Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:14]([NH2:15])=[C:13]([C:16](=[O:24])[CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][Cl:9])#[N:2].[CH:25]([NH2:28])([CH3:27])[CH3:26]>C(O)C>[ClH:9].[C:1]([C:3]1[C:14]([NH2:15])=[C:13]([C:16](=[O:24])[CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:28][CH:25]([CH3:27])[CH3:26])#[N:2]
Reactant: CC(C)N
Reactant: CCCCC(CC)C(=O)c1ccc(OCC(O)CCl)c(C#N)c1N
Solvent: CCO
Product: CCCCC(CC)C(=O)c1ccc(OCC(O)CNC(C)C)c(C#N)c1N
Product: Cl

Procedure:
Fifteen grams (0.043 mol) of 1-[2-cyano-4-(2-ethylhexanoyl)-amino-phenoxy]-3-chloro-2-propanol were dissolved in 80 ml of ethanol, 14.4 ml (0.17 mol) of isopropylamine were added, and the mixture was refluxed for two hours. The solvent was then distilled off, and the residue was purified on a silica gel column [mixture of eluants: ethyl acetate/isopropanol/NH4OH (14:6:1)]. The pure base obtained was recrystallized from ethyl acetate with the addition of petroleum ether. The crystals were dissolved in acetonitrile and acidified with alcoholic hydrochloric acid, and crystallization was initiated by the addition of ether. The crystals were pure white. Yield: 2.9 gm. M.p: 169°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 89%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[H][H].[C:12]([OH:15])(=[O:14])[CH3:13]>[Pt]=O>[C:12]([OH:15])(=[O:14])[CH3:13].[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: OCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OCCC1CCNCC1
Yield: 100 %

Procedure:
Combined 4-(2-hydroxyeth-1-yl)pyridine (25 g, 0.2 mol) and platinum oxide (1 g, 4.4 mmol) in 400 mL acetic acid. Placed under 45 psi hydrogen at 60° C. for 24 h. Decanted, then filtered through Celite and removed the solvent to afford 38 g (100%) of the crude product, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([OH:9])[CH:3]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1F
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1F
Temperature: 130 °C
Yield: 60.1 %

Procedure:
To a solution of 3-fluoro-p-cresol (2.5 g, 19.82 mmol) and 4-fluorobenzaldehyde (2.460 g, 19.82 mmol) in DMF (15 mL), was added K2CO3 (4.11 g, 29.7 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated and purified via flash chromatography to afford the title compound (2.741 g, 11.91 mmol, 60.1% yield) as a yellow oil. LCMS: rt=3.57 min, [M+H+]=231
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH2:21])=[CH:19][C:18]([CH:22]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH3:23])=[N:17][C:16]=13)=[CH:5]2.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][C:19]1[C:18]([CH:22]([NH:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH3:23])=[N:17][C:16]2[N:15]([N:14]=[CH:13][C:12]=2[C:6]2[CH:7]=[N:8][C:9]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[C:20]=1[NH2:21]
Reactant: CC(NC1CCOCC1)c1cc(N)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(NC1CCOCC1)c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N)c1Br
Reaction time: 0.17 h

Procedure:
To a solution of 3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine (Crude, ˜0.13 mmol) in DMF (2 ml) at room temperature was added NBS (25 mg, 0.14 mmol) and stirring continued for 10 minutes. LC/MS showed no starting material (M.W=406) remaining. This crude compound was submitted to the analytical group for purification to afford the desired 6-bromo-3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].CS(O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]1)(=O)=O>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29][CH2:28]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of 7-chloro-1,8-naphthyridin-2(1H)-one [J. Org. Chem. 1990, 55, 4744-4750] in dry DMF (20 mL) (540 mg, 3.0 mmol) at 0° C. was treated with sodium hydride (144 mg, 60% in mineral oil, 3.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was cooled using an ice bath. A solution of 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1yl}ethyl methanesulfonate in DMF (Intermediate 6), 0.33 mmol/mL, 10 mL, 3.3 mmol) was then added over 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated sodium chloride solution (3×10 mL), dried over sodium sulfate and evaporated. Chromatography on silica gel using methanol in dichloromethane (0-15%) gave the title compound as a brown foam (711 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CO.Cl[CH2:15]Cl.C[Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 2-(4-aminophenyl)acetic acid (170 mg, 1.1 mmol) in a mixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mL vial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N in hexane) at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hr. The volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using hexane/dichloromethane (2:1) followed by dichloromethane as eluent to give methyl 2-(4-aminophenyl)acetate as an yellowish oil (97 mg, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Cl:11]Cl.CCOC(C)=O.CCCCCC>CC(O)=O.CCOC(C)=O>[Cl:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: ClCl
Reactant: Nc1ccc2ncsc2c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Nc1ccc2ncsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 6-aminobenzothiazole (2.0 g, 13.4 mmol) in 100 mL of AcOH was added a solution of Cl2 saturated AcOH and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid which was dissolved in EtOAc and washed with aq. NaHCO3. Organic layer was dried over is Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (10-50% EtOAc/n-Hexane) to obtain 7.8 g (34 mmol, 80% ) of the desired product.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44]([NH:47][CH3:48])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44]([N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[CH:28][C:3]=3[C:2]([F:34])([F:1])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH3:48])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-Methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[Br-:14].[CH2:1]([N+:8]1[CH:12]=[CH:11][N:10]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:9]=1[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCn1ccnc1C
Reactant: COc1ccc(CCCCBr)cc1
Product: CCCCCCC[n+]1ccn(CCCCc2ccc(OC)cc2)c1C
Product: [Br-]
Temperature: 140 °C

Procedure:
A mixture of 2.50 g (0.0139 mole) of 1-heptyl-2-methyl-1H-imidazole and 3.37 g (0.0139 mole) of 1-(4-bromobutyl)-4-methoxybenzene is heated at 140° C. for about 2 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (methanol:1M sodium chloride, 95:5). At the completion of the reaction, the cooled reaction product is triturated thoroughly with ether and on drying, provides the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: CCCC(O)CCC
Product: CCCC(CCC)Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from heptan-4-ol and 2-amino-6-fluorobenzonitrile as a white solid (24%). 1H NR (400 MHz, CDCl3) δ 0.92 (t, J=7.2 Hz, 6H), 1.55-1.31 (m, 8H), 3.88 (s, br, 1H), 4.33-4.27 (m, 1H), 6.26 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](Cl)(=[O:14])[C:11]([Cl:13])=[O:12].C1COCC1>C(OCC)C>[ClH:13].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([Cl:13])=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cl
Product: O=C(Cl)C(=O)c1c[nH]c2ccccc12

Procedure:
Indole, intermediate A1, is treated with oxalyl chloride, in a solvent such as THF or diethyl ether, to provide the 3-indolylglyoxalyl chloride hydrochloride salt, which is further treated with NaOMe in MeOH, to yield the methyl 3-indolylglyoxylate, intermediate B1. A second indole, A1, is converted to the acetamide intermediate C1, by stirring A1 with NaH in DMF, followed by the addition of iodoacetamide. Intermediates B1 and C1 are suspended in THF and treated with 3 to 4 equivalents of a base such as KOtBu, to provide compound 1, which falls under the general class of 3-(indol-3-yl)-4-(1N-indolyl)-1H-pyrrole-2,5-diones.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][N:9]=1)=[O:7])(C)(C)C.O.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[C:15]([C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1)#[N:16]
Reactant: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C#N)cnc1C(=O)O
Temperature: 33 °C
Reaction time: 1 h

Procedure:
To the stirred solution of 5-cyano-3-methylpyridine-2-carboxylic acid tert-butyl ester (20.7 g, 94.9 mmol) in toluene (200 mL) was added H2O (3.4 mL) at ambient temperature. The mixture was then cooled to 0˜5° C. with stirring, at this point, TFA (200 mL) was added to the mixture slowly while maintaining the reaction temperature at 25˜35° C. The reaction mixture was then heated at 33° C. with stirring. After 60 min, to the reaction mixture was added toluene and the mixture was concentrated in vacuo to ˜¼ of the original volume to remove TFA by azeotropic distillation with toluene. To the concentrated mixture was added toluene and the mixture was evaporated in vacuo to ˜¼ of the original volume. The same evaporation manipulation was repeated once and the precipitated product was collected by filtration. The filter cake was washed with toluene and dried in vacuum oven at 50° C. for 8 h to give the title compound as a pale yellow crystalline solid: ESIMS: 163; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.35 (s, 1H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(Cl)(=O)C(Cl)=O.[CH3:43][N:44]([CH3:55])[CH2:45][CH2:46][CH2:47][NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH3:54][N:52]([CH3:53])[CH2:51][CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][N:44]([CH3:43])[CH3:55])[C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:35])([F:36])[F:34])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25]
Reactant: CN(C)CCCNCCCN(C)C
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(CCCN(C)C)CCCN(C)C)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A suspension of 10-[(2-methyl-2′-trifluoromethyl-[1,1 l′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) in dichloromethane (5 mL) containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (0.12 mL, 1.38 mmol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes. The cooled solution was evaporated to dryness to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of bis-(3-dimethylamino-propyl)-amine (0.90 mL, 4.04 mmol) and N,N-diisopropylethyl amine (1.1 mL, 6.31 mmol) in dichloromethane (5 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was sequentially washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification was achieved by preparative HPLC on a Primesphere S C18 column (0.21×15 cm) using a solvent gradient from 60:40:0.1 to 80:20:0.1 acetonitrile-water-trifluoroacetic acid. After removal of the acetonitrile in vacuo, the aqueous solution was basified with 2.5 N sodium hydroxide then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.24 g) as a white foam, m.p. 55–64 ° C.
Reaction SMILES: [CH3:1][C:2]([CH3:56])([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([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.CCCCCC>ClCCl>[F:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])/[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]([CH3:52])([CH2:21][CH2:22]3)[C@@:19]3([CH3:53])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:55])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:56])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)=[CH:46][CH:47]=1
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)Nc2ccc(F)cc2)CC1=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
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(F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((4-fluorophenyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-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 (250 mg, 0.323 mmol), TFA (1 mL, 12.98 mmol) in dichloromethane (4 mL) stirred at rt. The reaction mixture was stirred at rt for 2 h, washed with saturated NaHCO3 in water (300 mL×8); followed by 2 M HCl (300 mL), water, and then brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was solved into DCM (80 mL) and hexane (120 mL) was added. The suspension was filtered, washed with hexane to afford the crude product, and then purified by preparative-HPLC to afford the title compound (160 mg, 68%) as a light white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.56 (br. s., 3H), 7.23-6.93 (m, 3H), 5.96-5.75 (m, 1H), 4.52 (dd, J=5.1, 10.9 Hz, 1H), 3.33-3.13 (m, 1H), 2.88-2.51 (m, 3H), 2.45-0.72 (m, 47H); LC/MS: m/z calculated 717.4. Found 718.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10](C=O)=[N:9]1.[Li+].[Cl-].C[C:29](P(OC)(O)=O)([C:31]([O-:33])=[O:32])[CH3:30].[CH2:39]1CCN2C(=NCCC2)CC1>CC#N>[CH3:39][O:33][C:31](=[O:32])/[CH:29]=[CH:30]/[C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([CH2:7][C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:9]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: Cc1cc(C=O)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)/C=C/c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1

Procedure:
A solution of aldehyde 5 (0.25 g, 0.65 mmol), LiCl (0.03 g, 1.21 mmol), trimethylphosphonoacetate (0.11 mL, 0.71 mmol) and DBU (0.19 mL, 1.21 mmol) in CH3CN (10 mL) was stirred under a N2 atmosphere at RT for 2 h. The reaction mixture was partitioned between 2 M HCl (15 mL) and EtOAc (20 mL). The organic layer was separated, washed with sat. NaHCO3 (15 mL), brine (15 mL), dried (Na2SO4) and the volatiles were removed in vacuo to give a crude ester 6, 0.31 g (99%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]3([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25]3)C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[N:6][CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:33]1[C:28]([C:24]2([CH2:23][NH:15][C:12]3[N:13]=[N:14][C:9]([C:7]4[S:8][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][N:6]=4)=[CH:10][CH:11]=3)[CH2:25][CH2:26][CH2:27]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(C(N)=O)s2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cnc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a crude mixture of t-butyl 6-(5-carbamoylthiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (141 mg, crude) in DCM (6 mL) was added TFA (2 mL) at rt. The reaction mixture was further stirred at rt for 2 hr followed by concentration to dryness. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to provide the title compound as a pale yellow solid (98.5 mg, 99% for 2 steps), LRMS (M+H+) m/z 385.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6-benzyloxycarbonylamino-hexanoic acid(2.65 g, 10 mmol) in thionyl chloride (15 ml) was heated to reflux 1 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo to give (5-chlorocarbonyl-pentyl)-carbamic acid benzyl ester as tan oil. The oil was used without further purification. (5-Chlorocarbonyl-pentyl)-carbamic acid benzyl ester was dissolved in THF (50 ml). To this solution was added 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5 mmol). The resulting suspension was to reflux for 4 hours. The solvent was evaporated in vacuo and the resulting solid was partially purified by flash chromatography (60/40 ethyl acetate/hexane) to give a light yellow solid. The solid was recystallized from minimal ethyl acetate to give 1.24 g (48%) of product as an off-white solid: mp 122-125° C.; 1H NMR (DMSO-d6) 11.18 (s, 1H), 9.70 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.34-7.24 (m, 6H), 5.16 (dd, J=5.1 and 12.6 Hz, 1H), 5.00 (s, 2H), 3.02-2.84 (m, 3H), 2.65-2.43 (m, 4H), 2.12-2.05 (m, 1H), 1.65-1.15 (m, 6H; 13C NMR (DMSO-d6) 172.75, 171.95, 169.77, 167.72, 166.67, 156.08, 137.29, 136.57, 136.09, 131.43, 128.32, 127.70, 126.21, 118.25, 116.90, 65.08, 48.92, 36.47, 30.94, 30.67, 29.14, 25.77, 24.47, 21.99; Anal. Calcd. For C27H28N4O7: C, 62.30; H, 5.42; N, 10.76. Found: C, 62.40; H, 5.31; N, 10.48.