Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:19]([NH:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)c1ccc(N)o1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)o1
Reaction time: 48 h

Procedure:
To a solution of 28.7 g. of ethyl 5-amino-2-furancarboxylate, 50 ml. of triethylamine and 300 ml. of methylene chloride is added 51.7 g. of palmitoyl chloride dropwise. The reaction mixture is allowed to stir for 48 hours. The solvent is evaporated and the residue dissolved in a small amount of methylene chloride. The methylene chloride solution is filtered through Magnesol and concentrated to an oil. The product is obtained by cryytallization of the residual oil from hexane.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C([O-])=O.[NH4+]>O1CCCC1.[Zn]>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:6]1[C:7]2[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=2[C:4]2[CH:3]=[CH:2][CH:24]=[N:23][C:5]1=2
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cccnc21
Temperature: 75 °C
Yield: 79.3 %

Procedure:
A mixture of 3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (5.6 g, 14 mmol), ammonium formate (8.8 g, 139 mmol), and zinc (9.1 g, 139 mmol) in tetrahydrofuran (85 mL) was heated at 75° C. for 10 hours. The reaction was allowed to cool, filtered over a pad of Celite, and washed with methylene chloride (200 mL). The filtrate was concentrated in vacuo and then purified by flash chromatography (silica, 120 g, ISCO, 5-45% ethyl acetate in heptane) to afford the title compound as a white solid (3.6 g, 80%). 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.73 (dd, J=4.8, 1.5, 1H), 8.46 (dd, J=7.8, 1.5, 1 H), 8.39 (s, 1H), 7.39 (dd, J=7.8, 4.8, 1H), 6.01 (s, 2H), 3.60 (t, J=8.0, 2H), 0.93 (t, J=8.0, 2H), −0.09 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: COc1ccc(O)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC1CCC(O)CC1
Temperature: 50 °C

Procedure:
A mixture of 4-methoxyphenol (0.10 g, 0.806 mmol) in acetic acid (10 mL) was added to platinum oxide (0.020 g, 0.088 mmol) in a 50 mL pressure bottle and heated at 50° C. under hydrogen at 30 psi for 1 hour. The solid was removed by filtration, and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]2N(C4C=CC=CC=4)CCN2C2C=CC=CC=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:36])(C)C.Cl>O>[CH:16]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:36]
Reactant: c1ccc(-c2[nH]c3ccccc3c2C2N(c3ccccc3)CCN2c2ccccc2)cc1
Reactant: CC(C)O
Agent: Cl
Solvent: O
Product: O=Cc1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
4.0 parts by weight of 2-(2-phenylindol-3-yl)-1,3-diphenyl imidazolidine are suspended in 10 parts by volume of isopropanol and 4 parts by volume of 10% aqueous hydrochloric acid added. Thereafter water is added and 1.7 parts by weight of 3-formyl-2-phenyl indole are obtained by filtering off.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[CH:18]1([NH:24][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([O:16][CH3:17])[CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Reactant: NC1CCCCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)NC2CCCCC2)ccc1OC(C)=O

Procedure:
Using 3 g of 4-acetoxy-3-methoxycinnamoyl chloride, 1.4 ml of cyclohexylamine, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 2.64 g of N-cyclohexyl-4-acetoxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][C:20]([CH3:35])([CH3:34])[C:21]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:25][CH:24]=1)=[O:22]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:27][C:23]([C:21](=[O:22])[C:20]([CH3:34])([CH3:19])[CH3:35])=[CH:24][N:25]=2)[CH2:29][CH2:30]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CC(C)(C)C(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(=O)C(C)(C)C)s2)CC1
Yield: 28 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 2,2-dimethyl-1-(2-piperazin-1-yl-thiazol-5-yl)-propan-1-one hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a light brown crystalline solid (yield 28%). MS (m/e): 494.1 (M+H+, 100%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].[Cl-].[NH4+]>O1CCCC1.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:33]=[O:34])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)cc(-c1ccccc1)n2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-2-phenylindole (958 mg) in tetrahydrofuran (11.6 mL) was added dropwise n-butyllithium (2.76 mol/L hexane solution, 0.84 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. Then N,N-dimethylformamide (0.535 mL) was added dropwise, and the mixture was stirred at −78° C. for 30 minutes and at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (225 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:12])=[O:11])[CH:3]=[CH:2]1.C[O:15][C:16](=O)[NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([CH3:26])[N:19]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([CH3:26])[N:19]=[C:18]([NH:17][C:16]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)(=[O:11])=[O:12])=[O:15])[N:23]=1
Reactant: NS(=O)(=O)c1cccc2cc[nH]c12
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3cc[nH]c23)n1

Procedure:
To a solution of 1H-indole-7-sulfonamide (1.0 g) and (4-methoxy-6-methylpyrimidin-2-yl)carbamic acid methyl ester (1.0 g) in methylene chloride (100 ml) was added trimethylaluminum (3.2 ml of a 2.0M solution in toluene). The mixture was heated at reflux for 18 hours under a nitrogen atmosphere. Work-up was achieved by careful addition of 100 ml of 1N HCl followed by separation of the organic layer. The methylene chloride was dried over MgSO4 and evaporated to an oil. The oil was dissolved in ether from which it quickly crystallized to give pure product (TLC) (0.56 g, m.p. 207°-209° C.).
Reaction SMILES: C(Cl)CCl.[C:5]1([CH2:17][N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:19]2[CH2:23][CH2:22][C@@H:21]([C:24](O)=[O:25])[CH2:20]2)[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.Cl.[CH3:35][NH:36][O:37][CH3:38].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[C:30]([O:29][C:27](=[O:28])[N:18]([CH2:17][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[C@H:19]1[CH2:23][CH2:22][C@@H:21]([C:24](=[O:25])[N:36]([O:37][CH3:38])[CH3:35])[CH2:20]1)([CH3:32])([CH3:33])[CH3:31]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2ccccc2)cc1)[C@H]1CC[C@@H](C(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CON(C)C(=O)[C@@H]1CC[C@H](N(Cc2ccc(-c3ccccc3)cc2)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
EDC (901 mg, 4.7 mmol) was added portion wise to a stirred solution of (1R,3S)-3-{(biphen-4-ylmethyl)-(tert-butoxycarbonyl)amino}-cyclopentane carboxylic acid (930 mg, 2.35 mmol), DMAP (10 mg), and N,O-dimethylhydroxylamine hydrochloride (459 mg, 4.7 mmol) in dichloromethane (15 mL). Triethylamine (1.31 mL, 9.4 mmol) was added drop wise, and the reaction mixture was stirred at room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 10-60% ethyl acetate in heptane) gave tert-Butyl-biphen-4-ylmethyl-{(1S,3R)-3-(methoxy(methyl)carbamoyl)-cyclopentyl}-carbamate (800 mg, 78%) as a colorless oil; 1H NMR (CDCl3, 400 MHz) δ 7.61 (d, J=7.5 Hz, 2H), 7.54 (d, J=7.5 Hz, 2H), 7.45 (t, J=7.5 Hz, 2H), 7.35 (m, 1H), 7.30 (m, 2H), 4.72 (br, s, 1H), 4.49 (m, 2H), 3.68 (s, 3H), 3.19 (s, 3H), 3.10-3.20 (m, 1H), 2.10 (m, 1H), 1.64-2.01 (m, 5H), 1.41 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29](=O)[C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClCCCl.C([SiH](CC)CC)C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCCl
Product: CCCCCCC(c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 103 %

Procedure:
In a 1-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 14.4 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)heptane, 60 milliliters of 1,2-dichloroethane and 19.4 g of boron trifluoride diethyl ether complex were introduced and heated at reflux. 14.4 g of triethylsilane was added dropwise for 15 minutes with maintaining the temperature. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured in water and extracted with chloroform. The solution was washed with an aqueous solution of sodium hydrogencarbonate and water, and then dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator, the solution was dissolved in toluene and subjected to a separating operation by a column chromatography with silica gel. After removing off the solvent again, 14.08 g of 1,1-bis(4-(4-nitrobenzyl)phenyl) heptane was obtained as red oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[I:14]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[I:14]
Reactant: Fc1cccc(F)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
(Roe, A. M.; Burton, R. A.; Willey, G. L.; Baines, M. W.; Rasmussen, A. C. J. Med. Chem. 1968, 11, 814–819. Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746–749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972–1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature, and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1–5 mm at ˜80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H). GCMS m/e 240 (M+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:49])([CH3:48])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:47])([C@@:18]4([CH3:46])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:49])([CH3:48])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:47])([C@@:18]4([CH3:46])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.075 g, 0.111 mmol) in 1,4-dioxane (1 mL) was added NaOH (1M) (0.5 mL, 0.500 mmol). The mixture was heated to 75° C. for 15 h then was cooled to rt. The mixture was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (30 mg, 0.043 mmol, 38.8% yield) as a white solid. LCMS: m/e 661.5 (M+H)+, 1.66 min (method 2). 1H NMR (500 MHz, Acetic Acid d4) δ ppm 7.96 (1H, t, J=7.9 Hz), 7.09 (1H, dd, J=8.2, 1.2 Hz), 7.03 (1H, d, J=11.6 Hz), 5.42 (1H, d, J=4.6 Hz), 4.86 (1H, s), 4.74 (1H, s), 3.89-3.99 (4H, m), 3.53-3.69 (4H, m), 3.29 (4H, br. s.), 2.81-2.90 (1H, m), 1.77 (3H, s), 1.23 (3H, s), 1.13 (3H, s), 1.08 (3H, s), 1.04 (3H, s), 1.01 (3H, s), 0.85-2.26 (22H, m).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14]#[N:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14](=[NH:15])[NH:18][OH:19])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(NC(=O)OCc2ccccc2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 15.8 %

Procedure:
To a solution of (1-cyano-cyclopropyl)-carbamic acid benzyl ester (3.7 g, 17.11 mmol) in EtOH (40 mL) was added hydroxylamine hydrochloride (3.6 g, 51 mmol) and K2CO3 (9.5 g, 68 mmol). The reaction mixture was heated at reflux for 24 h. The resulting white suspension was cooled to RT and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered, concentrated and purified by reverse phase HPLC to give [1-(N-hydroxycarbamimidoyl)-cyclopropyl]-carbamic acid benzyl ester (0.68 g, 2.7 mmol) as a white solid.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[CH:5]([CH2:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH2:4][O:3]1.Cl>O1CCOCC1>[NH2:6][C@H:5]([CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1C(CCc2ccsc2)COC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CO)CCc1ccsc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 131.3 %

Procedure:
A suspension of 1.8 g of tert-butyl 2.2-dimethyl-4-(2-thien-3-yl-ethyl)-oxazolidine-3-carboxylate in 5 mL of an aqueous solution of 5N hydrochloric acid and 5 mL of dioxane is stirred at a temperature of about 20° C. for 3 hours. The reaction mixture is then concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. About 1.3 g of (2R)-2-amino-4-(3-thienyl)-1-butanol, chlorhydrate are obtained in the form of a thick oil. [1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): from 1.70 to 1.95 (mt, 2H); 2.70 (t large, J=8 Hz, 2H); 3.05 (mt, 1H); 3.50 (dd, J=11 and 6 Hz, 1H); 3.64 (dd, J=11 and 4 Hz, 1H); 7.02 (dd, J=5 and 1.5 Hz, 1H); 7.23 (d large, J=3 Hz, 1H); 7.49 (dd, J=5 and 3 Hz, 1H); 8.02 (mf, 3H)].
Reaction SMILES: C(S([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:35])(=O)=O)(C)C.[OH-].[Na+].C(#N)C>O.C(OCC)(=O)C>[NH2:35][C:8]1[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([C:27]4[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=4[F:33])[NH:19][C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:12][C:11]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(-c4c(F)cccc4F)[nH]c3-c3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Nc1nc2cc(-c3nc(-c4c(F)cccc4F)[nH]c3-c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Yield: 93 %

Procedure:
Stir a mixture of 1-isopropylsulfonyl-2-amino-6-(2-(2,6-difluorophenyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.07 g, 0.142 mmol) and 1.42 mL 1 N sodium hydroxide in 1:1 water:acetonitrile at 60° C. for 1 hour. Cool the mixture to room temperature and dilute with water and ethyl acetate. Extract the aqueous phase with ethyl acetate (3 times). Wash the combined organic phases sequentially with water and saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 2:1 dichloromethane:methanol to provide the title compound in 93% yield. MS(ES+): m/z=388.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH:33]([C:35]1[CH:39]=[CH:38][O:37][C:36]=1B(O)O)=[O:34]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:36]2[O:37][CH:38]=[CH:39][C:35]=2[CH:33]=[O:34])=[CH:4][N:3]=1
Reactant: O=Cc1ccoc1B(O)O
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4occc4C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.120 g, 0.217 mmol), 3-formyl-2-furylboronic acid (0.247 mmol) and the procedure described in General Procedure A. 1H NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 7.96 (d, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.57 (m, 2H), 7.51 (s, 1H), 7.33 (s, 1H), 7.29 (m, 1H), 7.26 (d, 1H), 7.17 (m, 1H), 7.13 (t, 1H), 7.05 (m, 1H), 4.04 (s, 3H), 3.91 (s, 3H); MS: (M−H)− 521.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25].[CH:26]([NH2:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:39][CH:26]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(C=O)c4)cc3CC[C@@H]12
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(CNC(c5ccccc5)c5ccccc5)c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 60 h
Yield: 79.9 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-4-methyl-8-(3-formylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (30 mg, 0.09 mmol), in 0.75 mL of methanol was added benzhydryl amine (0.09 mmol), sodium cyanoborohydride (0.09 mmol) and 2 drops of glacial acetic acid (mixture became homogeneous; pH =4). The reaction was stirred at room temperature for 60 h. The mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted repeatedly with ethyl acetate. The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by trituration of the resulting oil with ether/hexanes, to give 36 mg (80%) of the title compound as a white solid. mp 55°-57°. FDMS: m/e=500. α[D]589 =+48.40 (c=0.64, methanol).