Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C1COCC1>[C:19]([C:4]1([CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][CH:3]1[O:2][CH3:1])[NH2:5])([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC1C=C([N+](=O)[O-])C=CC1(N)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 2-methoxy-4-nitroaniline (3.0 g) and pyridine (1.6 ml) in THF (30 ml) was cooled to 0° C. FmocCl (5.07 g) was added in portions and after complete addition the ice-bath was removed and the mixture was stirred for 5 h. The THF was removed in vacuo and the residue dissolved in CH2Cl2 (175 ml). Methanol (ca 100 ml) was added and the CH2Cl2 was partly removed in vacuo until a precipitate formed. The mixture was allowed to stand for 1 h, after which time the crystals were collected by filtration and dried in vacuo to give the title compound.
Reaction SMILES: C(O[K])(C)(C)C.[CH2:7]([C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)[CH3:8].[CH2:16]([O:18][C:19](=[O:27])[CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH3:17]>CC(O)(C)C>[CH2:16]([O:18][C:19](/[C:20](=[CH:14]/[C:12]1[O:13][C:9]([CH2:7][CH3:8])=[CH:10][CH:11]=1)/[CH2:21][C:22]([OH:24])=[O:23])=[O:27])[CH3:17]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CCc1ccc(C=O)o1
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Product: CCOC(=O)/C(=C/c1ccc(CC)o1)CC(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of tBuOK (61.4 g, 0.54 mol) in tBuOH (180 mL) was added a suspension of 5-ethyl-2-furaldehyde (22.5 g, 0.18 mol) in succinic acid diethyl ester (142.1 g, 0.82 mol). The reaction mixture was refluxed for 1 h. Then the same amounts of tBuOK, tBuOH and succinic acid diethyl ester were added at the same temperature, and the reaction mixture was stirred at reflux for another 1 h. TLC (petroleum ether/EtOAc 2:1) indicated the complete consumption of the furaldehyde. The reaction mixture was allowed to cool to room temperature, acidified to a pH˜2 by 20% aqueous HCl (200 mL) and extracted with EtOAc (500 mL×3). The organic phase was washed with 10% aqueous Na2CO3 (500 mL×3). The combined aqueous layers was washed with ethyl ether (500 mL) and acidified to a pH˜2 with 20% aqueous HCl (100 mL). The aqueous phase was finally extracted with EtOAc (500 mL×4). The combined organic layers were dried over Na2SO4 and concentrated to give the crude acid (45.4 g, 100%), which was directly used to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][S:38](Cl)(=[O:40])=[O:39])=[CH:33][CH:32]=1>>[C:17]([C:16]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:38]([CH2:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:39])=[O:40])[C:12]([C:21]#[N:22])=[C:13]([CH3:20])[NH:14][C:15]=1[CH3:19])#[N:18]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)Cc4ccc(Cl)cc4)c3c2)C(C#N)=C(C)N1

Procedure:
The title compound was prepared following the procedure described for Example 6 starting from 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) and 346 mg (1.54 mmol) (4-chlorophenyl)methane-sulfonyl chloride. Yield: 4 mg (3% of th.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].P([O-])(O)(O)=O.[K+]>CS(C)=O.C(OC(C)C)(=O)C.[Cu]>[CH2:13]([O:12][C:10](=[O:11])[C:9]([F:16])([F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 67107.4 %

Procedure:
To the solution of 2-bromopyridine (18 mL, 0.2 mmol) and ethyl bromodifluoroacetate (27 g, 0.22 mol) in DMSO (70 mL) was added copper powder (29 g, 0.46 mol). The mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with isopropyl acetate (100 mL). A solution of potassium dihydrogen phosphate (1.27 M, 150 mL) was added and stirred for 30 min. the copper salt was removed by filtration and washed with isopropyl acetate (100 mL). The filtrate layer was separated. The organic layer was washed with water (2×100 mL) and dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 5%-40% methyl t-butyl ether in hexanes in 40 min) afforded difluoro-pyridin-2-yl-acetic acid ethyl ester (27 g, 68%) as a colorless oil. LC-MS m/e 202 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:20])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.Br.O.C(=O)([O-])[OH:24].[Na+]>CS(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:20])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:24])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: Cc1cccc(CC(=O)c2ccc3nnn(C)c3c2)n1
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)C(=O)c2ccc3nnn(C)c3c2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone (280 mg, 1.05 mmol) in 16 ml dimethyl sulfoxide was heated to 60° C. 48% hydrobromic acid solution in water (7.4 ml, 65.1 mmol) was slowly added over several minutes. Once the addition was complete, the reaction was stirred at 60° C. for 3 hours. The reaction was cooled to room temperature and poured into 75 ml water. The pH was adjusted to 8 with the addition of saturated sodium hydrogen carbonate solution. The aqueous layer was then extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to afford 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione (146 mg, 50%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][Mg]Br.[CH3:7][O:8][C:9](=[O:32])[C:10](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[CH:10]([CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][CH:17]=1)[CH:1]=[C:2]([CH3:6])[CH3:3])[C:9]([O:8][CH3:7])=[O:32]
Reactant: COC(=O)C(=Cc1ccc(OCc2cccc(OC)c2)cc1)C(=O)OC
Reactant: CC(C)=C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(C=C(C)C)c1ccc(OCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-methyl-1-propenylmagnesium bromide (3 mL, 0.5 M in THF) was added dropwise to a solution of compound 33.1 (1.0 mmol) in THF. The reaction mixture was stirred at room temperature for 1 hr and then quenched with saturated NH4Cl(aq) and the aqueous layer extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate=2/1) to give compound 33.2 as a white solid (0.93 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:18]([O-])=O)[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl-].[NH4+].C>C(O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:18])[C:14]=1[S:15][CH2:16][CH3:17])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 60 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A 50 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-ethylsulfanyl-8-nitro-9H-β-carboline (85.0 mg, 0.28 mmol) in 10 ml anhydrous ethanol. To the resulting orange mixture at RT was added 0.33 M aqueous ammonium chloride (2.0 ml, 0.66 mmol) and iron powder (680 mg, 12.2 mmol). The reaction mixture was heated to 60° C. and stirred vigorously for 20 hr. Next, the mixture was cooled to RT, diluted with ethyl acetate (15 ml), and activated charcoal (180 mg) was added. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated to afford 77.8 mg of 6-chloro-7-ethylsulfanyl-9H-β-carbolin-8-ylamine as a yellow solid (>99%). 1H-NMR (300 MHz, CD3OD, ppm) δ 8.94 (1H, s) 8.33-8.29 (1H, m) 8.21-8.18 (1H, m) 7.73 (1H, s) 2.85 (2H, q) 1.21 (3H, t). LCMS (ammonium acetate standard method) retention time=2.13 min. (M+=278; M=276).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2ccoc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2ccoc12
Yield: 90.7 %

Procedure:
A solution of methyl benzofuran-7-carboxylate (5.34 g, 30 mmol) was added to a suspension of LAH (2.31 g, 61 mmol) in THF and then heated to reflux for 30 min. The reaction was quenched with ethyl acetate and water. The mixture was made acidic with 12N HCl until all the precipitate dissolved. The ethyl acetate layer was separated, washed with water, dried with brine, and concentrated in vacuo to give a yellow oil (4.03 g, 91%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10](Br)[CH2:9][CH2:8][N:7]([C:12](=[O:25])[C@H:13]([CH:22]([CH3:24])[CH3:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH:10]=[CH:9][CH2:8][N:7]([C:12](=[O:25])[C@@H:13]([CH:22]([CH3:23])[CH3:24])[NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CCC1Br
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OC1C=CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)C1

Procedure:
1.684 g of 3-acetoxy-4-bromo-N—(N-BOC-valyl)-piperidine dissolved in 4 ml of toluene are treated with 4 ml of DBU in a sealed tube and heated to 90°. The mixture obtained is treated with EE, extracted with aqueous HCl, washed and from the organic phase obtained solvent is evaporated. 3-Acetoxy-N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridine is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31]([OH:33])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]I.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31]([O:33][CH3:34])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@@H]3C=C[C@H](O)C3)c3ccccc3n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@H]1C=C[C@@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,4R)-(4-hydroxycyclopent-2-en-1-yl)oxy]quinazoline [cf. Example 33(3)] (750 mg) and methyl iodide (445 mg) in dimethylformamide (6 ml) is added 60% sodium hydride (oil) (94 mg) with stirring at room temperature, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate, and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified by medium pressure liquid column chromatography [eluent, chloroform, (chloroform:methanol=200:1, v/v)] to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,4R)-(4-methoxycyclopent-2-en-1-yl)oxy]quinazoline (710 mg) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:35])[CH3:34])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.0145 ml acetylchloride (0.2 mmol). After 1.5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 68 mg of an off-white solid (84%). MS (ISP) 493.3 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17](=O)[CH3:18].O>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17]([CH3:18])=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)CCCc1ccccc1I
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=C(C)CCCc1ccccc1I
Yield: 90.2 %

Procedure:
To a stirred solution of potassium t-butoxide (7.96 g, 71 mmol) in anhydrous ether (100 ml) under nitrogen, was added methyltriphenylphosphonium bromide (25.6 g, 71 mmol). The yellow mixture was stirred under reflux for 0.5 h, allowed to cool for 10 min, and then a solution of 5-(2-iodophenyl)pentan-2-one (Intermediate 1) (9.3 g, 32.3 mmol) in anhydrous ether (70 ml) was added over 20 min. The reaction mixture was refluxed for 1 h, allowed to cool and then poured onto ice. Ether (100 ml) and water (100 ml) were added and the layers were separated. The aqueous layer was re-extracted with ether (100 ml) and the combined organic layers were washed successively with water (100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was treated with heptane (200 ml), solid was filtered off and washed with heptane and the filtrate was evaporated. The oil obtained was purified on a 90 g silica cartridge eluted with heptane to give the title compound as a liquid (8.34 g, 90%).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][CH:5]([NH:6][CH2:7]1)[CH2:4][O:3]2.FC(F)(F)S([O-])(=O)=O.[N:17]1([S:22](N2C=C[NH+](C)C2)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([S:22]([N:6]2[CH2:7][C@@H:2]3[CH2:8][C@H:5]2[CH2:4][O:3]3)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: C1O[C@@H]2CNC1C2
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1C[C@@H]2C[C@H]1CO2)n1ccnc1

Procedure:
(1S,4S)-5-(Imidazole-1-sulfonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane was prepared in accordance with step A of the general method described in example 76 from all-(S)-(+)-2-oxa-5-aza-bicyclo[2.2.1]heptane hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=230.5 (M+H−).
Reaction SMILES: C(O)C.C([BH3-])#N.[Na+].[CH2:8]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH:23](C=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29]C)=[O:27])[CH2:19][CH2:18]2)=[C:13]([F:35])[C:12]=1[F:36])[CH3:9].Cl>O>[CH2:8]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:29][O:28][C:26](=[O:27])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:13]([F:35])[C:12]=1[F:36])[CH3:9]
Reactant: CCOC(=O)CCC(C=O)C1CCC(COc2ccc(OCC)c(F)c2F)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(OCC2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
In a reactor under nitrogen atmosphere, 20 mL of ethanol and 0.4 g of sodium cyanoborohydride were added to 5.4 g of ethyl 4-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]5-oxopentanoate obtained in the eleventh step, and pH of the mixture was adjusted to about 3 with hydrochloric acid (2M), followed by stirring at room temperature for 15 hours. 30 mL of water was added to the reaction solution, which was extracted three times with 20 mL of toluene. The mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was placed in a flask equipped with a Dean-Stark apparatus, to which 100 mL of toluene and 0.1 g of p-toluenesulfonic acid monohydrate were added, and the mixture was refluxed for 1 hour while the solvent was distilled off with the Dean-Stark apparatus. The solution was cooled to room temperature, washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to provide 4.5 g of 5-[4-(4-ethoxy2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one.
Reaction SMILES: [S:1]([O:5][C:6]1[C:23]2[C@@H:22]3[C@@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C@@H:17]([OH:24])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:7]=1)([CH3:4])(=[O:3])=[O:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[S:1]([O:5][C:6]1[C:23]2[C@@H:22]3[C@@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C@@H:17]([O:24][C:30](=[O:32])[CH3:31])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:7]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: C[C@]12CC[C@@H]3c4c(cc(OS(C)(=O)=O)cc4OS(C)(=O)=O)CC[C@@H]3[C@@H]1CC[C@@H]2O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2[C@H]3CCc4cc(OS(C)(=O)=O)cc(OS(C)(=O)=O)c4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A solution of 200 mg. of 1,3-bis(mesyloxy)-8α-estra-1,3,5(10)-trien-17β-ol in 3 ml. of pyridine is combined with 2 ml. of acetic anhydride and allowed to stand at room temperature for 3 days. Then, the mixture is introduced into ice water, extracted with methylene chloride, washed with water, dried, and evaporated. The residue (180 mg.) is purified by layer chromatography, thus obtaining 150 mg. of 1,3-bis(mesyloxy)-17β-acetoxy-8α-estra- 1,3,5(100-triene.
Reaction SMILES: C[O:2][C:3](=[O:60])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][C:44]5[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:51]([C:53]1[N:54]=[C:55]([CH3:59])[O:56][C:57]=1[CH3:58])=[O:52])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.CO.[Li+].[OH-]>C1COCC1>[Cl:50][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][CH:47]=1)[O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:60])=[O:2])=[O:22])[N:24]([C:51]([C:53]5[N:54]=[C:55]([CH3:59])[O:56][C:57]=5[CH3:58])=[O:52])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(Oc2cccc(Cl)c2)cc1)CO3
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(Oc3cccc(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
(S)-2-{[(3S,8S)-3-[4-(3-Chloro-phenoxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (0.020 g) dissolved in THF (0.3 mL) and MeOH (0.3 mL) and 0.3 mL of 2.0 N LiOH was added at 0° C. and stirred at that temperature for 30 minutes. The pH was adjusted to 6-7, and the mixture was extracted with EtOAc, dried with (Na2SO4), and evaporated and dried under vacuum to get the title compound (0.015 g). LCMS (m/z): 814.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][N:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][N:4]=1)(=[O:40])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2cnc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2cnc(C(N)=O)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To the 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 (2-cyano-pyrimidin-5-yl)-amide (30 mg, 0.05 mmol) prepared in Example 184 in DMSO (0.2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.09 g, 0.8 mmol), then aqueous solution (1N) of NaOH (0.3 mL, 0.3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) 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 (2-carbamoyl-pyrimidin-5-yl)-amide as a white solid (Yield 8 mg, 26%)
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CCCC(C)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCCC(C)CCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,7-dimethyl-1-octanol (50.0 ml, 0.264 mol) and triphenylphosphine (86.9 g, 0.331 mol) in 300 ml of CH2Cl2 were added N-bromosuccinimide (56.6 g, 0.318 mol) in portions at 0° C. After stirring at 0° C. for 2 h, the solvent was evaporated. The residue was treated with hexane and filtered. The solids were washed thoroughly with hexane and the combined hexane extracts evaporated. The residue was chromatographed on silica gel with hexane. Yield=54.13 g (93% based on 50.0 ml of 3,7-dimethyl-1-octanol). 1H NMR (360 MHz, CDCl3): δ 3.37-3.50 (m, 2H, —CH2Br), 1.07-1.94 (m, 10H, (CH3)2CHCH2CH2CH2CH(CH3)CH2CH2Br), 0.89 (d, 3H, J=6.5 Hz, —CH3), 0.87 (d, 6H, J=6.8 Hz, —CH3). CI MS m/z: 220.048 (M+) (calcd 220.083).