Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1.C(N(CC)CC)C.C(O)=O>[Pd].C1(C)C=CC=CC=1>[CH:11]1([C:9]([NH:8][C:5]2[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([CH3:17])[CH:2]=[CH:7][N:6]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1c(Br)cnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: Cc1ccccc1
Product: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Yield: 72.3 %

Procedure:
Toluene (60 ml) was added to 3.0 g (10.0 mmol) of 5-bromo-2-cyclopropanecarboxamido-4-methyl-3-nitropyridine, 10% Pd-C (100 mg) and 2.9 g (28.6 mmol) of triethylamine, followed by stirring and heating under reflux. 1.9 g (41.3 mmol) of formic acid was dropwise added to this solution, followed by stirring for 5 hours. The reaction liquid was brought to room temperature and filtered to remove the catalyst. The filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) once. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.6 g of the title compound (yield 72%).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C>CO>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([OH:8])[CH2:6][NH:5][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:24][CH:25]=2)=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(Oc2cnccn2)cc1
Reactant: NCC(O)c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC(CNCc1ccc(Oc2cnccn2)cc1)c1ccc(F)cc1
Reaction time: 8 h
Yield: 35.1 %

Procedure:
Sodium cyanoborohydride (0.62 mL, 1 M in THF) was added to a solution of 2-amino-1-(4-fluoro-phenyl)-ethanol (80 mg, 0.52 mmol), 4-(Pyrazin-2-yloxy)-benzaldehyde (103 mg, 0.52 mmol) and glacial acetic acid (0.5 mL), in methanol (3 mL) at RT and the flask was stirred overnight. The reaction mixture was concentrated in vacuo; the residue was quenched with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane (3×4 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated again in vacuo to yield 1-(4-fluoro-phenyl)-2-[4(pyrazin-2-yloxy)-benzyl amino]-ethanol as a white solid 62 mg, 35%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]2[O:21][C:1]([OH:2])=[N:23][N:22]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nnc(O)o2)cc1
Reaction time: 3.5 h

Procedure:
1,1′-Carbonyldiimidazole (3.86 g; 23.81 mmol; 1 eq.) is added to a 0° C. solution of 4-nitrobenzohydrazide (4.31 g; 23.81 mmol; 1 eq.) and triethylamine (4.95 ml; 35.71 mmol; 1.50 eq.) in DMF (150 ml). The reaction mixture is stirred between 0° C. and rt for 3.5 hours. Solvents are removed under vacuo affording an orange oil which is solubilized in DCM and washed with HCl 0.1 M. The organic phase is concentrated. The resulting precipitate is recovered by filtration, affording 5-(4-nitrophenyl)-1,3,4-oxadiazol-2-ol as a white solid (4.50 g; 91%).
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:14][O:13][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[Br:3])[CH2:10][CH2:9][CH2:8]2.[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13]
Reactant: O=C([O-])[O-]
Agent: Oc1cc2c(cc1Br)CCC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc2c(cc1Br)CCC2
Temperature: 51 °C
Yield: 74 %

Procedure:
Four oven dried 40 mL vials with Teflon lined caps were used in parallel for the reaction. The sealed vials were used to avoid loss of MeI. Each of the the vials was loaded with a fourth of 6-bromoindan-5-ol (12.01 g, 56.36 mmol), K2CO3 (15.58 g, 112.72 mmol), DMF (147.5 mL) and MeI (14.03 mL, 225.45 mmol) respectfully. The vials were sealed and heated on the orbital shaker for a total of 11 hours at 51° C. The reactions in the four vials were combined, poured in water and extracted twice with ethyl acetate. The organics were combined, dried with Na2SO4, filtered and concentrated to give 12.6 grams of a crude yellow oil. The crude was purified using the in two batches (120 g columns, 5% ethyl acetate). Like fractions were combined to give 9.53 grams (74%) of 6-bromo-2,3-dihydro-1H-inden-5-yl methyl ether as a white solid and 2.29 grams (19%) of recovered 6-bromoindan-5-ol. IR (diffuse reflectance) 2958, 2468, 2428, 2415, 2350, 2337, 1482, 1466, 1392, 1311, 1278, 1260, 865, 835, 733 cm−1. Anal. Calcd for C10H11BrO: C, 52.89; H, 4.88; Br, 35.18. Found: C, 52.87; H, 4.79; N, 0.21. Found: Br, 35.27. X-Ray supports the structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6]CCO.C=[O:11].[C:12]1([CH3:18])[CH:17]=CC=CC=1>>[OH:11][CH:12]([CH3:18])[CH2:17][N:5]1[CH2:4][CH2:3][CH2:2][O:1][CH2:6]1
Reactant: Cc1ccccc1
Reactant: C=O
Reactant: OCCCNCCCO
Product: CC(O)CN1CCCOC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(β-hydroxypropyl)tetrahydro-1,3-oxazine.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.ClCCCl>C(Cl)(Cl)Cl>[C:1]([N:8]1[CH2:11][CH:10]([NH:12][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(Nc2nccs2)C1
Temperature: 140 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A mixture of 5.0 g (29.1 mmol) of 1-Boc-3-aminoazetidine and 2.62 ml (29.1 mmol) of 2-bromothiazole was heated to 140° C. with stirring for 2 h. After cooling to RT, 800 mg (3.14 mmol, 11%) of 1-Boc-3-(thiazol-2-ylamino)azetidine were obtained from the mixture by CC (SiO2, 1 st DCE, 2nd chloroform).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C
Product: Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-methyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 314.1 ([M−H]−).
Reaction SMILES: Cl.NCC#N.C1CN([P+](ON2N=N[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C[N:49]([CH:51]=[O:52])C>>[C:51]([NH2:49])(=[O:52])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CN(C)C=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture comprised of 2R-benzoylamino-3-benzylsulfanylpropionic acid (0.508 g, 1.61 mmol), aminoacetonitrile hydrochloride (0.149 g, 1.61 mmol), PyBOP® (0.838 g, 1.61 mmol), N,N-diisopropylethylamine (0.84 mL, 4.83 mmol) and DMF (10 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated and the residue was taken up into dichloromethane. The dichloromethane mixture was washed with 1N hydrochloric acid, water and aqueous sodium bicarbonate, dried (MgSO4), filtered and concentrated. Product was purified from the residue by silica gel chromatography using 5% methanol in dichloromethane to provide N-(2-benzylsulfanyl-1R-cyanomethylcarbamoyl)ethyl)benzamide (541 mg, 1.53 mmol) as an oil. MS: m/e 353.8 (theory 353.1); Proton NMR Spectrum (DMSO-d6): δ 8.85 (t, 1H), δ 8.75 (d, 1H), δ 7.99 (d, 2H), 7.5 (m, 3H), δ 7.3 (m, 5H), δ 4.7 (m, 1H), δ 4.15 (d, 2H), δ 3.75 (s, 2H), δ 2.8 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Clc1ccncn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ccncn2)C3)cc1

Procedure:
Compound (dw) was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 4-chloropyrimidine. LC-MS: m/z=+475 (M+H)−.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.CC(O)C.N(OCCC(C)C)=O>C1COCC1>[Cl:13][C:9]1[CH:8]=[C:7]([N:6]2[CH:2]=[N:3][C:4]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[N:5]2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1-c1ccnc(Cl)c1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncn(-c3ccnc(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To a solution of 250 mg of 4-[5-amino-1-(2-chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide (0.686 mmol, 1 equiv) in 40 mL of 1:1 THF:iPrOH, 160 mg of isoamyl nitrite (1.37 mmol, 2 equiv) was added. The dark yellow solution was stirred for 12 h at 25° C. and then heated under reflux for 6 h. The reaction mixture was cooled and concentrated in vacuo. The resulting yellow solid was triturated with methanol and filtered to give the title compound as a yellow solid (118.9 mg, 50%); 1H NMR (400 MHz, (CD3)2SO) ∂ 10.20 (1H, s), 9.42 (1H, s), 8.55 (1H, d, J=5.6), 8.07 (1H, m), 7.95 (1H, dd, J=5.6 and 1.8), 7.77 (4H, m) and 7.18 (2H, s); MS (ES+) m/e 351.36, (ES−) m/e 349.48
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12]([O:14][C:15](=[O:29])[CH:16]([CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17](=O)[CH3:18])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([C:16]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:6]([C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[C:17]=1[CH3:18])=[O:29])[CH3:13]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C(F)(F)F)c2)c1C

Procedure:
m-Trifluoromethylaniline (5 mmol, 0.8 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The crude material was resuspended in chloroform and washed with water, then with brine. The organic layer was dried over NaSO4. The solids were separated and the solvents removed under vacuum. The resulting oil was purified over silica gel to yield the named product, 1H-NMR (CDCl3, ppm): 1.37 t (3H), 2.42 s (3H), 4.32 q (2H), 6.80 s (1H), 7.0-7.6 bm (9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[CH2:20]([CH2:22][NH2:23])[OH:21]>>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:23][CH2:22][CH2:20][OH:21])=[CH:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Reactant: NCCO
Product: COc1ccc2c(NCCO)cc(-c3ccccc3)nc2c1
Product: Cl

Procedure:
The title compound, m.p. 197° C. and MS: m/e=294 (M+), was prepared from 4-chloro-7-methoxy-2-phenyl-quinoline and ethanolamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[CH:20]1([C:23](=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21]1.[O-]CC.[Na+]>CN(C)C=O.C1COCC1.O>[CH:20]1([C:23]2[O:6][N:5]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: ON=Cc1c(Cl)cccc1Cl
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reaction time: 1 h
Yield: 7.6 %

Procedure:
To a water bath-cooled solution of 2,6-dichlorobenzaldehyde oxime (2.20 g, 11.6 mmol) in N,N-dimethylformamide (7 mL) was added solid N-chlorosuccinimide (1.55 g, 11.6 mmol). The solutions were stirred while in the water bath for approximately 20 min and the outside the bath for approximately 1 hour. The solution was poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and then concentrated. To a separate solution of ethyl 3-cyclopropyl-3-oxopropanoate (2.17 g, 13.9 mmol) in THF (3 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 4.36 mL, 13.9 mmol). The solution was stirred for a few minutes and then the above imidoyl chloride was added. The solution was stirred at 0° C. for 10 minutes and then at ambient temperature overnight. The solution was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (289 mg, 8%). 1H-NMR (400 MHz, DMSO-d6) δ 7.62-7.53 (m, 3H), 4.04 (q, J=7 Hz, 2H), 2.84-2.82 (m, 1H), 1.35-1.25 (m, 4H), 0.93 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1](N(C(C)C)CC)([CH3:3])[CH3:2].[N:10]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.C(I)C.[CH2:31]1[CH2:35]O[CH2:33][CH2:32]1>>[CH2:33]([C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:15][CH2:14]1)[C:32]1[CH:3]=[CH:1][CH:2]=[CH:35][CH:31]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -35 °C

Procedure:
Diisopropyl ethylamine (6.5 ml) in dry THF (25 ml) was cooled to −10° C. then N-butyl lithium (1.6 molar, 23 ml) was added drop wise under nitrogen atmosphere and maintain the reaction at −10° C. for 45 minutes then cool the reaction to −75° C. for 15 minutes then 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (Above step 1, 5 g in 30 ml THF) was added and stirred the reaction at same temp for 30 minutes, again raise the reaction temperature to −35° C. and stirred for 45 minutes then again cool the reaction to −75° C. then ethyl iodide (3.5 g in 20 ml THF) was added drop wise and slowly allowed the reaction to room temperature and stirred the reaction at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 followed by brine and the organic layer dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound as a light yellow color liquid. 1H NMR (300 MHz, CDCl3): 1.16-1.18 (t, 3H); 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, 1H); 2.82 (s, 2H); 2.92-2.95 (m, 1H); 3.46-3.52 (m, 3H); 4.09-4.11 (m, 2H); ES Mass: 308 (100%) [M+Na].
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:3][N:2]=[C:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=NO)=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 5.8 g of hydroxylamine hydrochloride are added to the mixture of 15 g of 1-(2-oxopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]-azepin-2-one, 6.2 g of powdered potassium carbonate, 120 ml of methanol and 10 ml of water. It is refluxed for three hours and stirred at room temperature overnight. The suspension is evaporated, the residue is suspended in 200 ml of chloroform-water (3:1) and filtered off, to yield the 1-(2-hydroxyiminopropyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 216°-218°.
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:20])[C:17](O)=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1>C(O)(=O)C>[CH3:20][C@H:16]1[NH:15][C:13](=[O:14])[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[CH:8]2)[CH:12]2[CH2:1][CH2:2][CH2:3][CH:4]2[N:5]3[C:17]1=[O:18]
Reactant: C[C@@H](NC(=O)c1cccc2c1NC1CCCC21)C(=O)O
Solvent: CC(=O)O
Product: C[C@H]1NC(=O)c2cccc3c2N(C1=O)C1CCCC31

Procedure:
Following the procedure of method 1E, (2R)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoic acid was cyclized by refluxing in acetic acid (50 mL). Purification by flash chromatography through silica gel (elution with 5% methanol-chloroform) provided each diastereomer: less polar product (1.5 mmol, 0.39 g, 56% over 2 steps) arbitrarily assigned as the R,R configuration and more polar product (0.47 mmol, 0.11 g, 17% over 2 steps) assigned as the S,S configuration.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Br)[CH3:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>C(#N)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CBr
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: CCOC(=O)Cc1cn2cc(Br)ccc2n1
Yield: 70.3 %

Procedure:
Add 4-bromo-3-oxo-butyric acid ethyl ester (12.08 g, 57.8 mmol) to a solution of 2-amino-5-bromo pyridine (5.0 g, 28.9 mmol) in acetonitrile (80 mL). Reflux for 4 days and concentrate to dryness. Purify by flash chromatography using appropriate ethyl acetate/methanol mixtures to give the subtitled compound (5.75 g, 70%) as a brown oil. TOF MS ES+ exact mass calculated for C, HI BrN2O2 (p+1): m/z=283.0082 Found: 283.0084. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (m, 1H), 7.82 (s, 1H), 7.45 (d, J=10 Hz, 1H), 7.30 (dd, J=10, 2.0 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.77 (s, 2H), 1.18 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([C:7]2([CH2:22]OS(C)(=O)=O)[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][S-:29].[Na+].C(OCC)C>CN(C=O)C>[CH:1]1([C:7]2([CH2:22][S:29][CH3:28])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(COS(C)(=O)=O)(C1CCCCC1)C2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSCC1(C2CCCCC2)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 3-cyclohexyl-3-{[(methylsulfonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylate (3-4) (1.01 g, 2.69 mmol) in 50 mL of DMF was added sodium thiomethoxide (0.943 g, 13.5 mmol). The mixture was stirred at 60° C. for 3 days. After cooling to room temperature, 200 mL of diethyl ether was added. The solid was filtered and the filtrates were washed with water three times. The organics were dried over anhydrous MgSO4, filtered, and concentrated to give (3-5) as a clear yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=2[CH:27]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[C:44]([O:46][CH3:47])=[O:45].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:47][O:46][C:44]([C:43]1[CH:42]=[CH:41][C:40]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=4[CH:27]=3)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:39][C:38]=1[Cl:37])=[O:45]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)OC)c(Cl)c4)cc3Cl)C(F)(F)F)cc21
Temperature: 70 °C
Reaction time: 6.5 h
Yield: 71.2 %

Procedure:
Trifluoromethanesulfonic acid 3-chloro-4-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (150 mg, 0.27 mmol), 3-chloro-4-(methoxycarbonyl)phenylboronic acid (86 mg, 0.4 mmol) and 1,1,bis(diphenylphosphino)-ferrocenpalladium(II)dichloromethane (11 mg, 0.05% mol) in dioxane (0.8 ml) was treated with water (0.6 ml) and 1M-Na2CO3 (0.4 ml, 0.4 mmol) and stirred at 70° C. under argon for 6.5 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography (10 g silica gel, heptane/AcOEt 4:1) to give the title compound (112 mg) as a white solid. MS (m/e)=582.3 [M+H+]