Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][C:24]=1[CH2:25]Br>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:25][C:24]1[CH:27]=[C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:29]=[CH:30][C:23]=1[F:22]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Fc1ccc(Oc2ccc(F)c(CBr)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(F)c(COc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)c2)cc1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a mixture of 0.51 g of 2,6-dichloro-4-(3,3,-dichloro-2-propenyloxy)phenol, 0.17 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.34 g of 2-fluoro-5-(4-fluorophenoxy)benzyl bromide dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.50 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(2-fluoro-5-(4-fluorophenoxy) benzyloxy)benzene (68% yield), nD26.0 1.5871.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.[BH3-]C#N.[Na+].[CH3:19][C:20](OC(C)=O)=[O:21]>CC(O)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)N1c2cccc(C(F)(F)F)c2CC1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-4-(trifluoromethyl)-1H-indole (Example 114D) (0.48 g, 2.41 mmol) was dissolved in HOAc (3.0 mL), cooled to 0° C. and NaBH3CN (0.454 g, 7.23 mmol) was added in one portion. After 5 min the mixture was removed from the cooling bath and stirred at rt for 14 h. The mixture cooled to 0° C. and the pH was adjusted to ca. 13 by addition of 1 N NaOH (20 mL) and further addition of solid NaOH pellets. The mixture was extracted with Et2O (×3), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry CH2Cl2 (10 mL) and treated with DMAP (0.884 g, 7.23 mmol). The mixture was cooled to 0° C. and Ac2O (0.455 mL, 4.81 mmol) was added dropwise via syringe. The mixture was stirred overnight, slowly warming to rt, diluted with CH2Cl2, washed (10% HCl, H2O, brine), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.25 g of the title compound as a pale yellow oil: MS (ES) m/z 244 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][C:12]#[CH:13])[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[C:15]([OH:20])(=[O:19])[CH2:16][C:17]#[CH:18]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[C:1]([O:5][C:6]([N:7]1[CH2:8][C:9]2[C:12](=[CH:13][CH:18]=[C:17]([CH2:16][C:15]([OH:20])=[O:19])[CH:10]=2)[CH2:11]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN(CC#C)C(=O)OC(C)(C)C
Reactant: C#CCC(=O)O
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccc(CC(=O)O)cc2C1
Temperature: 0 °C

Procedure:
A mixture of di-prop-2-ynyl-carbamic acid tert-butyl ester (4.78 g, 24.7 mmol) and ethanol (120 mL) was prepared under argon and cooled to 0° C. for 15 min. 3-Butynoic acid (3.64 g, 43.3 mmol) and tris(triphenylphosphine)rhodium (I) chloride (1.14 g, 1.23 mmol) were added and reaction was gradually warmed to room temperature over 1.3 hr. The reaction was then heated to 45° C. for 17 hr. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with 1N NaOH and extracted with diethyl ether (3×). The aqueous layer was acidified to pH ˜1 with 1N HCl and extracted with EtOAc (3×). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc:Hexane, 5-100%). ESI-MS m/z 278 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[CH3:12].[CH:13]([Mg]Br)=[CH2:14].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]2[C:7]=1[CH:13]=[CH:14][NH:8]2
Reactant: C=C[Mg]Br
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2[nH]ccc2c1Br
Temperature: -40 °C
Reaction time: 4 h
Yield: 31.5 %

Procedure:
To a solution of 1-bromo-2,4-dimethyl-5-nitro-benzene (7.5 g, 32.6 mmol) in THF (100 mL) at −78° C. was added vinylmagnesium bromide (110 mL of 1.0 M solution in THF, 1.1 mol) dropwise. The reaction was allowed to warm slowly to −40° C. then stirred for 4 h. Water was added, and the reaction mixture allowed to warm slowly to rt and extracted with EtOAc. The organic phase was then dried over Na2SO4 and concentrated to give 4-bromo-5,7-dimethylindole (2.3 g) which was used in the subsequent step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:20](I)=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:22])[CH:3]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:20]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:22])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(F)cc1Oc1cc(I)c(N)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)cc1Oc1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 242B (3.0 g), bis(triphenylphosphine)palladium(II) dichloride (242 mg), CuI (66 mg) in triethylamine (30 mL) was added trimethylsilylacetylene (2.2 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NH4Cl, water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH2:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1cc(NCc2ccco2)cc(C2CN3CCSC3=N2)c1
Reaction time: 2 h

Procedure:
A mixture of 4.4 g. (0.020 mole) of 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, 2.1 g. (0.022 mole) furfural, 3.5 ml. acetic acid and 50 ml. methanol are placed in a reaction flask along with some molecular sieves. To this 0.63 g. (0.01 mole) of sodium cyanoborohydride is added slowly and the mixture stirred two hours. The mixture is now acidified to pH 1 with hydrochloric acid. A solid material is removed by trituration and the solvent evaporated leaving an oily residue.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:16])=[CH:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1.CCO>[F:17][C:2]([F:1])([F:18])[C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:16])=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=C(C)c1ccc(C(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Yield: 90.9 %

Procedure:
To a solution of ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoate (2.9 g, 11 mmol) in EtOH/THF 1/1 (34 mL) was added 1M NaOH (aq.) (34 mL). The resulting mixture was heated at 60° C. for 1 h after which the reaction mixture was allowed to cool to rt. The volatiles were evaporated and the remaining water phase neutralized with 1 M HCl(aq.). The title compound (2.4 g, 10 mmol, 91%), which precipitated as a white solid, was filtered off and dried under vacuum at 55° C. over night. This material was used directly in the next step, without further purification.
Reaction SMILES: [C:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:19]1[CH2:24][CH2:23][CH:22]=[CH:21][C:20]1=[O:25].C(N(CC)CC)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:22]3[CH2:23][CH2:24][O:19][C:20](=[O:25])[CH2:21]3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(I)ccc21
Reactant: O=C1C=CCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCc2cc(C3CCOC(=O)C3)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 1-boc-6-iodo-1,2,3,4-tetrahydroquinoline (2.0 g, Reference Example 12), 5,6-dihydro-pyran-2-one (1.1 g), tetrakis(triphenylphosphine)palladium(0) and triethylamine (2.2 g) in dimethylformamide (5 ml) was stirred at about 95° C. in a sealed vessel under an atmosphere of nitrogen overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the layers separated, and the organic layer washed with sodium bicarbonate solution, then dried, and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:3,v/v) to give the title compound as a brown oil, 1.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1C=CN=C1.[N+:19]([CH:22]=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)([O-:21])=[O:20]>C(COC)OC.C(Cl)Cl>[N+:19]([C:22](=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)[C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:9])([O-:21])=[O:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])C=C1NCCCS1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(C(=C1NCCCS1)[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution/suspension of 20.4 g of p-nitrobenzoyl chloride in 25 ml of monoglyme was added dropwise at 5°-10° to a solution of 9.09 g of N-methylimidazole in 75 ml of monoglyme and the mixture was stirred for an additional 30 minutes at 5°-10°, after which was added dropwise (same temperature) a solution/suspension of 16.0 g of tetrahydro-2-(nitromethylene)-2H-1,3-thiazine in 25 ml of monoglyme, after which the stirred mixture was allowed to warm to room temperature and stirred for 96 hours. The mixture then was taken up in methylene chloride, washed with water and saturated sodium chloride solution, dried (Na2SO4) and the solvent evaporated under reduced pressure to give an oil which was chromatographed on florosil using methylene chloride as eluent to give a gum, which was washed with ether to give 17, as a yellow solid, m.p.: 158°-160.5°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C@:27]1([CH3:33])[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH:21]=[CH:20]2.N1C=CC=CC=1.C(Cl)Cl>>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C@:27]3([CH3:33])[CH2:31][O:30][C:29](=[O:32])[NH:28]3)[CH:23]=2)[CH:18]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@]1(c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)COC(=O)N1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.144 mL, 0.000859 mol) was slowly added to a solution containing (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (190 mg, 0.00078 mol), pyridine (2 mL, 0.02 mol), and methylene chloride (2 mL, 0.03 mol) at 0° C. After stirring overnight TLC showed complete reaction. After concentration, the crude was purified by chromatography using a 0-100% EtOAc/hexane gradient to give (R)-6-(4-methyl-2-oxooxazolidin-4-yl)naphthalen-2-yl trifluoromethanesulfonate as a yellow gel (259 mg, 88%). 1H NMR (400 MHz, CDCl3-d) δ=7.95 (s, 1 H), 7.94-7.89 (m, 2 H), 7.77 (d, J=1.9 Hz, 1 H), 7.59 (dd, J=1.6, 8.6 Hz, 1 H), 7.42 (d, J=9.0 Hz, 1 H), 4.48 (d, J=8.4 Hz, 1 H), 4.43 (d, J=8.4 Hz, 1 H), 1.88 (s, 3 H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.CCCCCC.C[O:27][B:28]([O:31]C)[O:29]C.Cl>O1CCCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:27][B:28]([OH:31])[OH:29]
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (20.0 g, 76.6 mmol) in tetrahydrofuran (200 mL) which had been cooled in a dry ice-acetone bath was added 1.58M n-butyllithium in hexane (50.9 mL, 80.4 mmol) under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. A solution of trimethoxyborane (8.75 g, 84.2 mmol) in tetrahydrofuran (20 mL) was then added to the reaction mixture, and the reaction temperature was increased to 0° C. while stirring. After adding 1N hydrochloric acid (200 mL) to the reaction mixture, it was stirred for 30 minutes at room temperature. After the reaction terminated, toluene (200 mL) was added to the reaction mixture and the organic layer was separated off, after which the aqueous layer was extracted with toluene (100 mL). The combined organic extracts were washed with water (100 mL) and then concentrated under reduced pressure. The residue was dissolved in tert-butyl methyl ether (75 mL) and the reaction mixture was stirred for 30 minutes, after which heptane (223 mL) was added thereto and the reaction mixture was further stirred for 2 hours. The precipitate was filtered out and washed with a mixed solution of tert-butyl methyl ether and heptane (1:3, 3.75 mL), and then dried at 40° C. for 24 hours to afford 12.4 g of the title compound (71.8% yield).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]1([CH2:1][NH:49][CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCCN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-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 (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and N-(3-Aminopropyl)morpholine (0.029 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h and an additional 0.1 g of sodium triacetoxyborohydride was added. The mixture was stirred overnight at rt then was quenched with 7 ml of sat. NaHCO3. The mixture was extracted with dichloromethane (3×7 ml) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give the title compound as a white foam (69 mg, 0.095 mmol, 56.8% yield). LCMS: m/e 727.5 (M+H)+, 2.81 min (method 6).
Reaction SMILES: [C:1]([C:9]1[N:10]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Na+].[Na+].CI>CN(C)C=O>[C:1]([C:9]1[N:10]([N:14]([CH3:20])[C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(2-Benzoyl-1H-pyrrol-1-yl)-carbamic acid, ethyl ester (18.5 g, 71.6 mmol) was combined with sodium carbonate (16.0 g, 157 mmol) and methyl iodide (13.2 g, 93 mmol) in 100 ml of dimethylformamide. The resulting slurry was stirred at ambient temperature for 20 hours and then at 75° C. for 2 hours. This reaction mixture was poured into 300 ml of crushed ice and extracted with four 200 ml portions of ether. The combined extracts were washed with water, dried over MgSO4, filtered and evaporated to an oil which was purified by HPLC (silica gel, 15% hexane/DCM). The resulting material was recrystallized from ether-hexane to give 18.4 g (94%) of cubes, m.p. 50°-52°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[N:20]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:18]([CH3:32])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:32][C:18]1[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[N:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cnc(Cl)nc1Cc1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cc1cccc(C(F)(F)F)c1
Yield: 51.9 %

Procedure:
A stirred mixture of 4-(trifluoromethyl)benzene boronic acid (430 mg, 2.3 mmol), the title compound of Step A (500 mg, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (120 mg, 0.17 mmol) and sodium carbonate (550 mg, 5.2 mmol) in a mixture of 6 mL of water and 2 mL of tetrahydrofuran was heated at reflux for 1.5 h. The reaction mixture was then partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (20 to 25% ethyl acetate in hexane) followed by trituration with 10% diethyl ether in hexane afforded 350 mg of the title compound of Step B, a compound of this invention, as a yellow-tinted solid melting at 112-113° C. 1H NMR (CDCl3): δ8.55 (m, 3H), 7.70 (d, 2H), 7.60 (s, 1H), 7.55-7.40 (m, 3H), 4.25 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][P:3]([O:6]C)[O:4][CH3:5].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[CH3:1][O:2][P:3]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP(OC)OC
Reactant: Clc1ccc(CBr)cc1
Product: COP(=O)(Cc1ccc(Cl)cc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To a stirred solution of trimethylphosphite (0.57 ml, 4.9 mmol) was added 4-chlorobenzylbromide (1.0 g, 4.9 mmol) at rt. The resulting mixture was stirred at rt for 5 min. and then heated in an oil bath at 80° C. for 20 min. It was cooled to rt and the product purified on a silica-gel column with 25% EtOAc in hexane to give 1.05 g of (4-chloro-benzyl)-phosphonic acid dimethyl ester (93%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH2:14])([O-])=[O:2].[N:15]#[C:16][NH2:17].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=[CH:6][C:5]=2[N:14]=[C:16]([NH2:17])[N:15]=1
Reactant: N#CN
Reactant: Nc1ccc2c(c1[N+](=O)[O-])CCCC2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccc3c(c2[n+]([O-])n1)CCCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A mixture of nitroaniline 169 (0.73 g, 3.8 mmol) and cyanamide (0.63 g, 15.1 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (5 mL) added carefully and the mixture heated at 100° C. for 2 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (50 mL), filtered, washed with water (2×25 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give amine 170 (124 mg, 15%) as a yellow powder: mp (MeOH) 271° C. (dec.); 1H NMR [(CD3)2SO] δ 7.43 (d, J=8.6 Hz, 1H, H-6), 7.26 (d, J=8.6 Hz, 1H, H-5), 7.00 (br s, 2H, NH2), 3.36-3.40 (m, 2H, CH2), 2.75-2.80 (m, 2H, CH2), 1.67-1.75 (m, 4H, 2×CH2); 13C NMR [(CD3)2SO] δ 159.5, 149.5, 137.3, 133.8, 131.1, 129.9, 123.0, 29.8, 28.7, 22.5, 21.0. Anal. calcd for C11H12N4O: C, 61.1; H, 5.6; N, 25.9. Found: C, 61.0; H, 5.6; N, 26.0%.