Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[SiH:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11]>>[CH2:10]([Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:1][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:11]
Reactant: CC[SiH](CC)CC
Reactant: C=CCCCCCC
Product: CCCCCC=CC[Si](CC)(CC)CC
Temperature: 23 °C
Reaction time: 24 h

Procedure:
In a nitrogen-filled drybox, a scintillation vial was charged with 0.100 g (0.891 mmol) of 1-octene and 0.449 mmol (0.5 equiv) of 0.052 g Et3SiH. 0.001 g (0.002 mmol, 0.5 mol %) of (MesPDI)CoMe was then added to the mixture and the reaction was stirred at room temperature (23° C.) for 24 hours. The reaction was quenched by exposure to air, and the product mixture was analyzed by gas chromatography and 1H and 13C NMR spectroscopy. Conversion of the SiH and olefin functional groups was greater than 99%. GC analysis showed 46% of the alkenylsilane and 52% octane. Both E and Z isomers of 1-triethylsilyl-2-octene were formed. The alkenylsilane product was purified by passing the mixture through a silica gel column with hexane followed by removal of the volatiles in vacuo. In another experiment, during which the progress of the reaction was monitored by NMR, 37% conversion occurred in 30 minutes at 23° C. Product distribution at that point was 36% E isomer, 21% Z isomer and 41% octane. The 1H and 13C NMR details of 1-triethylsilyl-2-octene are presented below.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[CH3:22][P:23]([O:26]C)[O:24][CH3:25]>>[CH3:22][P:23]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])(=[O:26])[O:24][CH3:25]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1[N+](=O)[O-]
Reactant: COP(C)OC
Product: COP(C)(=O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 11, 4-(2,4-dichlorophenoxy)-1,2-dinitrobenzene is reacted with dimethyl methylphosphonite to give methyl P-methyl-2-nitro-5-(2,4-dichloro-phenoxy)phenylphosphinate, m/s 376 (M+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH:20]([C:26](=O)[CH2:27][CH3:28])[CH2:21][C:22]([O:24]C)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:27]([CH3:28])=[C:26]2[CH:20]([CH3:19])[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: CCC(=O)C(C)CC(=O)OC
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Product: Cc1c(C(C)CC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-(4-fluorophenyl) hydrazine hydrochloride and methyl 3-methyl-4-oxohexanoate as starting materials, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][NH:15][N:14]=2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[O:36])[N:14]=2)=[CH:25][CH:26]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1ccc(Oc2ccccc2C2=NNCC2c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CC(c2ccc(F)cc2)C(c2ccccc2Oc2ccc(F)cc2)=N1
Temperature: 25 °C

Procedure:
3-[(4-Fluorophenoxy)phenyl]-4-(4-fluorophenyl)-4,5-dihydropyrazole (3 g; 8.6 mmol) was dissolved in dichloromethane (25 ml) and treated with 4-fluorophenyl isocyanate (1.04 g; 7.6 mmol), with stirring at room temperature. After an hour, the reaction mixture was filtered through silica gel, the filtrate was concentrated and treated with diisopropyl ether (50 ml). The precipitated crystals were separated and dried in vacuo (100 Torr).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13](COCC[Si](C)(C)C)[CH:12]=2)[CH:10]=1)[C:6]#[N:7].B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)[CH:10]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(C#N)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 75.6 %

Procedure:
(S)-3-Methoxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (34 mg, 0.05 mmol) was treated with boron tribromide (1M in dichloromethane, 526 μL, 0.53 mmol) in dichloromethane (680 μL) and then with a solution of ammonia (7N in methanol, 680 μl, 4.76 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 19 mg (69% yield) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:22]=[CH:21][CH:20]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)C(=NOC)c1ccccc1Oc1cccc(-c2ccc(Cl)cc2)c1
Yield: 75.9 %

Procedure:
A solution of 13 g of the product from Example 7 in 105 ml of dimethoxyethane was admixed with 9.9 g of 4-chlorophenylboronic acid, 6.7 g of sodium carbonate, 34 ml of water and 200 mg of tetrakis(triphenylphosphine)palladium(0) and refluxed for 3 hours. The mixture was then poured into water and extracted with ethyl acetate, and the extract was washed with 1N aqueous sodium hydroxide solution and then with water and dried. Distillative removal of the solvent and silica gel chromatography (MtBE: cyclohexane=9:1) gave 9.5 g of product as colorless crystals of m.p. 118-121° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:25]=4[O:37][C:38]([F:41])([F:40])[F:39])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:47])=O)(C)(C)C.[ClH:48]>O1CCCC1.O1CCOCC1>[ClH:48].[CH3:36][N:33]1[CH2:32][CH2:31][N:30]([C:28]2[CH:27]=[CH:26][C:25]([O:37][C:38]([F:41])([F:39])[F:40])=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:15]4[N:14]([CH2:42][C:43]([F:45])([F:46])[F:44])[C:11]5[CH2:12][CH2:13][NH:8][C:9](=[O:47])[C:10]=5[CH:16]=4)[CH:22]=[CH:21][N:20]=3)[CH:29]=2)[CH2:35][CH2:34]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3nccc(-c4cc5c(n4CC(F)(F)F)CCN(C(=O)OC(C)(C)C)C5=O)n3)c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3nccc(-c4cc5c(n4CC(F)(F)F)CCNC5=O)n3)c2)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 2-{2-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-pyrimidin-4-yl}-4-oxo-1-(2,2,2-trifluoro-ethyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (25 mg, 0.037 mmol) in tetrahydrofuran (1 mL), 4M HCl in dioxane (0.4 mL) were added. The solution was stirred at room temperature over night. The solvent was evaporated under vacuo to yield 22 mg (98%) of the title compound as a beige powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([OH:19])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[N:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[S:29][C:28]=1[NH2:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:17]([NH:36][C:28]3[S:29][C:30]4[C:35]([N:27]=3)=[CH:34][CH:33]=[CH:32][N:31]=4)=[O:19])=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: Nc1nc2cccnc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cccnc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Yield: 21.6 %

Procedure:
The compound of example A4 was obtained by similar method described in example A2 using 2-(4-morpholinosulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (Preparation 11, 0.1 g, 0.25 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.050 g, 0.31 mmol), HOBt (0.042 g, 0.31 mmol), and EDCl (0.060 g, 0.31 mmol), N-methyl morpholine (0.065 g, 0.64 mmol) in DMF (5 mL) to provide the title compound (0.028 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[NH:16]1[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[N:16]2[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]2)[C:6]1=[O:14]
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Reactant: COC(=O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 90 °C
Yield: 8.4 %

Procedure:
4-Bromo-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (320.0 mg, 1.180 mmol), methyl isonipecotate (1.595 mL, 11.80 mmol), DIPEA (2.056 mL, 11.80 mmol) and DMF (5 mL) were mixed and heated in sealed tube at 90° C. for 3 days. The crude mixture was purified by MDP under basic conditions to obtain the title compound (33 mg, 8.4% yield). MS (ES+): m/z 334.16 (100) [MH+]; HPLC: tR=0.80 min (UPLC, Analytical).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[C:13]([O:16][CH2:17][C:18](=O)[C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:19]([C:18]1[N:14]2[N:15]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:13]2[O:16][CH:17]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)c1coc2c(-c3ccccc3)c(-c3ccc(S(C)(=O)=O)cc3)nn12
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 5-(4-(methylsulphonyl)phenyl)-4-phenyl-3-trimethylacetylmethoxy-pyrazole prepared according to the Example 32B [(100 mg, 0.24 mmol), p-toluenesulfonic acid hydrate (25 mg) in toluene (40 mL), and acetic acid (15 mL) was refluxed using a Dean-Stark trap to remove water, for 12 hours. The reaction mixture was concentrated in vacuo and the residue chromatographed (silica gel, 1:1 hexane/ethyl acetate) to provide the desired product (yield: 97 mg; 99%). MP 187-180° C.; MS (APCI+) m/z 395 (M+H)+; (APCI−) m/z 393 (M−H)−, 429 (M+Cl)−; 1H NMR (300 MHz, DMSO-d6) δ1.49 (s, 9H), 3.25 (s, 3H), 7.35 (m, 5H), 7.76 (d, J=9 Hz, 2H), 7.95 (s+d, J=9 Hz, 3H); Anal. calc. for C22H22N2O3S.0.5 H2O: C, 65.48; H, 5.74; N, 6.94. Found: C, 65.70; H, 5.69; N, 6.65.
Reaction SMILES: C([O-])(=O)C.[K+].[CH3:6][CH:7]([CH3:19])[CH2:8][C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Na].Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C>[CH2:23]([N:30]1[C:9]([CH2:8][CH:7]([CH3:19])[CH3:6])=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)C
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC(C)C)n(Cc2ccccc2)n1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
Potassium acetate (49.1 g, 0.500 mol) was added with stirring to a solution of ethyl 6-methyl-2,4-dioxoheptanoate, sodium salt (44.4 g, 0.200 mol), prepared as described in Part A of Examples 1-4, in acetic acid (280 mL). The solution was cooled to 10° C., and benzylhydrazine dihydrochloride (39.0 g, 0.200 mol) was added in portions over a period often minutes while the reaction temperature was maintained between 10° C. and 13.5° C. The reaction was stirred for 90 minutes at between 6° C. and 13.6° C., allowed to warm to ambient temperature, stirred overnight, and concentrated under reduced pressure. The residue was partitioned between 2 M aqueous sodium carbonate (900 mL) and tert-butyl methyl ether (600 mL). The aqueous layer was extracted with tert-butyl methyl ether (2×300 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 56.6 g of ethyl 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxylate as an oil orange. The product contained 10 mol % of ethyl 2-benzyl-5-(2-methylpropyl)-2H-pyrazole-3-carboxylate.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].CC(C)([O-])C.[K+]>CS(C)=O>[OH:1][C@@H:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C:13](=[O:23])[CH2:14][CH2:15]2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3]
Reactant: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 34.8 g (0.11 mol) of (20R)-20-hydroxy-pregn-4-en-3-one in 300 ml of dimethyl sulphoxide is treated with 18.7 g (0.16 mol) of potassium tert. butoxide and stirred for 4 hours at room temperature under argon. The red-brown mixture is poured on to 1 kg of ice and the product is extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated in a water-jet vacuum. The residue is chromatographed on 1 kg of silica gel with hexane/ether/methylene chloride (7:2:1) and gives 7.3 g (21%) of uniform, crystalline (20R)-20-hydroxy-pregn-5-en-3-one. The analytical sample is obtained by recrystallisation from ethanol/methylene chloride; melting point 171°-175° C.; [α]D25 =-33.2° (c=0.5 in chloroform).
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:45])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=3[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]2)[CH:12]=1>>[CH2:41]([C:15]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:22][C:21]=2[F:40])[C:17](=[O:18])[N:13]([C:11]2[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=2[Cl:45])[N:14]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 84 %

Procedure:
Propionyl bromide was reacted with 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) according to the procedure of Example 26. Flash chromatography of the crude product on silica gel (gradient elution with 3:1 to 1:1 hexane-EtOAc) gave an 84% yield of the title compound as a white solid, mp 103°-105° C.; homogeneous by TLC (1:1 hexane-EtOAc); mass spectrum (FAB) m/e 648 (M+Li)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)c1cc(O)ccc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-isopropylphenol (880.0 mg, 4.09 mmols) and imidazole (417.0 mg, 6.13 mmols) in 10 mL DMF was added chloro-triisopropylsilane (946.0 mg, 4.90 mmols). After stirring overnight at room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 1.30 g (92%), was isolated by column chromatography (1-2% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@:3]1([CH3:27])[C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH:15]=[CH:16][C:17]=1[F:18].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:38])[NH:4][C@:3]1([CH3:27])[C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cc(F)cc(F)c3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cc(F)cc(F)c3)ccc2F)C1(F)F
Yield: 107.2 %

Procedure:
The reaction of (R)-6,6-difluoro-5,7,7-trimethyl-5-(4,3′,5′-trifluoro-biphenyl-3-yl)-[1,4]oxazepan-3-one (159 mg, 398 μmol) with Lawesson's reagent (131 mg, 319 μmol) in 1,4-dioxane (13 ml) yielded the (R)-6,6-difluoro-5,7,7-trimethyl-5-(4,3′,5′-trifluoro-biphenyl-3-yl)-[1,4]oxazepan-3-thione (142 mg, 86% yield) as a white foam. MS (ISP): m/z=416.2 [M+H]+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)[C:13]([CH3:22])([CH3:21])[CH2:14][O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1.Cl>ClCCl>[CH3:21][C:13]([CH3:22])([CH2:14][O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1)[CH2:12][OH:11]
Reactant: COC(=O)C(C)(C)COC1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CO)COC1CCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
DIBAL (1.74 mL of a 1.0 M solution in hexanes) was added dropwise to a solution of 2,2-dimethyl-3-(tetrahydro-furan-3-yloxy)-propionic acid methyl ester (353 mg, 1.74 mmol) in dichloromethane (9.0 mL) at −78° C. After 2 h at this temperature, an additional equivalent of DIBAL was added and after 1 h the reaction was warmed to 0° C. After an additional 1 h at 0° C., 1.0 N HCl was added dropwise to quench the reaction. The reaction was warmed to room temperature and partitioned between dichloromethane and brine. The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated to give an oil. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes provided 2,2-dimethyl-3-(tetrahydro-furan-3-yloxy)-propan-1-ol (250 mg, 82%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:18])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(Trifluoromethyl)phenyl]acetic acid (4.1 g, 20.1 mmol) was dissolved in tetrahydrofuran (20 mL), and oxalyl chloride (2.1 mL, 24.5 mmol) and N,N-dimethylformamide (5 μL) were added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give [3-(trifluoromethyl)phenyl]acetyl chloride. To a solution of 3-amino-4-fluorophenol (2.43 g, 19.1 mmol) in tetrahydrofuran (20 mL) was added a suspension of sodium hydrogen carbonate (2.41 g, 28.6 mmol) in water (30 mL), and the mixture was vigorously stirred at room temperature. A solution of [3-(trifluoromethyl)phenyl]acetyl chloride produced above in tetrahydrofuran (10 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 min. Ethyl acetate (100 mL) was added to the reaction mixture to separate the aqueous layer. The organic layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the obtained solution was purified by silica gel chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (5.84 g, 98%) as a pale-brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30]N1C(=O)CCC1=O>ClCCl>[Cl:30][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCCCc1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCCc1ccncc1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
3-(4-Pyridyl)-1-propanol (2.68 g, 19.3724 mmol) was dissolved in dichloromethane (100 ml), triphenylphosphine (5.6 g. 21.3096 mmol) was added, and then N-chlorosuccinimide (2.6 g, 19.3724 mmol) was gradually added while cooling on ice prior to stirring overnight. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and extracted with 1N hydrochloric acid. Upon neutralization with saturated sodium bicarnobate water, the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2,375 g, 15.2605 mmol, 78.77%) as a yellowish-brown oil. This was used without further purification for the following reaction.