Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C1(CS(NC2C=CC(C(N3C4C=CC=CC=4CN4C=CC=C4C3)=O)=CC=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[C:27]=4[CH3:35])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(F)cccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Agent: O=C(c1ccc(NS(=O)(=O)Cc2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1 NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1 N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H, Cl35); 476(M+H, Cl37).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>>[Br:11][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(Br)nc1
Temperature: 145 °C
Yield: 81 %

Procedure:
6-Chloronicotinonitrile (13.8 g, 100 mmol) was heated at 145° C. in phosphorus tribromide (150 mL) for 32 h. After cooling, the mixture was concentrated in vacuo. To the residue was added phosphorus tribromide (150 mL), and the mixture was heated at 145° C. for another 32 h. After cooling, the mixture was concentrated in vacuo, and an ice-water mixture (500 mL) was added. Sodium bicarbonate was added to neutralize the mixture, and the product was extracted with ethyl acetate (3×250 mL). The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was chromatographed (hexanes-ethyl acetate) to give 14.9 g (81%) of 6-bromonicotinonitrile as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=11.0 Hz, 1H), 7.80 (dd, J=3.1, 11.0 Hz, 1H), 8.67 (d, J=3.1 Hz, 1H); MS m/z 183.0, 185.0 (M+H+).
Reaction SMILES: [C:1]([C:4]([CH3:24])([CH3:23])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[CH:8][CH:7]=1)([OH:3])=[O:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[O:15]=[C:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([CH3:24])([CH3:23])[C:1]([OH:3])=[O:2])=[CH:22][C:21]1=2
Reactant: CC(C)(Cc1ccc(OCc2ccccc2C(=O)O)cc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(Cc1ccc2c(c1)C(=O)c1ccccc1CO2)C(=O)O
Yield: 19.6 %

Procedure:
A slurry of 2-[4-(2-carboxy-2-methylpropyl)phenoxymethyl]benzoic acid (15.9 g) in 200 ml dry dichloromethane was treated dropwise with 12.5 ml trifluoroacetic anhydride then heated to reflux for 5 hours. Evaporation left an oil which was purified by HPLC (20:1 dichloromethane-methanol) to give 2.95 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-2,2-dimethyl-propanoic acid a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)([CH2:25][CH:26]([CH3:28])[CH3:27])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:25]\[CH:26]([CH3:28])[CH3:27])/[C:18]([CH3:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(O)(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(C)/C(=C/C(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 12 h
Yield: 82.6 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2,5-trimethylhexanoate (280 mg, 0.7 mmol) was dissolved in 10 mL MeOH and 5 mL H2SO4 and heated at 90° C. for 12 h. After 12 h, diluted with water and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with 1:9 EtOAc/hexane. Obtained 220 mg (82% yield) of (E)-methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate. MS found: (M+H)+=381.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][C:37]([C:36]2[CH:35]=[CH:34][C:33]([C:29]3[O:30][C:31]([CH3:32])=[C:27]([CH2:26][S:23]([CH:20]4[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:16])[CH2:18][CH2:19]4)(=[O:24])=[O:25])[N:28]=3)=[CH:41][CH:40]=2)=[O:38])[CH:2]=1
Reactant: NCCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.8 %

Procedure:
To a solution of 2-(pyridin-3-yl)ethanamine (940 mg, 7.70 mmol, 5.00 equiv), 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid (700 mg, 1.51 mmol, 1.00 equiv), HOBt (250 mg, 1.85 mmol, 1.20 equiv), EDCI (350 mg, 1.83 mmol, 1.20 equiv) in N,N-dimethylformamide (20 mL) at 30° C. was added triethylamine (460 mg, 4.55 mmol, 3.00 equiv) dropwise with stirring. The reaction mixture was stirred at 30° C. overnight and then quenched by the addition of 30 mL of water/ice. The precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 840 mg (98%) of tert-butyl 4-((2-(4-((2-(pyridin-3-yl)ethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 569 [M+H]+, 469, 361, 320, 169, 126. 1HNMR (400 MHz, DMSO-d6, ppm) δ 8.73 (s, 1H), 8.50-8.45 (d, 2H), 7.99-7.94 (d, 5H), 7.74 (s, 1H), 7.38 (s, 1H), 4.54 (s, 3H), 4.07 (s, 3H), 3.54 (s, 3H), 2.90 (m, 6H), 2.50-2.45 (s, 6H), 2.11 (s, 3H), 1.48-1.41 (s, 16H).
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[C:24]([O:27][CH2:28]Br)(=[O:26])[CH3:25]>C(#N)C>[CH3:28][O:27][C:24](=[O:26])[CH2:25][O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]=1[CH3:12]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: COC(=O)COc1cc(C(C)(C)C)c(SC#N)cc1C
Temperature: 25 °C

Procedure:
To a round bottom flask (500 mL) equipped with a magnetic stirrer and condenser were added 2.0 g (9.0 mmol) of 5-tert-butyl-2-methyl-4-thiocyanato-phenol (prepared in Example GGG), cesium carbonate (5.88 g, 18.0 mmol), sodium iodide (4.8 g, 32.0 mmol), and acetonitrile (100 mL ). This suspension was heated to reflux for 30 minutes and bromomethyl acetate (1.76 mL, 18.0 mmol) was added via syringe. The reaction was refluxed overnight, cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic layers were combined and dried (MgSO4). The solvent was evaporated and the residue dried under high vacuum to give the title compound. 1H NMR (CDCl3) δ 1.46 (s, 9 H), 2.26 (s, 3 H), 3.82 (s, 3 H), 4.68 (s, 2 H), 6.69 (s, 1 H), 7.52 (s, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C:3](=[O:5])[CH3:4].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1>ClCCl>[C:3]([CH2:2][NH:1][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)CN
Reactant: O=C(Cl)c1cccnc1
Solvent: ClCCl
Product: CC(=O)CNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 40 g (0.370 mol) of aminoacetone in 500 ml of dry dichloromethane, 50 g (0.350 mol) of nicotinoyl chloride was added dropwise at room temperature under a nitrogen atmosphere. The mixture was refluxed 5 h followed by stirring overnight at room temperature. The colorless precipitate was collected by filtration and dissolved in 400 ml of water. After basification with ammonia the aqueous solution was extracted with 3×400 ml of dichloromethane. The combined organic phases were treated with charcoal and dried over magnesium sulphate. Removal of the solvent in vacuo gave a colorless solid, 73. Yield: 30.0 g (0.170 mol, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:59]=[C:60]=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:60]([NH:59][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:61])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)NCc3ccccc3)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]-methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and benzyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.38 (s, 6H), 1.82 (m, 1H), 2.15-2.55 (m, 3H), 4.14 (s, 2H), 4.24 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.42 (m, 22H). FAB-MS: calculated for C44H45N5O5 723; found 724 (M+H, 100%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13]C(C)=[C:11]([F:16])[CH:10]=1.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:6]([CH:5]=[O:7])=[C:11]([F:16])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Br)cc1F
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)O
Product: O=Cc1ccc(Br)cc1F
Reaction time: 0.25 h

Procedure:
To a stirred mixture of glacial acetic acid (88 ml.), acetic anhydride (90 g.) and 4-bromo-2-fluorotoluene (10 g.) at -10° was added concentrated sulphuric acid (12 ml.) over 20 minutes, keeping the temperature around 0°. Solid chromium trioxide (14.7 g.) was added over 40 minutes keeping the temperature below 5°. The mixture was stirred for 15 minutes. The mixture was poured onto ice (300 g.) and stirred. The mixture was extracted with ether (2×300 ml.). The organic extracts were washed with 2% sodium carbonate solution (2×100 ml.). After evaporation the crude diacetate was treated with a mixture of water (30 ml.), ethanol (30 ml.) and conc sulphuric acid (3 ml.) and the mixture refluxed for 1 hour. After cooling the product was extracted into ether, dried and evaporated. Recrystallisation from hexane yielded the title product. Nuclear magnetic resonance (NMR) was as follows. 7.6, 3H, M; 10.0, 1H, s.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1>O=[Mn]=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=1
Reactant: OCc1ccc(OCc2cccc(F)c2)cn1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(OCc2cccc(F)c2)cn1
Yield: 79.6 %

Procedure:
A mixture of [5-(3-fluoro-benzyloxy)-pyridin-2-yl]-methanol (3.8 g, 16.3 mmol), MnO2 (12 g, 138 mmol) and chloroform (50 ml) was heated under reflux for 30 min. The dark solids were then removed by filtration over celite. The filtrate was evaporated and the residue purified by chromatography (SiO2, AcOEt-hexanes 1:1) to afford the title compound (3.0 g, 80%) as a light yellow oil with solidified on standing. MS: m/e=232.2 (M+H+).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1([B-](F)(F)F)[CH2:11][CH2:10]1.[K+].Cl[C:18]1[C:23]2[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=2[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH:9]1([C:18]2[C:23]3[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=3[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=2)[CH2:11][CH2:10]1
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Reactant: F[B-](F)(F)C1CC1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Temperature: 110 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
To a suspension of potassium phosphate, tribasic (0.141 g, 0.665 mmol), potassium cyclopropyltrifluoroborate (0.049 g, 0.332 mmol), 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.05 g, 0.222 mmol) in toluene (Ratio: 5.00, 5 mL) and water (Ratio: 1.000, 1.0 mL) was added PdOAc2 (3.73 mg, 0.017 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.016 g, 0.033 mmol) at 23° C. The reaction was stirred at 110° C. for 14 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (0.25 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOH:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The late eluting fractions were dried in vacuo to provide the title compound as an off-white solid (0.0283 g, 0.122 mmol, 55.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69-0.81 (m, 2H) 0.91-1.04 (m, 2H) 1.48 (d, J=6.57 Hz, 3H) 2.15 (tt, J=8.49, 5.15 Hz, 1H) 4.85 (q, J=6.82 Hz, 1H) 7.13 (d, J=1.77 Hz, 1H) 7.19 (d, J=1.77 Hz, 1H) 9.79 (s, 1H) 10.89 (s, 1H). ESI-MS: m/z 232.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([CH3:12])[CH:8]=2)[N:3]=1>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([CH3:12])[CH:8]=2)[NH:3]1
Reactant: Cc1cnc2cc(C)c(C)cc2n1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C)N[C@@H](C)CN2
Temperature: 40 °C
Reaction time: 23 h
Yield: 96.8 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (2.3 mg, 2.0 μmol) and KO(t-Bu) (10.9 mg, 0.0971 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (0.4 mL) solution containing 2,6,7-trimethylquinoxaline (32.9 mg, 0.191 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 23 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified through a silica gel short path column (ethyl acetate subjected to nitrogen bubbling) to obtain (S)-1,2,3,4-tetrahydro-2,6,7-trimethylquinoxaline (32.6 mg, 97%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=90:10, 1 mL/min) showed that the optical purity of this product was 99% ee or higher.
Reaction SMILES: C(N(CC1C=CC=CC=1)C1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.N[C@H]1[C@H:52]([OH:53])[CH2:51][N:50](C(OCC2C=CC=CC=2)=O)[CH2:49]1>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][C@@H:14]3[CH2:49][NH:50][CH2:51][C@H:52]3[OH:53])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Product: O=S1(=O)CCN(c2cc(N[C@@H]3CNC[C@H]3O)c3ccccc3n2)Cc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromoquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1) and benzyl trans-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.29-8.22 (d, J=7.6 Hz, 1 H), 8.12-8.08 (d, J=1.2 Hz, 1 H), 7.98-7.92 (d, J=7.6 Hz, 1 H), 7.88-7.82 (d, J=0.8 Hz, 1 H), 7.80-7.71 (m, 2 H), 7.62-7.58 (t, J=1.2 Hz, 1 H), 7.50-7.42 (t, J=6.8 Hz, 1 H), 6.20 (s, 1 H), 5.45-5.30 (q, J=7.2 Hz, 2 H), 4.62-4.52 (m, 2 H), 4.52-4.45 (m, 2 H), 4.05-3.95 (q, J=4.4 Hz, 1 H), 3.80-3.75 (t, J=2.8 Hz, 2 H), 3.75-3.68 (m, 1 H), 3.62-3.55 (dd, J=2.8, 12.8 Hz, 1 H), 3.48-3.40 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]([NH:14][CH2:16][CH2:17][CH2:18][Cl:19])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCNC(c1ccccc1)c1ccccc1
Temperature: 75 °C
Yield: 100.1 %

Procedure:
A mixture of 0.1 mole of benzhydrylamine, 39.3 g (0.25 moles) of 1-bromo-3-chloropropane, 13.8 g (0.1 mole) of potassium carbonate, 20.0 ml of dimethylformamide and 20.0 ml of water were heated at 75° C. for 2 hr. The organic layer was separated and concentrated on a rotary high vacuum evaporator to give 26 g of title compound of 85-90% purity of title compound containing about 5% each of benzhydrylamine and 1-benzhydrylazetidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
The 4-fluorophenylacetic acid (20 g, 0.13 mol), benzoyl peroxide (130 mg, 0.540 mmol), and N-bromosuccinimide (23.1 g, 0.130 mol) were combined in 500 ml carbon tetrachloride under N2 and refluxed under UV irradiation (GE sunlamp) for 5 hours. The reaction was cooled to RT and the succinimide filtered away. The carbon tetrachloride was removed in vacuo and the remaining oil recrystallized from hexanes yielding 26.2 g (87%) of product as a light yellow solid. EA, MS(FD).
Reaction SMILES: C([N+](CCC)(CCC)CCC)CC.CO.[OH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22](=[O:32])[C:23]3[C:28]([C:29]=2[N:30]=1)=[CH:27][CH:26]=[C:25]([Br:31])[CH:24]=3>C(Cl)Cl.C(OCC)(=O)C>[CH:17]([C:18]1[CH:19]=[CH:20][C:21]2[C:22](=[O:32])[C:23]3[C:28]([C:29]=2[N:30]=1)=[CH:27][CH:26]=[C:25]([Br:31])[CH:24]=3)=[O:16]
Reactant: O=C1c2cc(Br)ccc2-c2nc(CO)ccc21
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1ccc2c(n1)-c1ccc(Br)cc1C2=O
Reaction time: 0.25 h

Procedure:
150 mg of finely powdered 3 Å molecular sieves, 350 mg (3 mM) of N-methylmorpholine n-oxide, and 70 mg (0.2) of tetrapropylammonium perrhuthenate are added. To a solution of 576 mg (2 mM) of the carbinol, 3-hydroxymethyl-7-bromo-4-aza-9-fluorenone, prepared as described in Example 38, in 20 mL of dry methylene chloride under nitrogen at R.T. the reaction mixture is stirred 15 minutes, diluted with 20 mL of ethyl acetate and filtered through a bed of silica gel, which is washed further with ethyl acetate 5 times. The combined filtrates are concentrated to give the desired aldehyde as yellow solid.
Reaction SMILES: [N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.[ClH:9].[NH2:10][OH:11]>CO>[ClH:9].[N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[N:10][OH:11])[CH2:2]2
Reactant: NO
Reactant: O=C1CN2CCC1C2
Agent: Cl
Solvent: CO
Product: ON=C1CN2CCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
1-Azabicyclo[2.2.1]heptan-3-one (2 g, 18 mmol) and hydroxylamine hydrochloride (1.25 g, 18 mmol) were dissolved in 10 mL MeOH and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The crystalline residue was recrystallized from ethanol to afford 2.04 g (70%) of the title product, mp 211° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[F:14].[CH2:15]([Mg]Br)[CH2:16][CH3:17]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[F:14]
Reactant: CCC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a stirred solution of 4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide (3.0 g, 12.19 mmol) in tetrahydrofuran (35 ml) was added 2M n-propylmagnesium bromide (12.2 ml, 24.38 mmol) dropwise under nitrogen at 0° C. The reaction mixture was stirred at room temperature for 2 h. This was quenched by sat. ammonium chloride and stirred at rt for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The extracts was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:10) to afford 2.44 g (81.7%) of the titled compound as a slight yellow oil.