Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][O:15]3)=[CH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].Cl.O>CS(C)=O>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[CH:10][C:11]([CH:14]([OH:15])[CH2:16][NH:20][CH2:17][CH2:18][CH3:19])=[CH:12][CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Reactant: CCCN
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCNCC(O)c1ccc(-n2c(C)ccc2C)nc1
Temperature: 40 °C
Yield: 100 %

Procedure:
To the epoxide from example 40 (900 mg, 4.2 mmol) in DMSO (5 ml) was added propylamine (4 ml, 4.8 mmol) and the reaction mixture was heated to 40° C. for 4 days. The reaction mixture was then cooled and 3M HCl (aq) (10 ml) and water (10 ml) were added before washing with diethyl ether (2×10 ml). This organic layer was discarded. The aqueous layer was basified with NH4OH (5 ml) and extracted with ethyl acetate (3×10 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an oil (1.15 g, 4.2 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.93 (t, 3H), 1.62 (m, 2H), 2.11 (s, 6H), 2.69-2.82 (m, 3H), 3.06 (dd, 1H), 3.60 (bs, 2H), 4.92 (dd, 1H), 5.84 (s, 2H), 7.20 (d, 1H), 7.88 (d, 1H), 8.61 (s, 1H). LRMS: m/z 274 (M−H+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-])=O)[CH3:2]>[Pt].C(OCC)(=O)C>[CH2:23]([O:22][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19])[CH3:24]
Reactant: CCOC(CCCNc1c([N+](=O)[O-])cnc2cccnc12)OCC
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(CCCNc1c(N)cnc2cccnc12)OCC

Procedure:
Catalyst (0.78 g of 5% platinum on carbon) was added to a suspension of (4,4-diethoxybutyl)(3-nitro[1,5]naphthyridin-4-yl)amine (7.8 g, 23.3 mmol) in ethyl acetate (100 mL). The mixture was placed under hydrogen pressure ((30 psi (2.1×105 Pa)) for 2 hours. The reaction mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure to provide N4-(4,4-diethoxybutyl)[1,5]naphthyridine-3,4-diamine as a thick yellow oil which was carried on to the next without further purification.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:22](=[O:42])[CH:23]([N:25]2[CH2:30][CH2:29][C:28]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)([OH:31])[CH2:27][CH2:26]2)[CH3:24])[CH:7]=[C:8]([CH3:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([C@@H:22]([OH:42])[C@H:23]([N:25]2[CH2:26][CH2:27][C:28]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)([OH:31])[CH2:29][CH2:30]2)[CH3:24])[CH:7]=[C:8]([CH3:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:16])[CH3:17])[CH:12]([CH3:13])[CH3:14]
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 31.3 %

Procedure:
A mixture of sodium borohydride (0.090 g, 2.38 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3,5-dimethyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (1.30 g, 2.25 mmol in 25 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white solid which precipitated was collected by filtration and dried to yield 0.408 g (31%) of (1R*,2R*)-1-(3,5-dimethyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 177-177.5° C. Analysis calculated for C32H48F3NO3Si.0.25 H2O: C, 65.78; H, 8.37; N, 2.40. Found: C, 65.65; H, 8.51; N, 2.57.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[CH:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([OH:25])[CH:17]=1>ClC1C=CC=CC=1>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=[C:6]2[C:11]=1[C:2]([O:25][C:18]1[CH:17]=[CH:16][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)=[CH:3][CH:4]=[N:5]2
Reactant: COc1cc(OC)c2c(Cl)ccnc2c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Clc1ccccc1
Product: COc1cc(OC)c2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chloro-5,7-dimethoxyquinoline (100 mg, 0.40 mmol) and p-nitrophenol (124 mg, 0.89 mmol) in chlorobenzene (2 mL) was heated at reflux for 14 h. Then the reaction mixture was cooled to rt, filtered, and the residue washed with toluene. The solid was suspended in 10% NaOH solution and stirred for 1 h at rt. The yellow solid was collected and washed with EtOAc to give 5,7-dimethoxy-4-(4-nitrophenoxyl)quinoline. LCMS m/z=327 (M+1); 1H NMR (CDCl3) δ: 8.60 (d, 1H, J=6.0 Hz), 8.44 (d, 2, J=8.8 Hz), 7.72 (s, 1H), 7.35 (d, 2H, J=8.4 Hz) 6.71 (s, 1H), 6.69 (d, 2H, J=6.4 Hz), 4.08 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=3)[C:32]2=[O:46])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:43])([CH3:42])[CH3:44])[CH:37]=3)[C:32]2=[O:46])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)[nH]n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 35 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 118a (142 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (310 mg, 0.75 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 121a as a brown solid (100 mg, 35%). MS-ESI: [M+H]+ 572.3
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:15](=[O:16])[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[O:9][C:10]([F:11])([F:12])[F:13])=[CH:19][CH:20]=2)=[N:26][CH:27]=1
Reactant: CNc1ccccc1OC(F)(F)F
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1OC(F)(F)F

Procedure:
The title product was prepared from N-methyl-2-(trifluoromethoxy)-aniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative H PLC (method C) (49%, colourless oil). HPLC-MS m/z=473.2 (M+1), Rt: 5.18 min.
Reaction SMILES: C(N1C=CN=C1)(N1[CH:7]=[CH:6]N=C1)=O.[CH:13]1([CH:18]([CH3:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14]1.CC[O-].[Na+].C(O)C>C1COCC1.[Na]>[CH:13]1([CH:18]([CH3:24])[CH2:19][CH2:20][C:21]([O:23][CH2:6][CH3:7])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(CCC(=O)O)C1CCCC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C)C1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48313.4 %

Procedure:
1,1′-Carbonyldiimidazole (101 g; 0.62 mmol) was added portionwise to 4-cyclopentylpentanoic acid (100 g; 0.58 mol) in THF (500 ml). After the gas evolution ceased, the reaction mixture was reacted with sodium ethylate solution prepared from sodium (0.3 g; 13 mmol) and ethanol (500 ml), stirred at room temperature for 2.5 hours, and the solvent evaporated in vacuo. The residue was dissolved in ether (300 ml), washed successively with water (300 ml), 1 N NaOH (300 ml), and 1 N HCl (300 ml), dried (MgSO4), concentrated in vacuo, and distilled over a 10 cm Vigreux column (66° C./0.08 torr) to give 59.4 g (52% yield) of ethyl 4-cyclopentylpentanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)=[O:25])[C:18](=O)[CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)([CH3:6])[CH3:5].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:38])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)[O:25][C:18]=2[CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: CCCC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OC)cc1)NC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)OC)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
A sample of 2-(4-{3-[(biphenyl-4-carbonyl)-amino]-4-oxo-heptyloxy}-phenoxy)-2-methyl-propionic acid methyl ester (514 mg, 0.99 mmol) was dissolved in 6 mL of dry DMF followed by addition of phosphorus oxychloride (0.28 mL, 2.88 mmol, 3 equiv.). The mixture was heated at 90° C. for 20 minutes under a nitrogen atmosphere. The reaction mixture was then allowed to cool to room temperature followed by addition of cold water (10 mL) and additional stirring for 10 minutes. Sufficient 1.0 N NaOH was then added to achieve neutral pH. The mixture was partitioned between ethyl ether (100 mL) and water (50 mL). The aqueous layer was back-extracted with ethyl ether (100 mL) and the organic phases combined, which were then washed with 5% aq LiCl, dried over NaCl, and concentrated in vacuo to yield an oil which was immediately subjected to silica gel chromatography (ethyl acetate/hexanes) to yield 484 mg (98%) of an oil. HPLC RT1=12.70 min; 1H NMR (400 MHz, CDCl3) δ8.02 (d, J=8.3 Hz, 2H), 7.64-7.58 (m, 4H), 7.43-7.33 (m, 3H), 6.78-6.72 (m, 4H), 4.17 (t, J=6.3 Hz, 2H), 3.73 (s, 3H), 2.94 (t, J=6.3 Hz, 2H), 2.66 (t, J=7.3 Hz, 2H), 1.73-1.67 (m, 2H), 1.48 (s, 6H), 0.97 (t, J=7.3 Hz, 3H); MS (EI) 500.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].C1COCC1.O.[OH-].[Li+].Cl>O>[C:20]([CH2:19][O:18][C:6]1[C:7]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:8]=2[S:9][C:5]=1[C:3]([OH:4])=[O:2])([OH:22])=[O:21]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc1ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1c(C(=O)O)sc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25 mL round bottom flask added 3-ethoxycarbonylmethoxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester (0.116 g, 0.34 mmol) and 5 mL THF. To this mixture added a solution of lithium hydroxide hydrate (0.057 g, 1.35 mmol) in 3 mL water. This mixture was allowed to stir at room temperature for 16 hours. At this time 15 mL 1.2 N HCl was added, and a precipitate formed. The solids were collected by filtration and dried in vacuo. 3-carboxymethoxy-naphtho[1,2-b]thiophene-2-carboxylic acid was isolated as a tan solid (0.096 g, 93%). 1H NMR (400 MHz, DMSO-D6) δ ppm 5.06 (s, 2H) 7.69 (m, 2H) 7.91 (d, J=8.84 Hz, 1H) 7.95 (m, 1H) 8.08 (m, 1 H) 8.19 (t, J=4.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[CH3:23])[C:16](=[O:24])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:33]([N:15]1[CH2:14][C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH3:23])[C:16]1=[O:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc2c1C1(CCN(C(=O)OC(C)(C)C)CC1)CNC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc2c1C1(CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)C2=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
1′-(tert-Butoxycarbonyl)-2,3-dihydro-5-methylspiro[isoquinoline-4(1H),4′-piperidin]-1-one (80.7 mg) was dissolved in toluene (1.6 ml), added with sodium hydroxide (powder, 34.2 mg), potassium carbonate (67.4 mg), tetrabutylammonium hydrogensulfate (8.3 mg) and benzyl bromide (44 μl) and stirred at 70° C. for 3 hours. The reaction mixture was added with water (2 ml) and extracted twice with dichloromethane (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:5) to obtain 86 mg of the title compound. Yield: 84%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27]C(=O)C)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[OH:27])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Yield: 79 %

Procedure:
The reaction and workup procedures of Example 164 were repeated except that 100 mg of 20-(1,3-dioxolan-2 -yl)-1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 72 mg of 20-(1,3-dioxolan-2-yl)-3β-(methoxymethyl)oxypregna-5,7-dien-1α-ol showing the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C([BH3-])#N.[Na+].[CH3:33][C:34]([CH2:36][OH:37])=O.C(O)(=O)C>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH:34]([CH3:33])[CH2:36][OH:37])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: CC(=O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (40 mg, 0.10 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride (16 mg, 0.25 mmol) followed by acetol (28 μL, 0.40 mmol) and stirred at room temperature for 1 h. The reaction mixture was quenched with acetic acid (100 μL, 1.8 mmol), diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired products as a mixture of diastereoisomers. This mixture of diastereoisomers was separated by chiral HPLC (RT=3.70 min and 6.58 min; Phenomenex Lux Cellulose C-4 column, 21.2×250 mm, 5 micron particle size, eluting with 20% ethanol in hexanes at 18 ml/min, 5 mg/inj) to give the desired peak 1 isomer (compound 272) (19 mg, 41%) and peak 2 isomer (compound 273) (23 mg, 50%) Peak 1: 1H NMR (300 MHz, DMSO-d5) δ 8.11 (s, 1H), 7.47 (s, 1H), 7.34 (br s, 2H), 6.24 (q, J=6.9 Hz, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.07-3.82 (m, 3H), 3.64 (s, 3H), 3.31-3.24 (m, 1H), 3.17-3.06 (m, 2H), 3.06-2.97 (m, 1H), 2.55 (s, 3H), 2.21-2.11 (m, 1H), 1.72 (d, J=7.1 Hz, 3H), 0.81 (d, J=6.3 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.2. Peak 2: 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.47 (s, 1H), 7.35 (br s, 2H), 6.24 (q, J=7.0 Hz, 1H), 4.43 (t, J=5.5 Hz, 1H), 4.06-3.91 (m, 2H), 3.89-3.79 (m, 1H), 3.64 (s, 3H), 3.30-3.24 (m, 1H), 3.15-3.00 (m, 3H), 2.55 (s, 3H), 2.21-2.10 (m, 1H), 1.72 (d, J=7.1 Hz, 3H), 0.82 (d, J=6.2 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.2.
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([CH:35]3[CH2:37][CH2:36]3)[O:33][CH:34]=2)=[CH:26][CH:25]=1)[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].C(N(CC)CC)C.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](Cl)=O>C1(C)C=CC=CC=1>[CH:35]1([C:32]2[O:33][CH:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:5]([C:2]4[N:1]=[C:50]([C:49]5[CH:53]=[CH:54][CH:55]=[C:47]([C:46]([F:45])([F:56])[F:57])[CH:48]=5)[O:4][N:3]=4)[CH2:6][CH2:7][C:8]4[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=4)=[CH:29][CH:28]=3)[N:31]=2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)/C(N)=N/O)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)c2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a cooled solution of ethyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.108 g, 0.21 mmol) in toluene (2 ml) was added triethylamine (0.028 mL, 0.20 mmol) dropwise. After 5 min, 3-(trifluoromethyl)benzoyl chloride (0.031 ml, 0.20 mmol) in toluene (0.1 ml) was added dropwise. The mixture was allowed to warm to rt over 2 h and then heated to 110C for 2 hr. Upon cooling, the mixture was filtered, and the solid was washed with EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was partitioned between EtOAc and a solution of 0.5N aqueous HCl. The organic phase was washed with 0.5N aqueous HCl (1×), 0.5N aqueous NaOH (2×), and brine (1×), dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexanes, 10:90 to 20:80) to yield ethyl 2-{4-[2-([4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoate (76 mg, 58%).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:8][C:9]([O:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23]Br)=[N:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C(O)C>[C:4]([O:8][C:9]([O:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23][C:1]#[N:2])=[N:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc2c(CBr)nn(OC(=O)OC(C)(C)C)c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(CC#N)nn(OC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
KCN (5.73 g, 88 mmol) in 23 ml of H2O was added dropwise at 0° C. to 1-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-bromomethyl-1H-indazole (10.5 g, 30.08 mmol) in 80 ml of ethanol and stirred at room temperature for 1 h 30. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4. Concentration and precipitation in diisopropyl ether gave the expected product (4.42 g, 50% as solid).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([CH3:18])[N:8]=1>C(N(CC)CC)C>[Cl:3][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([CH3:18])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(C)nc1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C)nc1Cl
Temperature: 40 °C
Yield: 53 %

Procedure:
In cold (˜0° C.) phosphorous oxychloride (40 mL) was carefully added triethylamine (1.87 mL) with stirring. To this was added, in parts, ethyl 4-hydroxy-2-methylpyrimidine-5-carboxylate (5.00 g, 27.4 mmol). The mixture then warmed to 40° C. and stirred under Argon for 2 hours. The mixture was evaporated free of phosphorous oxychloride, diluted with chloroform (150 mL) and poured carefully into ice (400 mL) and allowed to warm to RT. The organic phase was separated, washed with saturated sodium bicarbonate (75 mL), then brine (100 mL) and dried over sodium sulfate. The solvents evaporated to give a thick oil which was purified by chromatography (Biotage Si-40 column, 15-40% ethyl acetate/hexane) to give ethyl 4-chloro-2-methylpyrimidine-5-carboxylate as a clear oil (2.96 g, 53% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3 H), 2.66 (s, 3 H), 4.34 (q, 2 H), 9.06 (s, 1 H); MS (ESI) m/z: 201.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(Cl)cc(N=Cc2cccc(Br)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-7-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.