Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][NH:4][C:3]1=[O:7].[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH2:17][N:4]1[C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][O:5]1
Reactant: CC1(C)CONC1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC1(C)CON(Cc2ccc(F)cc2Cl)C1=O
Yield: 30.3 %

Procedure:
A solution of 0.52 grams (0.005 mole) of 4,4-dimethyl-3-isoxazolidinone, 1.0 gram (0.005 mole) of (2-chloro-4-fluorophenyl)methyl bromide and 0.62 gram (0.005 mole) of potassium carbonate in 40 ml of dimethylformamide was stirred at ambient temperature for 18 hours. The dimethylformamide was removed under high vacuum with mild heat. The residue was extracted with methylene chloride. The extract was filtered and dried with sodium sulfate. The mixture was refiltered and the filtrate concentrated under reduced pressure to give an oil residue. The residue was slurried in warm hexane and a solid was removed by filtration. The filtrate was concentrated under reduced pressure to give 0.39 gram of 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C@H:27]([OH:32])[C@@H:28]([OH:31])[CH2:29][OH:30]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][CH2:26][C@H:27]([OH:32])[C@@H:28]([OH:31])[CH2:29][OH:30])=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1
Reactant: NC[C@H](O)[C@@H](O)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NC[C@H](O)[C@@H](O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (2S,3S)-4-amino-1,2,3-butantriol (CAS registry number: 168113-19-7) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(O[C@@H:23]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]1[O:25][C:26](=[O:28])[CH3:27])(=O)C>ClCCl.C1(C)C=CC=CC=1>[C:26]([O:25][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:23]1[O:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a suspension of methyl 4-(2-hydroxybenzyl)benzoate (0.053 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.26 g) in dichloromethane (1 mL) and toluene (3 mL) was added boron trifluoride diethyl ether complex (0.083 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give 2-(4-methoxycarbonyl-benzyl)phenyl 2,3,4,6-tetra-O-acetyl-βD-glucopyranoside (0.067 g).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][CH:33]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23](=[O:30])OCC(Cl)(Cl)Cl)[N:21]=2)[N:18]=1)=[O:7].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(C(C)C)C(C)C)(C)C>CS(C)=O>[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:23]([NH:22][C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([O:12][C:11]4[CH:31]=[CH:32][CH:33]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:34]=[CH:35][CH:36]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:4]=5)[CH:10]=4)=[N:18][N:17]3[CH:19]=2)=[O:30])[CH2:42][CH2:41]1
Reactant: O=C(Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1)OCC(Cl)(Cl)Cl
Reactant: CN1CCNCC1
Agent: CC(C)N(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN1CCN(C(=O)Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C(F)(F)F)c5)c4)ccc3n2)CC1
Yield: 50.8 %

Procedure:
Using 2,2,2-trichloroethyl [6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (140 mg, 0.237 mmol), 1-methylpiperazine (40 μL, 0.356 mmol), N,N-diisopropylpropan-2-amine (123 μL, 0.713 mmol) and dimethyl sulfoxide (10 mL) as starting materials and in the same manner as in Example 386, the title compound (65 mg, 50%) was obtained as a pale-yellow powder.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[Na].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>CCOCC.CCOC(C)=O>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([C:15](=[O:16])[CH3:17])[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: [Na]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(C)=O)C(C[N+](=O)[O-])c1ccccc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a solution of (2-nitro-vinyl)-benzene (2.135 g, 14.3 mmol) in ether (30 mL) at 0° C. was added ethyl acetoacetate sodium salt (2.29 g, 14.3 mmol) portionwise in half minute; after addition, the mixture was stirred at that temperature for 1 hour; then it was diluted with EtOAc, washed with diluted hydrochloride aqueous solution and saturated sodium chloride aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, oil-pumped to dryness to give a brown oil, the crude titled product (4.266 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=7.4-7.2 (m, 5H), 4.73 (d, 1H, J=5.9 Hz), 4.2-3.9 (m, 4H), 2.30 (s, 3H), 1.01 (m, 3H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>ClC1C=CC=CC=1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Clc1ccccc1
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 6 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in chlorobenzene (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in chlorobenzene was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 6 hours. Then water was added to the liquid reaction mixture followed by extraction with ethylacetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 162.9 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)=[O:23].CC(C)([O-])C.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][C@@H:13]([C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[CH3:14])[CH2:17]2)=[CH:26][CH:25]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 2 ml of toluene were suspended 200 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride, 127 mg of 4-bromoacetophenone, 214 mg of sodium tert-butoxide, and 76 mg of biphenyl-2-yl-di-tert-butylphosphane, and nitrogen gas was ventilated for 15 minutes. After adding 59 mg of tris(dibenzylideneacetone) dipalladium to the mixture, the reaction vessel was sealed and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was separated and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain (S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine. (2) In 2 ml of tetrahydrofuran was dissolved (S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine obtained in the above-mentioned (1), and 0.2 ml of a solution of 4M hydrochloric acid-dioxane was added to the mixture. The precipitated solids were collected by filtration, washed with ether and dried to obtain 90 mg of (S)-1-(4-acetylphenyl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine hydrochloride (the following Table A1, Example 1.082).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[Cl:17][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:23][CH:24]=3)[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 120 °C
Yield: 74.3 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.100 g, 0.38 mmol) and (4-aminophenyl)acetamide (0.113 g, 0.75 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, diluted with water (50 mL) affording a solid. The solid was isolated by filtration and purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.107 g, 78%) as a white solid. MW=378.85. M.p. 174-176° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.51 (s, 1H), 8.27-8.22 (m, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.57-7.52 (m, 2H), 7.43 (br s, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.85 (br s, 1H), 6.63 (s, 1H), 3.35 (s, 2H), 2.07-2.00 (m, 1H), 1.12-1.06 (m, 2H), 1.03-0.95 (m, 2H); ESI MS m/z 379 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:28][C@H:23]1[O:24][C@@H:25]([CH3:27])[CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[S:11][C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][CH:6]=4)=[N:14][N:13]=3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(-c3nnc(-c4ccc(C(=O)O)cc4)s3)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A mixture of 4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester (527 mg) and 1.0 mol/l sodium hydroxide solution (2.6 ml) in a mixed solvent of methanol (10 ml) and tetrahydrofuran (25 ml) was refluxed for 6 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water and the mixture was adjusted with 1.0 mol/l hydrochloric acid. The resulting precipitates were filtered, washed with water and dried to give 4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoic acid (429.1 mg).
Reaction SMILES: C([NH:8][C@H:9]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][N:12]([C:17](=[O:19])[CH3:18])[CH2:11][CH2:10]1)C1C=CC=CC=1.Cl>[Pd].CCOC(C)=O>[NH2:8][C@H:9]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][N:12]([C:17](=[O:19])[CH3:18])[CH2:11][CH2:10]1
Reactant: CC(=O)N1CC[C@H](C)[C@H](NCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CC[C@@H](N)[C@@H](C)CC1

Procedure:
Racemic cis 1-(4-amino-5-methyl-azepan-1-yl)-ethanone was prepared in the same manner from racemic cis 1-(4-benzylamino-5-methyl-azepan-1-yl)-ethanone. In this instance, 1 atm H2 was used instead of 55 psi, Pd/C was used instead of Pd(OH)2/C, EtOAc was used instead of EtOH, and the HCl treatment was omitted.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[F:11][C:12]([F:33])([F:32])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([N+]([O-])=O)[CH:21]=2)=[N:17][CH:18]=1>C1(C)C=CC=CC=1>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:33])([F:11])[F:32])=[CH:18][N:17]=2)=[CH:25][C:24]=1[NH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])([O-:28])=[O:27]
Reactant: CCOP(=O)(CN)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOP(=O)(CNc1cc(Oc2ccc(C(F)(F)F)cn2)ccc1[N+](=O)[O-])OCC

Procedure:
With stirring, 7.6 g (0.045 mole) of diethyl aminomethylphosphonate are added dropwise to a solution of 15 g (0.045 mole) of (5-trifluoromethyl-2-pyridyloxy)-3,4-dinitrobenzene in 50 ml of toluene, and the mixture is heated for 12 hours to reflux. The mixture is then concentrated and the residue is chromatographed over silica gel with a 1:4 mixture of hexane/ethyl acetate, affording 9.8 g (48.7% of theory) of the title compound with a melting point of 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:23](OC)=[O:24])[CH:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([CH2:23][OH:24])[CH:12]([CH2:18][C:19]([F:20])([F:22])[F:21])[CH2:13][C:14]([F:16])([F:15])[F:17])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Cl)s1)C(CC(F)(F)F)CC(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C(CC(F)(F)F)CC(F)(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 0.2 %

Procedure:
To a solution of methyl N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvalinate (0.5 g, 1.11 mmol) in THF (10 mL) was added LiBH4 (2.28 mL, 4.46 mmol) under N2 atmosphere at 0° C. The reaction was allowed to warm to 25° C. for 19 h. The reaction was cooled to 0° C. and quenched with 2N HCl (slow addition), diluted in ether (40 mL) and the organic layer washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (0.362 g). The crude product was purified by the Biotage Flash™ 12 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 5-chloro-N-[4,4,4-trifluoro-1-(hydroxymethyl)-2-(2,2,2-trifluoroethyl)butyl]thiophene-2-sulfonamide as a colorless oil (0.001 g, 2.36%). Mass Spectrum (−ESI): 418 (M−H)−.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[Cl:6][CH2:7][C:8](=[O:32])[C@:9]1([OH:31])[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[C@@H:15]([F:29])[CH2:14]3)[CH2:11][C@@H:10]1[CH3:30].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[Cl:6][CH2:7][C:8](=[O:32])[C@:9]1([OH:31])[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[C@@H:15]([F:29])[CH2:14]3)[CH2:11][C@@H:10]1[CH3:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(=O)CCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCC(=O)O
Solvent: C1COCCO1
Product: C[C@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
Analogously to Example 12, 200 mg of 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregn-4-ene-3,20-dione propionate (see Example 10) are treated with 250 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 8 ml of dioxan and further processed to yield 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione propionate; melting point 216°-219° C. (from methylene chloride/ether).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[Br:20]Br>Br.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][C:3]1([Br:20])[CH2:18][CH3:19]
Reactant: CCC1Cc2cc(OCC(=O)O)c(C)c(C)c2C1=O
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CCC1(Br)Cc2cc(OCC(=O)O)c(C)c(C)c2C1=O

Procedure:
By following substantially the same procedure as described in Example 1, Step B, using as the reactants (1-oxo-2-ethyl-6,7-dimethyl-5indanyloxy)acetic acid (10.5 g., 0.04 mole), bromine (6.4 g., 0.04 mole), acetic acid (125 ml.) and 48% aqueous hydrobromic acid (2 drops), there is obtained 8.6 g. (63%) of (1oxo-2bromo-2-ethyl-6,7-dimethyl-5-indanyloxy)acetic acid which melts at 136°-139° C. after recrystallization from butyl chloride (200 ml.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1.[CH3:16][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:12])[CH3:16])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:14][CH2:15]3)[N:7]=2)[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Cl)cc2cn(C3CC3)nc12
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C

Procedure:
To a solution of 5-chloro-2-cyclopropyl-2H-indazole-7-carbaldehyde (0.30 g, 1.35 mmol) in tetrahydrofuran (5 mL) at −78° C. was added methyl magnesiumbromide (3 M in diethyl ether, 0.68 mL, 2.03 mmol). The reaction was allowed to gradually warm in the ice bath (ca. 1 h) to 0° C. The reaction which had been a suspension became a solution. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over sodium sulfate, and concentrated to give 240 mg (77%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 7.90 (s, 1H), 7.45 (m, 1H), 7.09 (m, 1H), 5.27 (q, J=6.6 Hz, 1H), 3.85-3.93 (m, 1H), 1.65 (d, J=6.6 Hz, 1H), 1.28-1.34 (m, 2H), 1.10-1.17 (m, 2H). Mass spec.: 237.28 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[CH2:15][CH2:14]4)=[CH:9][N:8]([CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.O1CCOCC1>CN(C=O)C.CO.C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[CH2:15][CH2:14]4)=[CH:9]2)[CH2:33]1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)ccc32)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CNC5)c5ncnc(N)c45)ccc32)c1
Temperature: 50 °C
Yield: 63.9 %

Procedure:
To 1,1-dimethylethyl 3-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (198 mg, 0.368 mmol) was added 4N HCl in dioxane (4 mL, 16.00 mmol). The starting material was oiling out of solution and even heating to 50 degrees C. overnight did not effect conversion. The reaction was then concentrated and DCM (4 mL) and TFA (2 ml) was added. The SM dissolved into solution and after 1 hr the reaction was complete. The reaction was concentrated then diluted with EtOAc (20 mL) and then washed with Sat. Na2CO3. A precipitate cashed out of solution and the mixture was extracted with a mixture of 20% isoproyl alcohol in DCM (3×50 ml). The organics were pooled and dried over Na2SO4, filtered and concentrated to give a yellow oil. The oil was dissolved in 1 ml of DMF and then loaded on to a 10 g Biotage column with 0 to 100% DCM in 95:5:1 mixture of DCM:MeOH:1NH4OH for 15 min then 100% 95:5:1 mixture of DCM:MeOH:1NH4OH for 15 minutes to isolate 7-(3-azetidinyl)-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (103 mg, 0.235 mmol, 63.9% yield) as a clear oil. LC-MS (ES) m/z=439.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=8.34 Hz, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 7.36 (s, 1H), 7.25-7.30 (m, 1H), 7.23 (d, J=7.33 Hz, 1H), 7.06-7.14 (m, 3H), 6.09 (br. s., 2H), 5.50 (t, J=7.45 Hz, 1H), 4.22 (t, J=8.34 Hz, 2H), 3.91-3.96 (m, 2H), 3.78-3.85 (m, 4H), 3.18-3.25 (m, 2H), 2.31 (s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18]C(=O)C)[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@H:6]1[S:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([S:61][C@@H:62]3[O:99][C@H:98]([CH2:100][O:101]C(=O)C)[C@@H:73]([O:74][C@H:75]4[O:92][C@H:91]([CH2:93][O:94]C(=O)C)[C@@H:86]([O:87]C(=O)C)[C@H:81]([O:82]C(=O)C)[C@H:76]4[O:77]C(=O)C)[C@H:68]([O:69]C(=O)C)[C@H:63]3[O:64]C(=O)C)=[CH:57][CH:56]=2)=[O:53])=[CH:47][CH:46]=1)(=O)C.N>CO>[C@H:75]1([O:74][C@@H:73]2[C@@H:98]([CH2:100][OH:101])[O:99][C@@H:62]([S:61][C:58]3[CH:57]=[CH:56][C:55]([NH:54][C:52]([NH:51][C:48]4[CH:47]=[CH:46][C:45]([S:44][C@@H:6]5[O:7][C@H:8]([CH2:39][OH:40])[C@@H:9]([O:15][C@H:16]6[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]([OH:23])[C@H:17]6[OH:18])[C@H:10]([OH:11])[C@H:5]5[OH:4])=[CH:50][CH:49]=4)=[O:53])=[CH:60][CH:59]=3)[C@H:63]([OH:64])[C@H:68]2[OH:69])[O:92][C@H:91]([CH2:93][OH:94])[C@@H:86]([OH:87])[C@H:81]([OH:82])[C@H:76]1[OH:77]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(NC(=O)Nc3ccc(S[C@@H]4O[C@H](COC(C)=O)[C@@H](O[C@H]5O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=C(Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reaction time: 6 h
Yield: 108 %

Procedure:
A mixture of 17.3 g of N,N'-bis[4-[[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-glucopyranosyl]thio]phenyl]urea in 500 ml of methanol saturated with ammonia was stirred in an ice bath for 6 hours and then refrigerated overnight. The mixture was filtered through a sintered glass funnel and concentrated in vacuo to a foam. The foam was triturated with ethanol, filtered, washed with ethanol then ether and dried, giving 11.42 g of the desired intermediate.