Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(=O)C.[NH2:5][C@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1>CO>[ClH:4].[CH3:1][O:18][C:17](=[O:19])[C@H:6]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:5]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Anhydrous methanol (50 mL) is taken in a 100 mL 2-necked round bottom flask fitted with a reflux condenser and an additional dropping funnel and cooled to ice temperature. Acetylchloride (3 mL) is added drop wise through the dropping funnel. After 15 min, L-tryptophan (3 g) is added and the reaction mixture is refluxed at 70° C. for 6 h. The reaction mixture is vacuo dried to obtain L-tryptophan methyl ester hydrochloride in quantitative yield and used for further reaction without purification. 1,4,5,8-Naphthalenetetracarboxylic dianhydride (200 mg, 0.746 mmol) and L-tryptophan methyl ester hydrochloride (380 mg 1.491 mmol) are suspended in 20 mL of DMF in a 100 mL round bottom flask. To this suspension is added 0.5 mL of triethylamine under inert atmosphere. The reaction mixture is refluxed at 65° C. for 21 h. Solvent is evaporated under vacuo and the residue is purified by column chromatography (15% methanol in chloroform) to obtain NDI 2 in good yield. Yield 86%. 1H NMR: (400 MHz, CDCl3-CF3COOH) δppm 3.64-3.70, (dd, 2H, CH2, J=8 Hz, 8 Hz); 3.78-3.84, (dd, 2H, CH2, J=8 Hz, 8 Hz); 3.90 (s, 6H, CH3); 6.12-6.16 (dd, 2H, αCH, J=8 Hz, 4 Hz); 6.86-7.02 (m, 6H, ArH); 7.13-7.15 (d, 2H, ArH, J=8 Hz); 7.46-7.48 (d, 2H, ArH, J=8 Hz); 8.57 (s, 4H, ArH). 13C NMR: (400 MHz, CDCl3-CF3COOH) δppm 24.5, 53.9, 55.1, 110.2, 110.4, 118.6, 119.8, 122.4, 123.2, 126.1, 126.6, 127.2, 131.8, 136.1, 163.0, 172.5. MS (EI): m/z=668.19[M]+ for C33H23N4O3. Elemental analysis: Found: C, 68.23; H, 4.25; N, 8.35; Calcd: C, 68.26; H, 4.22; N, 8.38 for C33H23N4O3.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH:43]([OH:65])[CH2:44]OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C(O)=[O:67].C([O-])(O)=O.[Na+]>C(OCC)C>[Si:25]([O:24][CH2:23][CH2:22][N:21]([CH:42]([OH:67])[CH:43]([OH:65])[CH3:44])[CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:38]([CH3:41])([CH3:39])[CH3:40])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=CO
Reactant: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)C(O)N(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
Another batch of XIII was prepared using the following procedure: to a solution of VIII (2.0 g, 2.23 mmol) in diethyl ether (3 mL) was added 85% formic acid (8.2 mL) and the resulting reaction mixture was stirred at room temperature. After 20 h, solid NaHCO3 was added portion wise to neutralize the acidic solution. The reaction mixture was then diluted with diethyl ether (80 mL) and sequentially washed with water (25 mL) and saturated aqueous NaCl (25 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, elution with 4% MeOH in CHCl3) furnished XIII (0.97 g, 67%) as oily liquid. NMR spectra coordinates are as follows: 1H NMR (CDCl3): δ 7.70-7.61 (m, 8H), 7.49-7.31 (m, 12H), 3.73-3.55 (m, 6H), 4.397 (dd, J=11.6, 4.4 Hz, 1H), 2.78-2.54 (m, 5H), 2.57 (d, J=6.8 Hz, 1H) 1.02 (s, 18H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:25]#[N:26])=[C:11]([O:17]C(C1OC=CC=1)=O)[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1.[OH-].[K+].O.Cl>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:11]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[OH:17])[C:25]#[N:26]
Reactant: N#CC(=C(OC(=O)c1ccco1)c1ccco1)c1nc2ccccc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC(=C(O)c1ccco1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of furan-2-carboxylic acid 2-benzothiazol-2-yl-2-cyano-1-furan-2-yl-vinyl ester (660 mg, 1.82 mmol) and KOH (108 mg, 1.93 mmol) in ethanol (20 mL) was stirred first at room temperature overnight and then at 50° C. for 2 hours. The resulting suspension was poured into water (200 mL), and the solution was adjusted to pH 7 using 5% HCl solution. The solids were isolated by filtration, washed with water, and air-dried to yield 474 mg (97%) of crude 2-benzothiazol-2-yl-3-furan-2-yl-3-hydroxy acrylonitrile which was used in the next step: without further purification. MS (m/z, ES+): 268.98 (M+1, 100%).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][C:26]([F:30])([F:29])[F:25])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: NCC(F)(F)F
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(CNCC(F)(F)F)ccc1-2
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde (180 mg, 0.53 mmol) in DCE (7 mL+5% AcOH) was added trifluoroethylamine (46 μL, 0.58 mmol) and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (134 mg, 0.64 mmol) was added and the solution was stirred under nitrogen for 65 hours. The reaction mixture was diluted with aqueous saturated sodium bicarbonate solution and DCM and the phases were separated. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% 2M NH3/MeOH in DCM) to give a colourless oil. The oil was triturated with ether/cyclohexane to give 119 as a grey solid (138 mg, 61%). LCMS: RT=9.52 min, [M+H]+=424. 1H NMR δ (ppm) (DMSO-d6): 8.91 (1H, s), 8.22 (1H, d, J=8.10 Hz), 7.09 (1H, dd, J=8.16, 1.68 Hz), 7.00 (1H, d, J=1.64 Hz), 5.49-5.39 (1H, m), 4.33-4.27 (2H, m), 3.74 (2H, s), 3.40-3.32 (2H, m), 3.21-3.09 (2H, m), 2.92 (1H, s), 1.52 (6H, d, J=6.71 Hz)
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1nn(CCl)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Br
Yield: 78.8 %

Procedure:
1.85 g of 4-bromo-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.18 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.02 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.91 g of [(4-bromo-3-t-butyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (12), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][N:5]2[CH:18]=1.C1C(=O)N([I:26])C(=O)C1>C(#N)C>[I:26][C:18]1[N:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Solvent: CC#N
Product: CCCC(CCC)c1cc(C)nn2c(I)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 50 mL round bottom flask is charged with 2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (0.51 g, 0.0021 moles) and acetonitrile (3 mL). The reaction mixture is placed on an ice bath and NIS (0.468 g, 0.00208 moles) is added neat. The reaction is stirred overnight and the ice bath melts. The next day, the reaction mixture is partitioned between dichloromethane and a saturated aqueous solution of NaHCO3. The organic layer is collected and the aqueous layer is extracted two more times with dichloromethane. The organic extracts are combined, washed with brine, and dried over Na2SO4. The solvent is evaporated and the crude material is purified via silica gel chromatography eluting with hexanes and then a 25:75 mixture of ethyl acetate and hexanes. Yield=0.435 g (56%). MS (APCI): 372 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:38][CH3:39])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:43]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:43])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:38][CH3:39])[CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
A mixture of 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylic acid (1.30 g), 1-hydroxybenzotriazole ammonia complex (0.58 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.73 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxamide as colorless crystals (1.29 g, yield 98%). Recrystallization from acetone-methanol gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH2:5][CH2:4]1.[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([Cl:27])[C:21]([CH2:25]Br)=[C:22]([Cl:24])[CH:23]=1>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([Cl:27])[C:21]([CH2:25][N:11]2[CH2:12][CH2:13][CH:9]([CH:6]3[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:8][CH2:7]3)[C:10]2=[O:14])=[C:22]([Cl:24])[CH:23]=1
Reactant: COC1CCC(C2CCNC2=O)CC1
Reactant: Clc1cc(Br)cc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC(C2CCN(Cc3c(Cl)cc(Br)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
Treat a solution of 3-(4-methoxycyclohexyl)-pyrrolidin-2-one (0.0.71 g, 3.6 mmol) in DMF (20 mL) with a sodium hydride (0.0.29 mL, 7.2 mmol) and stir at room temperature for 10 minutes under N2. Treat the reaction with 5-Bromo-2-bromomethyl-1,3-dichloro-benzene (1.36 g, 4.3 mmol). Stir the mixture for 14 hours. Quench the reaction with water and extract with ethyl acetate. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with 25% ethyl acetate in hexanes to afford 0.45 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].C(Cl)Cl.[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](Cl)=[S:25])=[CH:19][CH:18]=1>O>[C:20]1([O:23][C:24](=[S:25])[O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([F:11])([F:12])[F:10])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: OC(c1ccccc1Br)C(F)(F)F
Reactant: S=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)C(OC(=S)Oc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
The title compound was prepared by an adaptation of the method described in Robins, M. J. et al. (J. Am. Chem. Soc. 1983, 105, 4059-4065). 1-(2-Bromo-phenyl)-2,2,2-trifluoro-ethanol (615 mg, 2.41 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar. DCM (4 mL) and TEA (1.2 eq., 0.403 mL, 2.89 mmol) were added via syringe. Phenyl chlorothionoformate (1.1 eq., 0.367 mL, 2.65 mmol) was added dropwise via syringe to the water-cooled solution. After completion of the addition, the reaction was stirred at RT for 16 h, poured into water, and extracted three times with DCM (10 mL). The combined organic extracts were dried over anhydrous MgSO4 filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 695 mg (74%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.58-7.68 (m, 2H), 7.36-7.48 (m, 3H), 7.27-7.36 (m, 2H), 7.04-7.15 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)=[CH:11][CH:12]=[C:13]2[C:21]=1[NH:20][C:19]1[C:18]3[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:17]=3[CH2:16][CH2:15][C:14]2=1.ClCCl.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1>[F:8][C:9]1[C:10]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=2)=[CH:11][CH:12]=[C:13]2[C:21]=1[NH:20][C:19]1[C:18]3[CH:22]=[CH:23][C:24]([NH:26][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:25][C:17]=3[CH2:16][CH2:15][C:14]2=1
Reactant: Cc1cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(N)cc2CC4)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(NS(C)(=O)=O)cc2CC4)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of 10-Fluoro-9-(4-fluoro-3-methyl-phenyl)-5,11-dihydro-6H-benzo[a]carbazol-3-ylamine trifluoroacetate (example 90) (17.8 mg, 0.038 mmol) is treated with dichloromethane (1 mL) and pyridine (0.5 mL). The reaction is then treated with methanesulfonyl chloride (8.6 mg, 7.5 mmol) and the reaction is stirred overnight at room temperature. The reaction is then concentrated and purified by reverse phase mass triggered HPLC to afford the title compound as a white solid after lyophilization: 1H NMR (400 MHz, d6-DMSO) δ 11.82 (s, 1H), 11.21 (s, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.55 (m, 2H), 7.45 (m, 1M), 7.38 (m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.20 (m, 1H), 7.02 (dd, J=8.0, 7.0 Hz, 1H), 2.95 (m, 2H), 2.87 (m, 2H), 2.26 (s, 3H), 1.29 (s, 3H); LC/MS calculated for [M+H3O]+ C24H23F2N2O3S: 457.1, found: 457.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=[O:26])[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[O:18])[CH:12]2[CH2:27][CH:9]1CC2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:32]C(N1C(C(O)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:27][O:32][CH2:12][CH:13]1[C:14](=[O:26])[NH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Product: CC(C)(C)OC(=O)N1CCOCC1C(=O)NCC(=O)c1ccc(Br)cc1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AE), substituting Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester for 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][CH:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([NH2:25])[C:18]=2[O:17]1>>[CH3:15][CH:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([NH:25][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[C:18]=2[O:17]1
Reactant: CC1Cc2cccc(N)c2O1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: CC1Cc2cccc(Nc3ccc4c(N)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=292.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 2,3-dihydro-2-methyl-7-benzofuranamine (CAS 26210-74-2).
Reaction SMILES: C(OCC[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)(=O)C.[C:21](Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:21]([Br:22])[C:9]#[C:8][CH2:7][CH2:12][CH2:11][CH2:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCc1ccc(CCOC(C)=O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC#CCBr
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a reaction vessel equipped with a calcium chloride tube, 8.465 g of the compound of (2) above was dissolved in 85 ml of dichloromethane and 15.683 g of carbon tetrabromide and 14.867 g of triphenylphosphine were added thereto under ice-cooling. The mixture was stirred at 0° C. for 5 minutes. The reaction mixture was concentrated under reduced pressure and the residue was extracted with hexane. The hexane extract obtained was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 7.964 g of 2-pentadecynyl bromide.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:16]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].S.[S:37](=O)(=O)(O)O>C(Cl)Cl>[N+:16]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([OH:32])=[S:37])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=C(O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise in succession to a solution, cooled to -10°, of 2.82 g (10 mmol) of 4-p-nitrobenzyloxycarbonylaminobutyric acid in 50 ml of dry methylene chloride. The reaction mixture is stirred for one hour and subsequently a strong current of hydrogen sulphide is passed through for a period of 2 hours. After acidifying with 2 N sulphuric acid, the organic phase is separated, dried and concentrated in vacuo. The 4-p-nitrobenzyloxycarbonylaminothiobutyric acid obtained can be used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: Cc1cc(C(=O)Nc2ccc(OCc3ccccc3)cc2)n[nH]1
Agent: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: Cc1cc(C(=O)Nc2ccc(O)cc2)n[nH]1

Procedure:
This compound was prepared from 5-methyl-1H-pyrazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide, using the same method used to prepare pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM as the eluant, to give the product as an off white solid, 2.75 g (68%). MS m/z 218 MH+). 1H NMR(DMSO-d6) δ 2.28 (s, 3H), 6.47 (s, 1H), 6.71 (d, 2H), 7.55 (d, 2H), 9.19 (s, 1H), 9.67 (s, 1H) and 13.00 (s, 1H). Anal. calcd for C11H11N3O2; C, 60.08; H, 5.17; N, 19.10. Found: C, 60.00; H, 4.99; N, 19.25.
Reaction SMILES: [CH3:1][C:2]([CH3:55])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:52])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:51])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:50])[NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:54])[CH3:53])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57].CC#N.[Cl:66]CCl>>[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57].[OH2:4].[Cl:66][C:47]1[CH:48]=[CH:49][C:44]([NH:43][C:42](=[O:50])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:51])([CH2:21][CH2:22]3)[C@@:19]3([CH3:52])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:53])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:55])([CH3:1])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)=[N:45][CH:46]=1.[F:59][C:58]([F:61])([F:60])[C:56]([OH:62])=[O:57]
Reactant: ClCCl
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccccn2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccc(Cl)cn2)CC1=O
Product: O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-(pyridin-2-ylamino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 0.396 mmol) in dichloromethane (6 mL) was added TFA (3 mL, 0.396 mmol). The reaction mixture was stirred at rt for 2 hr and evaporated in vacuo to afford crude product which was purified by preparative-HPLC (Mobile Phase: A=0.05% TFA/H2O, B=MeCN) to give the title compound trifluoroacetic acid salt (100 mg, 0.119 mmol, 30.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=10.72 (br. s., 1H), 8.33 (br. s., 1H), 8.14 (br. s., 1H), 7.83 (br. s., 1H), 7.33-6.97 (m, 1H), 6.97-6.75 (m, 1H), 6.41-6.13 (m, 1H), 4.52-4.25 (m, 1H), 3.35-3.06 (m, 1H), 2.98-2.65 (m, 2H), 2.35-0.53 (m, 47H); LC/MS: m/z calculated 700.5. Found 701.3 (M+1)+.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[H][H]>CO.[Rh]>[C:1]([NH:8][CH:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1

Procedure:
N-BOC-α-phenylglycine, methyl ester (1.2 g) is dissolved in methanol (50 ml) containing acetic acid (1 ml). 5% rhodium on aluminum powder (0.60 g) is added and the mixture shaken under 50 psi hydrogen for about 18 hours. The mixture is filtered, evaporated in vacuo, and the residue taken up into ethyl acetate. The organic solution is washed with water, saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate, filtered, evaporated in vacuo to give N-BOC-α-cyclohexylglycine, methyl ester.