Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH2:12]([NH:15][CH2:16][CH2:17][CH:18]=[O:19])[C:13]#[CH:14]>C1C=CC=CC=1>[CH2:12]([N:15]([CH2:16][CH2:17][CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11])[C:13]#[CH:14]
Reactant: CS(=O)c1nnc(N=C=O)s1
Reactant: C#CCNCCC=O
Solvent: c1ccccc1
Product: C#CCN(CCC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propargylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propargyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: C([NH:8][C@@H:9]([C@@H:13]([O:15][CH3:16])[CH3:14])[C:10](O)=O)(OC(C)(C)C)=O.[CH3:17][CH:18]([C:20]1[CH:21]=[C:22]([NH2:27])[C:23]([NH2:26])=[CH:24][CH:25]=1)[CH3:19]>>[CH3:16][O:15][C@@H:13]([CH3:14])[C@@H:9]([C:10]1[NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:18]([CH3:19])[CH3:17])=[CH:21][C:22]=2[N:27]=1)[NH2:8]
Reactant: CO[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1ccc(N)c(N)c1
Product: CO[C@@H](C)[C@H](N)c1nc2cc(C(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using N-boc-(2S,3S)-2-amino-3-methoxybutanoic acid and 4-(1-methylethyl)-1,2-benzenediamine.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=1.OS([O-])(=O)=O.[K+]>CC(N(C)C)=O.[Cu]I.C(OCC)C.O>[F:27][C:19]1[CH:18]=[C:17]([NH:1][C@@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[C@H](Nc1cc(F)cc(C(F)(F)F)c1)C(=O)O
Yield: 69.8 %

Procedure:
(S)-2-amino-3,3-dimethylbutanoic acid (0.50 g, 3.81 mmol), K2CO3 (1.580 g, 11.44 mmol), copper(I) iodide (0.073 g, 0.38 mmol) and 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.32 g, 9.53 mmol) in DMA (4 mL) was heated at 95° C. for 32 hrs. H2O (15 mL) and ethyl ether (20 ml) was added. The aqueous phase was isolated and acidified with saturated KHSO4 solution, extracted with ether, dried over sodium sulfate. After removal of solvent, it gave (S)-2-(3-fluoro-5-(trifluoromethyl)phenylamino)-3,3-dimethylbutanoic acid (0.78 g, 70%) as white solid. LCMS (APCI−): 292.2. 1H NMR (400 MHz, d6-DMSO) δ 12.63 (s, 1H), 6.88 (s, 1H), 6.66 (d, J=12.4 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.40 (d, J=9.2 Hz, 1H), 3.71 (d, J=9.6 Hz, 1H), 0.98 (s, 9H).
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:10]([NH2:13])(=[S:12])[CH3:11]>N1C=CC=CC=1>[CH3:11][C:10]1[S:12][C:2]2[C:3](=[O:9])[CH2:4][CH2:5][CH2:6][C:7]=2[N:13]=1
Reactant: O=C1CCCC(=O)C1Br
Reactant: CC(N)=S
Solvent: c1ccncc1
Product: Cc1nc2c(s1)C(=O)CCC2
Temperature: 50 °C
Yield: 39.7 %

Procedure:
w To a solution of 2-bromo-cyclohexane-1,3-dione (20 g, 0.105 mol) in pyridine (150 mL) was added thioacetamide (7.9 g, 0.105 mol) and the mixture was stirred at 50° C. After 16 h the solvent was removed under vacuum. 10% aq NaCl solution (150 mL) was added and the product was extracted with CH2Cl2 (4×100 mL). The organic extracts were washed with additional 10% aq NaCl solution (2×100 mL) before being dried, filtered, and concentrated under vacuum. The dark viscous oil obtained was purified using a Kugelrohr distillation unit to afford the product as a yellow oil (6.97 g, 40%): 1H-NMR (CDCl3): δ 3.02 (t, 2H, J 6.1, CH2), 2.75 (s, 3H, CH3), 2.61 (t, 2H, J 6.1, CH2), 2.21 (qu, 2H, J 6.1, CH2). 13C-NMR (CDCl3): δ 192.1, 173.3, 166.8, 130.9, 37.8, 27.1, 23.1, 20.0. MS (ESI+): m/z 168.03 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH:9]1[CH2:10][CH2:11][O:6][CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanesulphonyl chloride (1.82 ml, 23.5 mmol) was added dropwise over 10 minutes to an ice-cold solution of tetrahydro-2H-pyran-4-ol (2.0 g, 19.6 mmol) and triethylamine (3.56 ml, 25.5 mmol) in dichloromethane (20 ml), and the reaction then stirred at room temperature for 72 hours. The reaction was washed with saturated aqueous sodium bicarbonate solution (10 ml), dried (MgSO4) and evaporated under reduced pressure to give an orange oil, that solidified on standing, 3.1 g.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1

Procedure:
tert-Butyl{1-[2-(6,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 151, 500 mg, 1.23 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 380 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[Si](C(C)C)(C(C)C)C(C)C)[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cc(O)cc(Nc4ccc(O)nc4)c3)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(Nc2ccc(O)nc2)cc(-c2cccc3[nH]ccc23)c1
Yield: 1.5 %

Procedure:
A solution of 5-[3-hydroxy-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenylamino]-pyridin-2-ol (taken as 0.126 mmol) in TFA/CH2Cl2 (5 mL/5 mL)) was stirred at 0° C. for 1 h. The resulting mixture was concentrated, and saturated aqueous NaHCO3 was added. The pH was adjusted to around 7 and the mixture was extracted with EtOAc (with a small amount of MeOH) several times. After filtering through Celite®, the organic layer was separated, dried and concentrated. Purification by chromatography and further purification by prep-SFC afforded 5-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridin-2-ol as a brown solid (0.6 mg, 1.5%). 1H NMR (400 MHz, CDCl3): δ 7.62 (dd, J=9.7, 2.8 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.28 (d, J=2.9 Hz, 1H), 7.23 (d, J=3.3 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.63-6.55 (m, 4H), 6.26 (t, J=2.0 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.O>C1(C)C(CCO)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:11]=[CH:12][C:13]=1[C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: [Pd]
Agent: Cc1ccccc1CCO
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccc(OC)cc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
After a 2M aqueous sodium carbonate solution (1.5 ml), tris(dibenzylideneacetone)dipalladium (0) (23 mg, 25 μmol) and bis(2-diphenylphosphinophenyl)ether (DPEphos) (28 mg, 52 μmol) were added to a solution of methyl (3-chloro-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (317 mg, 1.0 mmol) obtained in Example (23-1) and 4-methoxyphenylboronic acid (152 mg, 1.0 mmol) in a mixture of toluene-ethanol (5:1, 9 ml), the mixture was stirred at 100° C. for 5 hours under stirring. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate (three times). The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give methyl (2-chloro-4′-methoxy-1,1′-biphenyl-4-yl)acetate as a solid (192 mg, yield: 66%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:8]1[C:9]([S:14]([NH2:17])(=[O:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][F:7])(=[O:3])[CH3:2].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.CCOCC>[C:1]([O:4][CH:5]([C:8]1[C:9]([S:14]([NH:17][C:25]([NH:26][C:27]2[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=2)=[O:24])(=[O:15])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][F:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CF)c1cccnc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2C(CF)OC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To 4.1 g of 3-(1-acetoxy-2-fluoroethyl)-2-pyridinesulfonamide in 50 ml of acetonitrile is added 4.22 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate and 2.4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After stirring at room temperature for 2 hours the solution is acidified to pH 4.5 with 5% hydrochloric acid. The resultant solution is extracted with methylene chloride and the methylene chloride phase is dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with Et2O yields 6 g of the product (solid, Yield: 89%), which is washed with a mixture solvent of ethylacetate/n-hexane(1/1).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[N:13]=1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CO>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[S:10][CH:11]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)OCC(=O)Nc1nc(-c2ccc(Br)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reaction time: 2 h
Yield: 69 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-2-oxoethyl acetate (1.1 g, 3.1 mmol), prepared in the previous step, was suspended in 20 mL of methanol and K2CO3 (0.43 g, 3.1 mmol) was added. The mixture was stirred for 2 h, then diluted using methylene chloride. The mixture was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (2% methanol/chloroform) provided N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-2-hydroxyacetamide (670 mg, 68%) as a white solid. mp 222-224° C. HRMS: calcd for C11H9BrN2O2S+H+, 312.96408; found (ESI, [M+H]+), 312.9651. Analytical HPLC: retention time 9.0 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[O:21]=[C:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 8 h

Procedure:
Butyryl chloride (0.3 lmL, 2.94 mmol) was added to a solution of N-[4-(4-oxo-piperidine-1-yl)-phenyl]amine (which was obtained in Example 224) (0.70 g, 2.77 mmol) and triethylamine (1.9 mL, 13.9 mmol) in anhydrous methylene chloride (10 mL). The reaction was stirred overnight. The reaction was quenched with water (50 mL) and washed with methylene chloride (3×20 mL). The organic extracts were combined, dried (sodium sulfate) and concentrated. The desired product was isolated using silica gel flash chromatography to give the title compound as a yellow solid (0.41 g); 1H NMR (300 MHz, CDCl3) δ 1.01 (t, 3H, J=7.38 Hz), 1.72 (m, 2H), 2.29 (t, 2H, J=7.62 Hz), 2.55 (t, 4H, J=6.03 Hz), 3.55 (t, 4H, J=5.97 Hz), 6.95 (d, 2H, J=7.91), 7.42 (d, 2H, J=8.97 Hz). MS (ES) m/z: 260.9 (MH+); HRMS found for C15H20N2O2: 260.1511. Anal. Calcd. for C, 69.20; H, 7.74, N, 10.76. Found: C, 69.03; H, 7.94; N, 10.59.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[H-].[Na+].[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Br)[CH:29]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([O:26][CH3:25])=[O:36])[CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (1.30 g) in dimethylformamide (20 ml) was added sodium hydride (oil, 216 mg), and the mixture was stirred at room temperature for 20 min. 3-Bromomethylbenzoic acid methyl ester (990 mg) was added and the mixture was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure and 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→4/1) to give the title compound (719 mg, 39%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N([O-])=O.[Na+].[BrH:19]>O.[Cu]Br>[Br:19][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a mixture of methyl 3-amino-5-nitrobenzoate (2.5 g, 13 mmol) in 40% HBr (50 mL) was added drop-wise solution of sodium nitrite (1.1 g, 16 mmol) in water (5 mL) at 0° C. The mixture was stirred for 15 min and was then poured into a cold solution of copper (I) bromide (9.2 g, 65 mmol) in 40% HBr (50 mL). The resulting dark brown mixture was stirred for 30 min, and then was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford methyl 3-bromo-5-nitrobenzoate (2.2 g, 67% yield). 1H NMR (400 MHz, CDCl3) δ 8.79 (dd, J=1.6, 2.0 Hz, 1H), 8.55 (t, J=1.6 Hz, 1H), 8.49 (t, J=1.6 Hz, 1H), 4.00 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:45]=[CH:44][CH:43]=[CH:42][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:41]=[C:13]2[N:14]=[C:15]([CH3:40])[C:16]([C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]([N:18]3[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH:27]=C)([CH3:24])[CH2:20][CH2:19]3)[N:12]2[N:11]=1)=[O:7])[CH:2]=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:36]([O:35][C@@H:29]([C:16]1[C:15]([CH3:40])=[N:14][C:13]2=[CH:41][C:10]3=[N:11][N:12]2[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:24])([O:25][CH2:26][CH:27]=[CH:2][CH2:1][C:4]2[CH:45]=[CH:44][CH:43]=[CH:42][C:5]=2[C:6](=[O:7])[NH:8][CH2:9]3)[CH2:20][CH2:19]1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:38])([CH3:39])[CH3:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CNC(=O)c4ccccc4CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OC/C=C/Cc1ccccc1C(=O)NC3
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CCc1ccccc1C(=O)NC3

Procedure:
To a stirred solution of (S)-ethyl 2-(2-((2-allylbenzamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.058 g, 0.094 mmol) in 1,2-dichloroethane (20 mL) at 70° C. was added Hoveyda-Grubbs catalyst 2nd generation (2.94 mg, 4.69 μmol) and refluxed for 2 h. Then, cooled, concentrated and the resulting residue was purified by flash chromatography using 1:1 and 1:3 Hex/EtOAc to afford ethyl (2S)-2-(tert-butoxy)-2-[(20E)-4,24-dimethyl-12-oxo-23-oxa-1,5,7,8,11-pentaazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16,20-octaen-3-yl]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[C:15](=[O:16])[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:18]([N:11]1[CH2:10][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:13]([CH2:14][C:15]2=[O:16])[CH2:12]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(C23CNCC2CC3=O)c1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(C23CN(CCc4ccccc4)CC2CC3=O)c1

Procedure:
In the manner of Example 9, 5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal can be reacted with 1-bromo-2-phenylethane and sodium carbonate in toluene to give 3-phenethyl-5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal.
Reaction SMILES: C([C:4]1[O:5][C:6]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:7]=2[C:8](=O)[C:9]=1[CH3:10])(=O)C.[CH3:19][C:20]([CH3:41])([O:22][C:23]([NH:25]C1OC2C(C=CC)=CC=CC=2C(=O)C=1C)=[O:24])[CH3:21]>>[C:16]([C:15]1[C:6]2[O:5][C:4]([NH:25][C:23]([O:22][C:20]([CH3:41])([CH3:21])[CH3:19])=[O:24])=[C:9]([CH3:10])[CH2:8][C:7]=2[CH:12]=[CH:13][CH:14]=1)([OH:18])=[O:17]
Reactant: CC=Cc1cccc2c(=O)c(C)c(NC(=O)OC(C)(C)C)oc12
Reactant: CC(=O)c1oc2c(C(=O)O)cccc2c(=O)c1C
Product: CC1=C(NC(=O)OC(C)(C)C)Oc2c(cccc2C(=O)O)C1
Reaction time: 2 h

Procedure:
The title compound was synthesised following the procedure described for Compound 2C, except that Compound 3A was used instead of Compound 2B. The reaction was carried out at 40° C. Treatment of the reaction mixture with sodium dithionite and extraction with chloroform afforded a crude which was rinsed with 50 mL of ethyl acetate, boiled for 2 hours and filtered to give a first crop of Compound 3B. The mother liquor was evaporated and the residue was purified by flash chromatography (ethyl acetate/petroleum ether/glacial acetic acid 50:50:1) to give a second crop of Compound 3B. Total yield: 34%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)OCCc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To an ethyl acetate (100 ml) suspension of 4-aminophenylethyl acetate (10 g), saturated aqueous sodium bicarbonate solution (100 ml) was added, and further, benzyloxycarbonyl chloride (12.3 ml) was added dropwise under ice-cooling. After stirring for 1 hour, hydrochloric acid was added to the reaction mixture to make it acidic, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized from ethyl acetate-hexane, to give the titled compound (17.3 g).
Reaction SMILES: CN(C)C=O.FC(F)(F)S(O[C:12]1[C:13]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:14][C:15]([CH2:18][CH2:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])=[CH:16][CH:17]=1)(=O)=O.[C:34]([C:36]1([OH:44])[CH:41]2[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]2)[CH2:37]1)#[CH:35].C(N(CC)CC)C>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.C(OCC)(=O)C>[CH2:25]([C:13]1[C:12]([C:35]#[C:34][C:36]2([OH:44])[CH:41]3[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]3)[CH2:37]2)=[CH:17][CH:16]=[C:15]([CH2:18][CH2:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[N:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COCC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)CCc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
10 ml of N,N-dimethylformamide was added to a mixture of 1.9 g of 2-benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridyl trifluoromethanesulfonate, 773 mg of 3-ethynyl-3-quinuclidinol, 525 mg of tetrakis(triphenylphosphine)palladium(0), 267 mg of cuprous iodide and 2.2 ml of triethylamine, followed by stirring for one hour at 50° C. in an oil bath in a nitrogen atmosphere. After cooling as it was, ethyl acetate was added thereto. The mixture was filtered through Celite, followed by washing with water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using chloroform/methanol/36% aqueous ammonia (46:5:0.5) as an eluent for separation and purification, to give 1.3 g of the target compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.O.Cl.[Cl:16][C:17]1[C:26]2[C:25](=O)[O:24][C:23](=O)[N:22](C)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[C:25]([OH:24])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:5](=[O:7])[N:22]2[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Sodium hydride (1.9 g, 79.17 mmol, 1.60 equiv) was added in several portions to the mixture of 5-chloro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione in N,N-dimethylformamide from Step 2. Diethyl malonate (7.7 g, 48.07 mmol, 1.00 equiv) was then added dropwise to the stirred mixture over a period of about 30 minutes. The resulting solution was stirred at about 85° C. for about 1 hour, water (800 ml) was added, and the pH of the solution was adjusted to 2 with a solution of hydrochloric acid (5 mol/L). The resulting crude product was collected by filtration and then re-crystallized in ethanol to give the title product as a light yellow solid (2.5 g, yield: 18% 2 steps).