Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.CS(C)=O.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:1][N:2]2[CH:6]=[N:5][N:4]=[CH:3]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: Nn1cnnc1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Nn2cnnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.52 Grams of 4-amino-1,2,4-triazole was added little by little to a dimethylsulfoxide suspension of 1.2 g of sodium hydride at room temperature. After stirred for 3 hours at room temperature, 1.21 g of 4-fluorobenzonitrile was added thereto all at a time, and stirring was continued for further one hour. Water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The crystals obtained were washed with ethyl acetate to give 1.09 g of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[C:3]=1[NH2:4].C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.Cl>O1CCOCC1>[NH2:4][C:3]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[C:17](=[O:19])[CH3:18]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(F)cc(Br)c1N
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(F)cc(C(C)=O)c1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 2-bromo-4-fluoro-6-methoxy aniline (4.80 g, 21.8 mmol), which had been obtained in Reference example 5 (5a), in 1,4-dioxane (200 mL), tributyl (1-ethoxy vinyl) tin (11.1 mL, 32.7 mmol) and tetrakistriphenyl phosphine palladium (2.52 g, 2.18 mmol) were added, and the mixture was stirred for 16 hours at 100° C. After cooling the reaction solution to room temperature, 1 N aqueous hydrogen chloride solution (100 mL) was added and stirred further for 2 hours. The reaction solution was concentrated under reduced pressure, neutralized by adding 1 N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a yellow solid substance (2.80 g, yield 70%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[N-]=[N+]=[N-].[Na+].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].C([N:30](CC)C(C)C)(C)C>CN(C)C=O.ClCCl>[OH:1][CH:2]([CH2:3][NH:30][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1)(=[O:25])=[O:24])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCC1CO1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCN(C(C)C)C(C)C
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(O)CNS(=O)(=O)c1ccccn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
First, 21 g (121 mmol) of tert-butyl 2-oxiranylmethylcarbamate was dissolved in 90 mL of dimethylformamide and 11.8 g (182 mmol) of sodium azide was added. The reaction mixture was stirred at 65° C. overnight. The dimethylformamide was removed and ether was added. The ether layer was washed with brine (3×), dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in 50 mL of methanol and hydrogenated with 2 g of 10% palladium on carbon under 45 psi of hydrogen gas at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated. The residue was dissolved in 30 mL of dichloromethane, and 17.7 mL (17.7 mmol) of 1M 2-pyridinylsulfonyl chloride in dichloromethane and 3.8 mL (21.8 mmol) of N,N-diisopropylethylamine were added. The reaction mixture was stirred at room temperature overnight. After removal of solvent, purification by column chromatography with hexane:ethyl acetate (1:2) as eluant gave 350 mg (0.9%) of tert-butyl 2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate. 1H-NMR (300 MHz CDCl3): δ 8.72 (d, J=6 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.97 (t, J=8 Hz, 1H), 7.55 (m, 1H), 6.10 (br s, 1H), 5.11 (br s, 1H), 4.33 (d, J=5 Hz, 1H), 3.81 (m, 1H), 3.36–3.20 (m, 4H), 1.44 (s, 9H). ES-LCMS: 332 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1>ClCCl>[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([C:5](=[O:7])[CH3:6])=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCCO2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Aluminium chloride (1.19 g, 8.9 mmol) was added portionwise to a stirred solution of acetyl chloride (1.21 mL, 17.0 mmol) in dry dichloromethane (20 mL), previously cooled to −10° C., until homogeneous (5 min). The solution was added, via cannula, to a solution of 3,4-dihydro-2H-1-benzopyran (9a) (1.20 g, 8.9 mmol) in dry dichloromethane (17 mL) at −10° C. The mixture was stirred at the same temperature for 30 minutes before being poured into ice/concentrated hydrochloric acid (5:1, v/v, 126 mL). The stirring was maintained at room temperature for 2 hours and the solution was extracted with dichloromethane (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (49a) (1.55 g, 8.8 mmol, 99%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](N)([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:4][N:3]=1.NC1N=NC(Cl)=CC=1.N1CCCC1.CN(C)C1C=CC=CC=1>[Cu].C(O)(C)C>[NH2:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NC1=NNC(N)(N2CCCC2)C=C1
Agent: [Cu]
Agent: Nc1ccc(Cl)nn1
Solvent: CC(C)O
Solvent: CN(C)c1ccccc1
Solvent: C1CCNC1
Product: Nc1ccc(N2CCCC2)nn1
Temperature: 30 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A better procedure for preparing 3-amino-6-amino-6-(1-pyrrolidinyl)pyridazine is given as follows: a mixture containing 80 g. of 3-amino-6-chloropyridazine, 105 ml. of pyrrolidine, 1.2 liters of N,N-dimethylaniline and 1 g. of copper bronze powder was heated with stirring at 130°-135° C. for 18 hours. When a TLC test indicated that starting material was still present, an additional 50 ml. portion of pyrrolidine in 200 ml. of N,N-dimethylaniline was added to the reaction mixture followed by more copper bronze powder and the reaction mixture was heated for an additional 24 hours. The reaction mixture was cooled to 30° C. and filtered. The filtrate was concentrated under oil pump vacuum to leave a crystalline solid. The solid was slurried with isopropyl alcohol while chilling the mixture in an ice bath. The solid was collected, washed with a small amount of cold isopropyl alcohol and dried in a vacuum oven at 60° C. to produce 53 g. (76% yield) of 3-amino-6-(1-pyrrolidinyl)-pyridazine, m.p. 209°-211° C. A TLC check of the filtrate indicated that it contained more of the product, which was not isolated. The intermediate 3-amino-6-(1-pyrrolidinyl)pyridazine prepared by said better procedure was used in the preparation of the final product as described in the second paragraph of (Example D-4) described hereinbelow.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:15][CH2:16][CH3:17])[CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:18])[C:3]=1[NH2:19].C([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30])(C)C.O1C[CH2:36][CH2:35][CH2:34]1>>[ClH:1].[Cl:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([CH2:8][N:9]([CH2:15][CH2:16][CH3:17])[CH2:10]3)[C:6]=2[CH:5]=[C:4]([Cl:18])[C:3]=1[NH:19][S:29]([C:24]1[CH:23]=[CH:28][C:27]([CH:35]([CH3:36])[CH3:34])=[CH:26][CH:25]=1)(=[O:30])=[O:31]
Reactant: CCCN1CC2CCc3c(cc(Cl)c(N)c3Cl)C2C1
Reactant: CC(C)c1ccccc1S(=O)(=O)Cl
Reactant: C1CCOC1
Product: CCCN1CC2CCc3c(cc(Cl)c(NS(=O)(=O)c4ccc(C(C)C)cc4)c3Cl)C2C1
Product: Cl
Temperature: 150 °C
Reaction time: 5 h

Procedure:
6,8-Dichloro-2-propyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-7-yl-amine (100 mg, 0.33 mmol) and polystyrene-bound DMAP (4-(N,N-dimethylamino)pyridine) (loading 1.06 mmol/g, 32 mg) were treated with tetrahydrofuran (10 ml). Subsequently isopropylphenylsulfonyl chloride (73 mg, 0.33 mmol) was added and stirred for 5 hours at 150° C. in the microwave (CEM). Another portion of isopropylphenylsulfonyl chloride and polystyrene-bound DMAP was added and stirring continued for 7 hours at 160° C. in the microwave. The solvent was evaporated under reduced pressure, the residue treated with water (30 ml) and twice extracted with ethyl acetate (2×30 ml). The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give an oil (470 mg). The crude product was purified via HPLC chromatography. Fractions containing the product were combined and the solvent evaporated. The residue was converted into the hydrochloride salt (4 mg, 2%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:42][C:43]1[C:51]2[C:50]([N:52]3[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]3)=[N:49][CH:48]=[N:47][C:46]=2[NH:45][CH:44]=1>CN(C)C=O>[CH3:42][C:43]1[C:51]2[C:50]([N:52]3[CH2:57][CH2:56][CH:55]([NH:58][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:9])[CH2:54][CH2:53]3)=[N:49][CH:48]=[N:47][C:46]=2[NH:45][CH:44]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4ccncc4)CC3)c12
Reaction time: 18 h

Procedure:
To a solution of 4-pyridinecarboxylic acid (59.8 mg, 0.486 mmol), EDC.HCl (115 mg, 0.598 mmol), HOBt (92 mg, 0.598 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.934 mmol) in N,N-dimethylformamide (1 mL), stirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride (100 mg), DU, and the reaction stirred for 18 h. The solvent was removed in vacuo and the mixture purified by high pH MDAP to give the title compound E27 (45 mg). 1H NMR (d6-DMSO) δ 11.53 (1H, s), 8.72 (2H, d), 8.66 (1H, d), 8.22 (1H, s), 7.78 (2H, d), 7.07 (1H, s), 4.09 (1H, m), 4.02 (2H, d), 3.06 (2H, t), 2.37 (3H, s), 1.95 (2H, d), 1.74 (2H, ddd), MS(ES+) 337 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[CH3:27][Si:28]([CH3:38])([CH3:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>O>[O:1]=[C:2]1[C@H:7]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([Si:28]([CH3:27])([CH3:38])[CH3:37])[CH:30]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: C[Si](C)(C)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cccc([Si](C)(C)C)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 85.7 %

Procedure:
A dry 250 ml 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet was charged with 2.08 g of t-butyl (2R, 3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (Aldrich), 1.43 g of 3-(trimethylsilyl)benzyl bromide (Yamakawa, T., et al, J. Med. Chem., 1990, 33, 1430), and 45 mL of anhydrous THF. The solution was cooled to −780° C. and was treated with 6.17 mL of 1 M sodium bis(trimethylsilyl)amide/THF (Aldrich) via syringe through a rubber septum. The solution was stirred at −78° C. for 3.5 h and was then poured into 150 mL of water. The resulting mixture was extracted with EtOAc (4×50 mL). The combined EtOAc extracts were washed with saturated brine (3×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a light yellow oil. The crude material was purified by flash chromatography on silica gel (9:1 hexane:EtOAc) to afford 2.6 g (88%) of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(trimethylsilyl)benzyl)-4-morpholinecarboxylate as a white powder, m.p. 88-90° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:2]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
The above general procedure was followed using bromobenzene (157 mg, 1.00 mmol) and aniline (93 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.5 mL of toluene. After one hour, the reaction mixture was adsorbed onto silica gel and chromatographed with 5% ethyl acetate/hexanes to give 145 mg (86%) of diphenylamine as a grey solid. 1H NMR (500 MHz, C6D6) δ 7.11-7.08 (m, 4H), 6.85-6.80 (m, 6H), 4.97 (br s, 1H). 13C NMR (125 MHz, C6D6) δ 143.6, 129.5, 121.1, 118.2. In addition, 21 mg (8%) of triphenylamine was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][NH:17]3)=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=[S:25].C([N:38]([CH2:41]C)CC)C.N>C1COCC1.CO>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][N:17]3[C:41](=[S:25])[NH2:38])=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCCCCCOc2cccc3c2CCN3)cc1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCN(CC)CC
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)N1CCc2c(OCCCCCOc3ccc(Cl)cc3)cccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[5-(4-chloro-phenoxy)-pentyloxy]-2,3-dihydro-1H-indole (100 mg, 0.3 mmol) and thiocarbonyl diimidazole (64 mg, 0.36 mmol) in dry THF (3 mL) was added triethylamine (30 mg, 0.3 mmol). The reaction mixture was stirred at 50° C. for 3 hours and then 2.0 M ammonia in 4 mL methanol (excess) was added. The stirring was continued overnight at 50° C. After removal of the solvent, the residue was purified by silica gel column chromatography to give 4-[5-(4-chloro-phenoxy)-pentyloxy]-2,3-dihydro-indole-1-carbothioic acid amide, compound 8 (101 mg, 0.26 mmol, 85%) as a white solid. MS (EI): m/z 391 (M+H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH:13][C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>O.C(Cl)(Cl)Cl>[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:2][C@H:3]([C:11]([NH:13][C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:12])[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Yield: 81.8 %

Procedure:
In a mixture of 10 ml of water and 50 ml of chloroform were suspended 3.79 g of methyl phenylalanyltyrosinate hydrochloride and 0.53 g of sodium carbonate. To the mixture was added dropwise 1.75 g of 4-methoxybenzoylchloride in parallel with 10 ml of sodium carbonate solution (0.75 g), while stirring and cooling with ice. The mixture was stirred for 2 hours and the chloroform layer was collected. The layer was washed with 5% hydrochloric acid and water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 3.9 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate with a mp. 195°-197° C. in a yield of 82%. Analysis, calculated for C27H28O6N2 : C, 68.05; H, 5.92; N, 5.88; found C, 68.42; H, 6.08; N, 5.74.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38][Si](C(C)(C)C)(C)C)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCOCC1.Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([OH:38])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl 9-(4-(methoxycarbonyl)phenyl)-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]chrysene-3a-carboxylate (3.12 g, 4.54 mmol) in Dioxane (25 mL) was added TBAF (75% wt in water) (2.375 g, 6.81 mmol). The mixture was stirred at rt for 4 h then was diluted with 1N HCl (25 mL) and water (5 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4, filtered, and partially concentrated under reduced pressure to about 10 mL volume. To the partially concentrated mixture was added 1N HCl (50 mL). The solids that formed were collected by filtration and were washed with water. The expected product, (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-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]chrysene-3a-carboxylic acid (2.58 g, 4.50 mmol, 99% yield), was isolated as a white solid. LCMS: m/e 571.47 (M−H)−, 3.60 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.80 (br. s., 1H), 7.92 (d, J=8.24 Hz, 2H), 7.18 (d, J=8.24 Hz, 2H), 5.32-5.26 (m, 1H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.90 (s, 3H), 3.07-2.99 (m, 1H), 2.33-2.21 (m, 2H), 2.10 (dd, J=17.09, 6.10 Hz, 1H), 2.06-1.94 (m, 2H), 1.70 (s, 3H), 1.01 (br. s., 3H), 1.00 (br. s., 3H), 0.98 (s, 3H), 0.91 (s, 6H), 1.79-0.89 (m, 17H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[CH3:31][C@H:32]1[CH2:37][CH2:36][C@H:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:35]4[CH2:36][CH2:37][C@@H:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1
Reactant: C[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O[C@H]4CC[C@@H](C)CC4)cc3)n2)C2CCCC2)c1
Temperature: 25 °C

Procedure:
To a THF (2 mL) solution of 3-({cyclopentyl-[4-(4-hydroxy-phenyl)-pyrimidin-2-yl]-amino}-methyl)-benzoic acid methyl ester (44 mg, 0.11 mmol) was added trans-4-methyl-cyclohexanol (12.5 mg, 0.11 mmol) and triphenylphosphine (27 mg, 0.11 mmol). After the mixture was cooled 5 min. in an ice bath, diisopropyl azodicarboxylate (DIAD, 21.5 μL, 0.11 mmol) was added. The solution was stirred at room temperature until complete. Water was added, and the mixture was extracted with ethyl acetate (3×2 mL). The ethyl acetate layer was dried over Na2SO4 and concentrated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 then 4:1 to give 16 mg (30%) of 3-[(cyclopentyl-{4-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-pyrimidin-2-yl}-amino)-methyl]-benzoic acid methyl ester. LCMS m/z: 501 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C([N:42]([CH:45]([CH3:47])[CH3:46])CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.N[C:64]1C=CC=[CH:70][C:65]=1[C:66]([O:68][CH3:69])=[O:67]>ClCCl>[CH3:69][O:68][C:66](=[O:67])[C:65]1[CH:70]=[CH:46][C:45]([NH:42][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:47][CH:64]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid (0.86 g, 1.48 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (1.53 g, 11.9 mmol), diphenylphosphinic chloride (Aldrich) (1.41 g, 5.94 mmol) respectively. The mixture was stirred at room temperature for 0.5 h, then methyl aminobenzoate (Acros) (0.22 g, 1.48 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (3-10% of EtOAc in CH2Cl2) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester as a off white solid (0.34 g, 38%).