Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]=O)=O.[NH2:5][C:6]1[C:27]([NH2:28])=[CH:26][C:9]2[CH2:10][C@@H:11]3[C:16]([CH3:18])([CH3:17])[C@:15]([CH3:19])([C:8]=2[CH:7]=1)[CH2:14][CH2:13][N:12]3C(=O)C(F)(F)F>C(O)C>[CH3:19][C@@:15]12[C:16]([CH3:18])([CH3:17])[C@@H:11]([CH2:10][C:9]3[CH:26]=[C:27]4[N:28]=[CH:1][CH:3]=[N:5][C:6]4=[CH:7][C:8]=31)[NH:12][CH2:13][CH2:14]2
Reactant: O=CC=O
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Solvent: CCO
Product: CC1(C)[C@H]2Cc3cc4nccnc4cc3[C@]1(C)CCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glyoxal (40% in water, 95 μL) is added to (2R,6S)-1-(8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-2,2,2-trifluoro-ethanone (260 mg) dissolved in ethanol (3 mL) and chilled in an ice bath. The cooling bath is removed and the solution is stirred at ambient temperature overnight. Then, the solution is concentrated and the residue is taken up in methanol (1 mL) and treated with 4 M aqueous NaOH solution (0.38 mL). After stirring at ambient temperature overnight, brine is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO4), and the solvent is removed under reduced pressure to give the crude title compound that is used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].[H][H].C1C=CC=CC=1.CCCCCC>C(O)C.[Ni]>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][OH:21])[CH3:18])[CH3:13])[CH3:8])[CH3:1]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: c1ccccc1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Yield: 81.9 %

Procedure:
Phytol (30.0 g, 0.101 mol) was dissolved in 200 ml of ethanol. A suspension of 1.8 g of Raney-Ni (W-1) in 5 ml of ethanol was added thereto, and hydrogenation was carried out under hydrogen for about 5 hours so that 2405 ml of hydrogen (theoretical volume at 24° C.; 2465 ml) was absorbed. After filtering off the catalyst through a filter paper, the ethanol was evaporated. Yield 29.9 g. Silica gel column chromatography with benzene-hexane (1:1) gave 24.7 g of the title compound (yield 82.3%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[C@H:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[OH:15].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Cl>CCCCCC.O1CCCC1>[OH:15][C@H:14]([C:13]([O:23][CH2:24][CH3:25])=[O:22])[C@H:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C[C@H](O)C(=O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)[C@@H](O)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
31 ml of 1.69M n-butyllithium in hexane was dissolved in 30 ml of tetrahydrofuran, stirred with 7.1 ml of diisopropylamine under cooling with ice for 30 minutes and then cooled to -78° C. 4.94 g of diethyl (S)-malate in 20 ml of tetrahydrofuran was added dropwise at -50° C. or below, and the reaction solution was stirred at -20° C. for 1.5 hours. The reaction solution was cooled to -78° C., and 5.58 g of tert-butyl bromoacetate and 4.66 g of hexamethylphosphoryl triamide in 20 ml of tetrahydrofuran were added dropwise at -50° C. or below. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into 150 ml of 0.5N hydrochloric acid and extracted with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→4/1] to give 3.88 g of the title compound as a yellow oily substance.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[N:27]([CH2:30][C:31]([C:33]1[CH:34]=[CH:35][C:36]2[N:40]=[C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][NH:42]3)[NH:38][C:37]=2[CH:46]=1)=[O:32])=[N+:28]=[N-:29].N(CC(C1C=CC2N=C([C@@H]3CCCN3)NC=2C=1)=O)=[N+]=[N-].Cl.[CH3:68][N:69]([CH3:80])[C@H:70]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:71](O)=[O:72].CCN(C(C)C)C(C)C>CN(C)C=O>[N:27]([CH2:30][C:31]([C:33]1[CH:34]=[CH:35][C:36]2[N:40]=[C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:71](=[O:72])[C@H:70]([N:69]([CH3:68])[CH3:80])[C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[NH:38][C:37]=2[CH:46]=1)=[O:32])=[N+:28]=[N-:29]
Reactant: CN(C)[C@@H](C(=O)O)c1ccccc1
Reactant: [N-]=[N+]=NCC(=O)c1ccc2nc([C@@H]3CCCN3)[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@@H](C(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CN=[N+]=[N-])cc2[nH]1)c1ccccc1
Reaction time: 6 h
Yield: 50 %

Procedure:
To a solution of J.31 (1.8 g, 4.86 mmol) in ethyl acetate (5 mL) was added HCl/dioxane (10 mL of 4N), and the reaction was stirred 4 hr. The solvents were removed in vacuo, and the HCl salt was exposed to high vacuum for 18 h to give (S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone 2HCl a yellow solid. HATU (1.94 g, 5.10 mmol) was added to the HCl salt of (S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone (1.8 g, 4.86 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid HCl salt (1.05 g, 4.86 mmol), and Hunig's base (3.4 mL, 19.4 mmol) in dimethylformamide (50 mL) while being rapidly stirred 6 h. The solvent was removed in vacuo and the reside was partitioned into two lots and separately pre-absorbed onto SiO2 (dichloromethane), and subjected to flash chromatography on a 40 M Biotage silica gel column pre-equilibrated 2% B, and eluted with 2% B (150 mL); Segment 2: 2-40% B (1200 mL); Segment 3: 40-80% (600 mL). A=dichloromethane; B=25% methanol/dichloromethane to give J.31a (R)-1-((S)-2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-(dimethylamino)-2-phenylethanone (combined lots: 1.05 g (50%)) as a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.82 (dd, J=8.8, 1.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.60-7.56 (m, 5H), 5.51 (s, 1H), 5.22 (dd, J=8.2, 2.8, 1H), 4.95 (m, 2H), 4.09-4.05 (m, 1H), 3.17-3.12 (m, 1H), 2.90/2.84 (br. s, 6H), 2.23-2.19 (m, 1H), 2.21-1.89 (m, 3H). LC (D-Cond. 1): RT=1.5 min; LC/MS: Anal. Calcd. for [M+H]+ C23H26N7O2: 432.22; found: 431.93. HRMS: Anal. Calcd. for [M+H]+ C23H26N702: 432.2148; found: 432.2127.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])[CH3:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH:29][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1)[CH3:24]
Reactant: CCOC(=O)CCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 4-formylbenzoic acid (27.4 g, 0.18 mol) in DMF (300 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (34.5 g, 0.18 mol) and N-hydroxybenzotriazole (29.9 g, 0.22 mol). The resulting mixture was stirred at room temperature for 1 hour, then β-alanine ethyl ester hydrochloride (65.4 g, 0.42 mol) and diisopropylethylamine (76 mL, 0.44 mol) was added. After 16 hours stirring at ambient temperature the reaction mixture was partitioned between water (600 mL) and ethyl acetate (600 mL). The organic phase was washed successively with hydrochloric acid (1N, 300 mL), saturated aqueous ammonium chloride (300 mL), water (2×300 mL) and brine (300 mL). The solvent was removed by rotary evaporation to leave an oil, which crystallised upon standing to afford 29.0 g (65%) of 3-(4-formylbenzoylamino)propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[N:21][C:22]=3[CH2:23][O:24]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:31]([N:33]([CH2:50][CH3:51])[CH2:34]/[CH:35]=[CH:36]\[Sn](CCCC)(CCCC)CCCC)[CH3:32].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.CS(C)=O.C(OCC)(=O)C.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:31]([N:33]([CH2:50][CH3:51])[CH2:34]/[CH:35]=[CH:36]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[N:21][C:22]=3[CH2:23][O:24]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:32]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1nnccc1-2
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1nnccc1-2
Temperature: 95 °C
Yield: 58.9 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (Intermediate 5, 0.403 g), N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 2, 0.656 g), tris(dibenzylidene-acetone)dipalladium(0) (0.037 g) and tri-tert-butylphosphonium tetrafluoroborate (0.024 g) in dioxan (10 mL) and DMSO (1 mL) was stirred and heated at 95° C. under nitrogen for 90 minutes. Further N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 2, 0.656 g), tris(dibenzylideneacetone)dipalladium(0) (0.037 g) and tri-tert-butylphosphonium tetrafluoroborate (0.024 g) were added and the mixture was heated at 95° C. under nitrogen for a further 45 minutes. After cooling, the mixture was diluted with ethyl acetate and washed three times with water. The combined aqueous extracts were extracted with DCM and the combined organic layers were filtered through a phase separator. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (0.253 g) as a sandy coloured solid.
Reaction SMILES: [CH3:1][C:2]1C=CC(S(O)(=O)=O)=C[CH:3]=1.[NH2:12][C:13]1[N:17]([C:18]([CH3:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:25]#[N:26])[CH:14]=1.COC(OC)CC(OC)OC>C1(C)C=CC=CC=1>[F:21][C:19]([F:22])([F:20])[C:18]([N:17]1[C:13]2=[N:12][CH:1]=[CH:2][CH:3]=[C:14]2[C:15]([C:25]#[N:26])=[CH:16]1)([CH3:23])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(n1cc(C#N)cc1N)C(F)(F)F
Agent: COC(CC(OC)OC)OC
Solvent: Cc1ccccc1
Product: CC(C)(n1cc(C#N)c2cccnc21)C(F)(F)F
Temperature: 100 °C

Procedure:
4-Methylbenzenesulfonic acid (10.57 mg, 0.061 mmol) was added in one portion to a solution of 5-amino-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrrole-3-carbonitrile (133.3 mg, 0.614 mmol) and 1,1,3,3-tetramethoxypropane (111 μl, 0.675 mmol) in toluene (1227 μl) at RT. The mixture was heated at 100° C. for 1 h and purified directly by HPLC to afford the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:36])[CH:24](I)[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:24]([C:23]([O:22][CH3:21])=[O:36])[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(I)CCO[Si](C)(C)C(C)(C)C
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CCN1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 6.95 g (28.0 mmol) of 5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 85 ml of N,N-dimethylformamide was treated at 0° C. with 1.47 g (33.6 mmol) of NaH (55% in oil) in three portions. After 30 min, 10.0 g (28.0 mmol) of (rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-iodo-butyric acid methyl ester (intermediate 1) were added during 5 min. The solution was stirred 2¼ h at 0° C. and neutralized with cold 10% aq. potassium hydrogensulfate solution and extracted with diethyl ether (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane/ethyl acetate 4:1 to 2:1) to yield 8.45 g (63%) of the title compound as yellow viscous oil. MS: 479.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:16]=1/[CH:17]=[N:18]/[S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@@H:17]([C:16]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:15]=2[F:14])[NH:18][S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(F)cc1F
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
1,4-dibromobenzene (10.58 g, 44.8 mmol) was dissolved in THF (150 ml) and cooled to −78° C. under nitrogen. Then n-BuLi (18 ml, 44.8 mmol) was added dropwise below −60° C. After addition, the mixture was stirred at −78° C. for additional 1 h and then (S,E)-N-(2,4-difluorobenzylidene)-2-methylpropane-2-sulfinamide, 21-a, (10 g, 40.77 mmol) in anhydrous THF was added dropwise below −60° C. Then the mixture was allowed to stir at room temperature for 6 h. The mixture was quenched with saturated NH4Cl followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to provide the product, 21-b, (7.5 g, 42%). HPLC implicated that only the single isomer was formed.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:23][O:24][Si](C(C)(C)C)(C)C)=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].C1COCC1.C(O)C>O>[Br:1][C:2]1[C:3]([CH2:23][OH:24])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[S:12][C:11]=2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1CNc1cccc(Br)c1CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CNc2cccc(Br)c2CO)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A 50-mL single-necked round-bottomed flask equipped with a magnetic stirrer was charged with 114e (1.10 g, 2.09 mmol), lithium hydroxide (201 mg, 8.36 mmol), THF (10 mL), ethanol (10 mL) and water (10 mL). After stirring at room temperature for 2 h, the solvent was removed under reduced pressure and the resulting residue was acidified with 2N hydrochloric acid to pH of 4. The resulting aqueous solution was extracted with ethyl acetate (3×30 mL), and the organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 114f in 65% yield (540 mg) as a white solid: mp 68-69° C.; 1H NMR (500 MHz, CDCl3) δ 7.03-6.97 (m, 2H), 6.86 (s, 1H), 6.71 (d, 1H, J=8.0 Hz), 4.94 (s, 2H), 4.60 (s, 2H), 1.35 (s, 9H); MS (ESI+) m/z 398.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:12]1[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:9](=[O:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.C([O-])(O)=O.[Na+].[Pd](Cl)Cl>[C:9]([N:8]1[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:18]=[CH:19][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:20][C:6]=2[CH2:7]1)(=[O:11])[CH3:10]
Reactant: C=Cc1cccnc1N(Cc1cc(Br)ccc1I)C(C)=O
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2cc(Br)ccc2C=Cc2cccnc21
Temperature: 65 °C
Yield: 77 %

Procedure:
To a stirred mixture of N-(5-Bromo-2-iodo-benzyl)-N-(3-vinyl-pyridin-2-yl)-acetamide E (60.0 mg, 0.13 mmol) and triethyl amine (55.0 μL, 0.39 mmol) in anhydrous DMF (1.4 mL) under argon was added Palladium dichloride (4.60 mg, 26 μmol). This mixture was heated at 65° C. for 1 h, cooled and diluted with saturated NaHCO3 solution (20 mL). The mixture was extracted with EtOAc (4×30 mL). The combined EtOAc extracts were washed with water (3×10 mL), brine (1×10 mL), dried (MgSO4), filtered and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 4 g column, eluted with CH2Cl2-EtOAc, detected at 254 nM to give 33 mg of 78F in 77% yield. HPLC Rt=3.04 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=329.
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(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>>[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[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])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:66][CH:65]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Nc1ccc(F)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(F)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 46.8 %

Procedure:
In a manner similar to the method described in Example 5, 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 prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.17 g, 0.71 mmol), then reacted with 4-fluoroaniline (Aldrich) (0.047 g, 0.43 mmol) to give 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 (4-fluoro-phenyl)-amide as a yellow solid (Yield 0.094 g, 47%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2>>[Cl:11][C:12]1[CH:20]=[C:19](/[CH:21]=[C:3]2/[C:2](=[O:10])[NH:1][C:9]3[C:4]/2=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2
Reactant: O=Cc1cc(Cl)c2cn[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2/C1=C\c1cc(Cl)c2cn[nH]c2c1
Yield: 16.9 %

Procedure:
The compound was synthesized according to the method described for Example A1. Oxindole (8 mg, 0.06 mmol) was reacted with 4-chloro-1H-indazole-6-carbaldehyde (11 mg, 0.06 mmol) to give the title compound as an orange solid (3 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H, J=7.8 Hz), 7.48 (s, 1H), 7.28 (t, 1H, J=7.9 Hz), 6.95 (d, 1H, J=7.7 Hz), 6.90 (t, 1H, J=8.2 Hz); MS ESI [M+H]+, calcd for [C16H10ClN3O+H]+ 296.1; found m/z 296.1.
Reaction SMILES: C1(NC(C2(C)CCC3C(C)=C(OC(=O)C)C(C)=C(C)C=3O2)=O)C=CC=CC=1.[CH3:28][C:29]1([CH3:57])[O:34][CH2:33][C:32]([NH:36][C:37]([C:39]2([CH3:56])[CH2:44][CH2:43][C:42]3[C:45]([CH3:55])=[C:46]([O:51]C(=O)C)[C:47]([CH3:50])=[C:48]([CH3:49])[C:41]=3[O:40]2)=[S:38])([CH3:35])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:57])[O:34][CH2:33][C:32]([NH:36][C:37]([C:39]2([CH3:56])[CH2:44][CH2:43][C:42]3[C:45]([CH3:55])=[C:46]([OH:51])[C:47]([CH3:50])=[C:48]([CH3:49])[C:41]=3[O:40]2)=[S:38])([CH3:35])[CH2:31][O:30]1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=S)NC1(C)COC(C)(C)OC1)O2
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Nc1ccccc1)O2
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=S)NC1(C)COC(C)(C)OC1)O2

Procedure:
By carrying out the reaction as in Example 2 (2nd process), but replacing the compound of Example 1 with the compound of Example 64, the title product is obtained.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:30]1[CH2:54][O:53][C:32]2([CH2:37][CH2:36][C@H:35]3[C@H:38]4[C@H:48]([CH2:49][CH2:50][C@:33]23[CH3:34])[C@:46]2([CH3:47])[C@:41]([OH:52])([CH2:42][C:43](=[CH2:51])[CH2:44][CH2:45]2)[CH2:40][CH2:39]4)[O:31]1>>[CH2:54]1[CH2:30][O:31][C:32]2([CH2:37][CH2:36][C@H:35]3[C@H:38]4[C@H:48]([CH2:49][CH2:50][C@:33]23[CH3:34])[C@:46]2([CH3:47])[C@:41]([OH:52])([CH2:42][C@H:43]([CH2:51][OH:2])[CH2:44][CH2:45]2)[CH2:40][CH2:39]4)[O:53]1
Reactant: C=C1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H](CCC45OCCO5)[C@@H]3CC[C@@]2(O)C1
Reactant: C[C@]12CCCCC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)C[C@H](CO)CC[C@]34C)[C@@H]1CCC21OCCO1
Yield: 98 %

Procedure:
Following the procedure described for the preparation of 3,3:17,17-bis(ethylendioxy)-6β-hydroxymethylandrostane (Prepn. 9) and starting from 17,17-(ethylendioxy)-3-methylenandrostane-5α-ol, 17,17-(ethylendioxy)-3α-hydroxymethylandrostane-5α-ol was obtained in 98% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.44 (t, 1H), 3.81 (s, 1H), 3.76 (m, 4H), 3.58 (m, 1H), 3.39 (m, 1H), 1.91-0.97 (m, 22H), 0.87 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:22])([F:21])[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:13]=1.[Br:23][CH2:24][CH2:25]Br>C(#N)C>[Br:23][CH2:24][CH2:25][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[N:13]=[C:9]([C:8]([F:7])([F:21])[F:22])[S:10][CH:11]=1
Reactant: Oc1ccccc1-c1csc(C(F)(F)F)n1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)c1nc(-c2ccccc2OCCBr)cs1
Temperature: 70 °C

Procedure:
Cesium carbonate (266 mg, 0.816 mmol) was added to a solution of 2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenol (C4) (100 mg, 0.408 mmol) and 1,2-dibromoethane (0.35 mL, 4.1 mmol) in acetonitrile (33 mL), and the mixture was heated at 70° C. for 18 hours. After cooling to room temperature, the reaction was partitioned between dichloromethane and water; the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in heptane) afforded the title compound. Yield: 115 mg, 0.327 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 3.78 (br dd, J=5.5, 5.5 Hz, 2H), 4.48 (dd, J=5.7, 5.5 Hz, 2H), 6.97 (br d, J=8.4 Hz, 1H), 7.13 (ddd, J=7.7, 7.4, 1.1 Hz, 1H), 7.35 (ddd, J=8.3, 7.3, 1.8 Hz, 1H), 8.31 (dd, J=7.8, 1.8 Hz, 1H), 8.37 (s, 1H).