, 40.85, 42.49, 50.45, 79.76, 108.41, 108.54, 113.47, 134.57, 143.38, 145.21, 154.70, 161.76, 173.04. MS (ISP): 413.1 [M−H]−.
Reaction SMILES: [Li][Li].Br[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH:24]=[CH:25][C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[CH:29]=[O:30])=[N:21]2)=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH:24]=[CH:25][C:26]3[CH:27]=[C:28]([CH:29]([OH:30])[C:4]4[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=4)[C:7]([OH:9])=[O:8])[CH:31]=[CH:32][CH:33]=3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Li][Li]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(O)c2cccc(C=Cc3ccc4ccc(Cl)cc4n3)c2)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To the dilithium salt (5.92 mmol) obtained from 3-bromobenzoic acid (W. E. Parham and Y. A. Sayed, J. Org. Chem., 39, 2051 (1974)), a solution of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (1.503 g, 5.12 mmol) (U.S. Pat. No. 4,851,409, Jul. 25, 1989, Example 24, Step 1) in THF (25 mL) was added dropwise at -78° C. The mixture was stirred for 2 h at -78° C. and was quenched with 25% aqueous NH4OAc. The mixture was acidified to pH 5 with AcOH and extracted with EtOAc. The organic fractions were dried over Na2SO4 and evaporated. Flash chromatography of the residue on silica using EtOAc:toluene:AcOH 30:70:1 yielded the title compound.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH:45]1([C:48]2[CH:49]=[C:50]([CH:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)[C:51](=[O:54])[NH:52][N:53]=2)[CH2:47][CH2:46]1.N1CCC(C2C(=O)NN=C(CCC)C=2)CC1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:45]1([C:48]2[CH:49]=[C:50]([CH:55]3[CH2:60][CH2:59][N:58]([C:33]([NH:31][C@@H:19]4[CH2:18][CH2:17][C@@H:16]([C:10]5[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=5[F:8])[CH2:22][N:21]5[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]45)=[O:34])[CH2:57][CH2:56]3)[C:51](=[O:54])[NH:52][N:53]=2)[CH2:46][CH2:47]1
Reactant: O=c1[nH]nc(C2CC2)cc1C1CCNCC1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CCCc1cc(C2CCNCC2)c(=O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(c2cc(C3CC3)n[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (34 μL, 0.24 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (36 mg, 0.081 mmol) and 4-nitrophenyl chloroformate (16 mg, 0.081 mmol) in dichloromethane (1 mL) at 0° C. After 15 min, a solution of a mixture of 6-cyclopropyl-4-piperidin-4-ylpyridazin-3(2H)-one and 4-piperidin-4-yl-6-propylpyridazin-3(2H)-one (18 mg, 0.081 mmol) in dichloromethane (1 mL) and triethylamine (11 μL, 0.08 mmol) were added and the mixture allowed to warm to ambient temperature. After 3 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave 4-(6-cyclopropyl-3-oxo-2,3-dihydropyridazin-4-yl)-N-[(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]piperidine-1-carboxamide (11 mg); MS 591.2507 (M+1) and N-[(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]-4-(3-oxo-6-propyl-2,3-dihydropyridazin-4-yl)piperidine-1-carboxamide (14 mg); MS 593.2689 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=O)[CH:6]=[CH:7][CH3:8].C1CC=CC=1.Cl(O)(=O)(=O)=O.[CH2:21]([C@@H:28]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)[C:22]1[CH:27]=CC=C[CH:23]=1.[OH2:41]>>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5]([C@@H:6]1[C@@H:21]([CH3:28])[C@@H:22]2[CH2:27][C@@H:7]1[CH:8]=[CH:23]2)=[O:41]
Reactant: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Reactant: O
Reactant: CC=CC(=O)CCC(C)C
Agent: C1=CCC=C1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)CCC(=O)[C@@H]1[C@@H](C)[C@H]2C=C[C@H]1C2
Yield: 86 %

Procedure:
Prepared according to general procedure A from 7-methyloct-2-en-4-one (82 μL, 0.50 mmol), cyclopentadiene (62 μL, 0.75 mmol), 70% aqueous perchloric acid (8.6 μL, 0.10 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (27 mg, 0.10 mmol) in water (167 μL) for 38 hours at 0° C. Purification by silica gel chromatography (19:1 hexanes:ethyl acetate) provided the title compound as a colorless oil in 86% yield (89 mg, 0.43 mmol); 20:1 endo:exo, endo 92% ee. IR (film) 3061, 2957, 2870, 1708, 1462, 1367, 1332, 1269, 1141, 1107, 1064, 904.7, 799.8, 716.2 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.20 (dd, J=5.7, 3.0 Hz, 1H, CH═CH), 5.87 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 3.11 (m, 1H, CHCH═CH), 2.43 (m, 1H, CHCH═CH), 2.39 (m, 3H, CHCO and CH2CO), 1.86 (m, 1H, CHCH3), 1.58-1.37 (m, 5H, COCH2CH2CH, CHCH2CH), 1.13 (d, J=6.9 Hz, 3H, CH2CH3), 0.86 (d, J=6.3 Hz, 6H, CH(CH3)2); 13C NMR (75 MHz, CDCl3) δ 211.5, 138.6, 132.6, 61.2, 49.3, 46.6,40.0,35.9, 32.9, 28.1, 22.8, 22.7, 21.4; HRMS (CI) exact mass calc'd for (C14H22O) requires m/z 206.1671, found m/z 206.1671. [α]D=+89.4 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (150° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=7.4 min, and (1S, 2S, 3R, 4S) endo isomer tr=7.1 min, exo isomers tr=6.6, 6.8 min.