Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Si:18]([O:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[C:32](OCC)=[O:33])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:18]([O:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[CH:32]=[O:33])([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ncsc1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1scnc1C=O
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A 1.0 M diisobutylaluminum hydride/toluene solution (2.4 ml) was added dropwise to a solution of 578 mg of 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole in 10 ml of toluene under an argon atmosphere at −60° C. The mixture was stirred at the same temperature for 2 hr, water and ethyl acetate were added thereto and the mixture was adjusted to pH 5.5 by the addition of 1 N aqueous hydrochloric acid. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to ethyl acetate only) to give 308 mg of 5-t-butyldimethylsilyloxymethyl-4-formylthiazole.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]1.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O.O>CN(C=O)C>[F:28][C:27]([F:30])([F:29])[CH2:26][N:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1c[nH]c2c1CCc1cnccc1-2
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of methyl 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylate E1 (0.44 mmol) in dry DMF (5 mL) NaH (0.52 mmol) was added. The reaction mixture was stirred at rt for 2 h. After cooling to 0° C., trifluoroethyl triflate (0.52 mmol) in DMF (5 mL) was added dropwise. The mixture was maintained at rt overnight and then poured into icy water and extracted with DCM. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (eluant: DCM/acetone 9:1) afforded the title compound (65% yield). ESI (+) MS: m/z 311 (MH+). 1H NMR: 2.82 (t, J=7.70, 2H), 2.92 (t, J=7.70, 2H), 3.76 (s, 3H), 5.41 (q, J=8.90, 2H), 7.56 (d, J=5.24, 1H), 7.75 (s, 1H), 8.41 (d, J=5.24, 1H), 8.44 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].NC1C=C(C)C(O)=C(C)C=1.C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[Cl:49][C:50]1[N:55]=[C:54](Cl)[C:53]([F:57])=[CH:52][N:51]=1>>[Cl:49][C:50]1[N:55]=[C:54]([NH:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([OH:12])=[C:4]([CH3:11])[CH:5]=2)[C:53]([F:57])=[CH:52][N:51]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cc1cc(N)cc(C)c1O
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Cc1cc(Nc2nc(Cl)ncc2F)cc(C)c1O

Procedure:
Using general hydrogenation conditions, 2,6-dimethyl-4-nitrophenol was reduced to 4-amino-2,6-dimethylphenol. In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine. Compound 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine (500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg, 2.76 mmol) reacted to give N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (500 mg, 65%). 1H NMR (CD3OD): δ 2.16 (s, 6H), 3.76 (s, 3H), 4.51 (s, 2H), 6.79 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 7.01-7.06 (m, 2H), 7.15 (s, 2H), 7.26 (t, J=8.1 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS (m/e): 413.03 (MH+).
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.[F:12][C:13]([F:27])([C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:14](O)=[O:15].CCN=C=NCCC[N+](C)(C)C.[I-].CNC1C=NC=CC=1NC>ClCCl>[O:1]1[CH:6]([CH2:7][O:8][C:14](=[O:15])[C:13]([F:12])([F:27])[C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC1COc2cscc2O1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: CNc1ccncc1NC
Agent: [I-]
Solvent: ClCCl
Product: O=C(OCC1COc2cscc2O1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of (2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (“hydroxymethyl EDOT”, 1.20 g, 6.97 mmol) in dichloromethane (30 mL) was chilled to 0° C. under argon. Neat 2,2,3,3,4,4,5,5,5-nonafluoropentanoic acid (1.93 g, 7.35 mmol) was added by pipette. Quickly 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (2.30 g, 7.80 mmol) and 3,4-dimethylaminopyridine (0.1 g, 0.82 mmol) were added and the solution was allowed to come to room temperature overnight. The solvent was evaporated at <30° C. and the residue purified by repeated column chromatography on silica gel using a gradient elution starting with 3:1 hexane/dichloromethane and ending with 1:1 hexane/dichloromethane. The product (2.10 g, 5.02 mmol) was a colorless oil that solidifies at −20° C. (Formula (4), left-hand side). Overall product yield was 53%.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]([CH3:13])[CH:7]([OH:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:10]2[S:9](=[O:11])(=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(O)c2cccc(Br)c2S1(=O)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN1C(=O)c2cccc(Br)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.4 %

Procedure:
To a solution of 7-bromo-2-methyl-2,3-dihydro-1,2-benzisothiazol-3-ol 1,1-dioxide (0.34 g, 1.2 mmol) in methylene chloride (20 mL), prepared according to the method described in Example 3 was added PDC (1.4 g, 3.6 mmol). The reaction mixture is stirred at ambient temperature over 6 h, filtered through a pad of Celite and concentrated under the reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexane, 1:4) to afford the desired product 7-bromo-2-methyl-1,2-benzisothiazol-3-one 1,1-dioxide (0.24 g, 72%). 1H NMR (CDCl3): δ 3.9 (s, 3H), 7.71 (t, 1H), 7.99 (d, 1H), 8.03 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:28]([N:35]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:36]1[C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CN1CCOCC1>C1CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1.O.CN(C)C=O>[CH2:1]([O:8][C:9]([C@@H:10]([NH:11][C:37]([C@@H:36]1[CH2:40][CH2:41][CH2:42][CH2:43][N:35]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:38])[CH3:12])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
9.85 g (45.57 mmol) of alanine benzyl ester, 6.79 g of HOBT (50.23 mmol) and 10.07 g (52.52 mmol) of EDC are introduced into dimethylformamide (30 ml) at 0° C., treated with 10.47 g (45.67 mmol) of N-Boc-pipecolic acid. and 27.71 g (274 mmol) of N-methylmorpholine and stirred overnight at room temperature. Subsequently, the mixture is treated with water and toluene, the phases are separated and the organic phase is washed with sat. aqueous sodium chloride solution. 14.9 g (83% of th.) of product are isolated by means of silica gel chromatography using cyclohexane/ethyl acetate 10/1.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.C([O-])(O)=O.[Na+]>CO.O>[CH2:16]([C:13]1[CH:14]=[CH:15][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH2:10][C:9]=2[CH:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCc1ccc2c(c1)CCNCC2
Yield: 98.4 %

Procedure:
To a solution of the product of Step D (0.17 g, 0.47 mmol) in a mixture of MeOH and H2O (10 ml: 1 ml), NaHCO3 (0.3 g, 3.6 mmol) was added and the reaction mixture was stirred at reflux for 2 h. The solvents were evaporated and the residue was diluted to 20 ml with EtOAc and washed with H2O, dried over MgSO4, filtered and the filtrate evaporated to dryness to give the title compound (0.12 g; 100%), as pale oil. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.93 Hz); 1.25-1.28 (m, 12H), 1.45-1.6 (m, 2H); 2.52 (tr, 2H, J=7.71 Hz); 2.85-2.93 (m, 8H); 6.85-6.92 (m, 2H); 6.97-7.0 (m, 1H).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)[CH:16]=[CH:17][CH:18]=1)=O)(C)(C)C>C(OCC)(=O)C>[CH3:28][O:27][C:25]([C:21]1[CH:20]=[C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][CH2:11][CH2:10][NH2:9])[CH:14]=2)[CH:24]=[CH:23][CH:22]=1)=[O:26]
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cccc(NCCN)c2)c1
Yield: 85.6 %

Procedure:
Hydrogen chloride was bubbled through a solution of methyl 3′-(2-(tert-butoxycarbonylamino)ethylamino)biphenyl-3-carboxylate (800 mg, 2.16 mmol, 1.00 equiv.) in ethyl acetate (20 mL), for about 1 hour. The solids were collected by filtration, and then dissolved in saturated solution of sodium bicarbonate (10 mL). After extracting with ethyl acetate (3×100 mL) the organic phases were combined and concentrated to give the title product as a light-yellow oil (500 mg; yield=86%). 1H NMR (300 MHz, DMSO-d6) δ: 8.14 (s, 1H), 7.93 (m, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 6.97 (m, 2H), 6.73 (d, J=1.5 Hz, 1H), 3.89 (s, 3H), 3.40 (t, J=6.3 Hz, 2H), 3.01 (m, 2H).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[C:16]2[C:11](=[C:12]([NH:17][C:18](=[O:27])[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][C:7]1[C:16]2[C:11](=[C:12]([NH:17][C:18](=[O:27])[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a suspension of 4-ethoxycarbonylmethyl-8-(2,6-dichlorobenzoylamino)quinoline (1.03 g) in ethanol (6 ml) was added 1N-aqueous sodium hydroxide solution (3.83 ml), and the mixture was stirred at 50° C. for two hours. The organic solvent was removed in vacuo and the aqueous residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated. The residue was crystallized spontaneously and it was triturated with ethyl acetate to give 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)quinoline (703 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Ni]
Product: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)c1

Procedure:
Prepared from (3′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B8) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (165 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[CH2:6][CH2:5]2.C([O:18][C:19](=[O:30])[C:20](=[CH:26]OCC)[C:21](OCC)=[O:22])C>>[F:1][C:2]1[CH:11]=[C:10]2[C:9]3[N:8]([CH:26]=[C:20]([C:19]([OH:30])=[O:18])[C:21]2=[O:22])[CH:7]([C:12]([F:13])([F:15])[F:14])[CH2:6][CH2:5][C:4]=3[CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Fc1ccc2c(c1)CCC(C(F)(F)F)N2
Product: O=C(O)c1cn2c3c(cc(F)cc3c1=O)CCC2C(F)(F)F

Procedure:
6-Fluoro-2-trifluoromethyltetrahydroquinoline is condensed with an equimolar amount of diethylethoxymethylenemalonate according to the method of Example 1. The ester intermediate of Formula III is hydrolyzed according to Example 1, and the solid product is recrystallized from N,N-dimethyl formamide to provide crystals of 6,7-dihydro-9-fluoro-1-oxo-5-trifluoromethyl-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 295°297° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>O1CCOCC1>[Br:23][C:24]1[CH:25]=[N:26][C:27]([NH:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:2]=2[F:1])=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCc1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzylamine (2.0 g) is dissolved in 1,4-dioxane (10 ml) and thereto are added N,N-diisopropylethylamine (2.7 ml) and 5-bromo-2-chloropyrimidine (3.02 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (1.69 g). MS (m/z): 350/352 [M+H]+
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][CH:7]=1)[CH2:3][OH:4].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]([CH3:42])([CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][CH:7]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution in methylene chloride (15 mL) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propan-1-ol (0.4 g, 0.72 mmol), prepared as in step 1, and DMSO (0.17 g, 2.17 mmol) was added oxalyl chloride (0.14 g, 1.08 mmol) and the reaction mixture was stirred for 0.5 hours. Triethylamine (0.37 g, 3.6 mmol) was added via syringe, the ice bath was removed, and the reaction was allowed to warm to room temperature. The mixture was concentrated in vacuo and triturated with dry THF. The THF solution was filtered and washed with additional THF. The THF solution and washings were combined and concentrated in vacuo to give crude 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propanal which was used without further purification for oxime formation.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[C:22]([N:33]1[C@@H:37]([CH3:38])[C:36](=O)[O:35]C1=O)(=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:36](=[O:35])[C@H:37]([CH3:38])[NH:33][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCCCCCCCC(=O)N1C(=O)OC(=O)[C@@H]1C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
L-Phenylalanine methyl ester hydrochloride (259 mg, 1.2 mmol) was suspended in tetrahydrofuran (6 mL), followed by the addition of N-methylmorpholine (121 mg, 1.2 mmol) at 0° C. The resulting mixture was stirred for 20 minutes. (S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (270 mg, 1 mmol) was added as crystals at 0° C., followed by stirring for 5 minutes. The mixture was allowed to rise in temperature to room temperature, at which the mixture was stirred for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (289 mg, 71%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]#[N:17])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.[Li].C[Si](N[Si](C)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:16]#[N:17])([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nccs1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)(c1nccs1)C2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
3-Cyano-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.15 g) and 2-chloro-1,3-thiazole (0.09 g, 0.75 mmol) were dissolved in THF (4 mL). The mixture was cooled to −78° C. and lithium HMDS (1 M in THF; 0.89 mL) was added dropwise. After 5 minutes, the mixture was allowed to warm to room temperature and after 0.5 hour saturated aqueous ammonium chloride was added and the products extracted into ethyl acetate. The organic solution was dried with anhydrous magnesium sulphate, filtered and the solvent removed by evaporation. The residue was purified by flash chromatography on silica eluting with 30% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (1 g, 5 mmol), in anhydrous CH2Cl2 (10 mL) under argon were added ethane sulfonyl chloride (0.57 mL, 5.99 mmol) and Pyridine (0.60 mL, 7.5 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (3×10 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid. 1H NMR (CDCl3) δ: 1.23 (t, J=7.5 Hz, 3 H), 1.52 (d, J=6.8 Hz, 3 H), 2.77 (q, J=14, 7.5 Hz, 2 H), 4.61-4.72 (m, 2 H), 7.24 (d, J=8.3 Hz, 2 H), 7.51 (d, J=8.3 Hz, 2 H). ESIMS (MH+): 293.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4]>[Pt](=O)=O.C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(Nc1ccc(Cc2ccncc2)cc1)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Reaction time: 16 h

Procedure:
2,2,2-Trifluoro-N-(4-(pyridin-4-ylmethyl)phenyl)acetamide (28.5 g, 102 mmol) and acetic acid (205 ml) were added to platinum(IV) oxide (3.42 g, 15.06 mmol) in a 500 mL stainless steel pressure bottle and the mixture was stirred for 16 hours at 40 psi. The mixture was filtered through a nylon membrane and concentrated in vacuo; and the resulting residue was taken up in methanol (100 mL) and poured into diethyl ether (600 mL). The precipitate was filtered, washed with ether and dried with sodium sulfate to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH:21][N:20]=1.CN(C=O)C>C(OCC)(=O)C.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>[C:16]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[CH:24]=1)#[N:17]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Cl)c(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(CC(=O)OC(C)(C)C)cc2C#N)ccn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl 2-(4-chloro-3-cyanophenyl)acetate 111-7 (572 mg, 2.28 mmol), 2-methyl-4-(tributylstannyl)pyridine 111-8 (870 mg, 2.28 mmol) and Pd(PPh3)4 (220 mg, 0.2 mmol) and DMF (9 mL) was stirred at 120° C. for 10 hours under argon. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with saturated aqueous Na2S2O3 solution, water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give tert-butyl 2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)acetate 111-9 as a yellow oil. MS m/z 309.2 (M+1).
Reaction SMILES: [F:1][C@:2]12[C@@H:24]([OH:25])[CH2:23][C@@:22]3([CH3:26])[C@@H:12]([CH2:13][C@@H:14]([OH:28])[C@:15]3([OH:27])[C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1.[C-]#N.[Na+].[CH:34](O)(C)[CH3:35]>>[F:1][C@:2]12[C@@H:24]([OH:25])[CH2:23][C@@:22]3([CH3:26])[C@@H:12]([CH2:13][C@@H:14]([OH:28])[C@:15]3([OH:27])[C:16](=[O:21])[C:17]([O:19][CH2:20][CH2:34][CH3:35])=[O:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:30])[CH:4]=[CH:5][C:6](=[O:29])[CH:7]=1
Reactant: COC(=O)C(=O)[C@@]1(O)[C@H](O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reactant: CC(C)O
Agent: [C-]#N
Agent: [Na+]
Product: CCCOC(=O)C(=O)[C@@]1(O)[C@H](O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
A solution of (11β,16α)-9-fluoro-11,16,17-trihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid, methyl ester (1.0 g) in anhydrous isopropyl alcohol (100 ml) containing sodium cyanide (100 mg) is refluxed for 3.0 hours. The isopropanol is then removed by distillation in vacuo and the residue is washed with water, dried and crystallized to afford the title compound.