Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1.[F:28][C@@H:29]1[C@H:33]([CH:34]=O)[CH2:32][N:31]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C[N+]1([O-])CCOCC1>C(Cl)Cl.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][CH2:34][C@H:33]2[C@@H:29]([F:28])[CH2:30][N:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:32]2)[C:15]([CH3:18])([CH3:16])[CH3:17])[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1
Reactant: O=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Reactant: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine (2.55 g, 6.8 mmol) in CH2Cl2 (58 mL) was added the crude (3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylate (obtained from 1.4 equiv. of (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate) in CH2Cl2 (10 mL) and NaBH(OAc)3 (2.2 g, 10.2 mmol). The reaction mixture was then stirred for 16 h at room temperature. After quenched with saturated NaHCO3 aqueous solution, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude reductive amination product was contaminated by the HF eliminated alkene product, which was not separable on either silica column chromatography or preparative reverse phase HPLC. Therefore, the crude mixture (2.89 g) was dissolved in acetone and water (5:1, 120 mL). 4-Methylmorpholine N-oxide (667 mg, 5.7 mmol) and OsO4 (1.51 mL of a 4% w/v solution) were added to this reaction mixture, which was then stirred for over the weekend at room temperature. After removal of acetone in vacuo, the remaining aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The desired (3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate was obtained on silica column chromatography (40% to 90% EtOAc in Hexanes, 2.16 g, 52%). LC/MS (uplc): MH+ 610.2, 0.99 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11])[CH:3]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>CC#N.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][O:10][CH2:9][C:8]([C:4]1[CH:3]=[C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:7]=[CH:6][CH:5]=1)([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: COCC(C)(C)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a solution of 1-bromo-3-(2-methoxy-1,1-dimethyl-ethyl)-benzene (1.62 g, 6.69 mmol) and trimethylsilylacetylene (1.2 mL, 8.7 mmol, 1.3 eq.) in MeCN-Et3N (50 mL, 7:3) was added Pd(PPh3)2Cl2 (0.23 g, 0.33 mmol. 0.05 eq.), CuI (0.038 g, 0.2 mmol, 0.03 eq.) and the mixture refluxed for 16 h. After cooling to ambient temperature and concentration under reduced pressure the residue was chromatographed (EtOAc-hexane, 2:98) to obtain 1.54 g (89%) of the desired product. NMR (DMSO-d6): 7.28-7.00 (m, 4H), 3.16 (s, 2H), 2.98 (s, 3H), 1.00 (s, 6H), 0.1 (s, 9H). MS (DCI): 261 (M+1).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>O1CCCC1>[C:17]1([CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[OH:8])[CH2:10][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [Li]c1cccs1
Reactant: O=C(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1cccs1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Dissolve phenyl[1-(2-phenylethyl)-4-piperidinyl]methanone (4.45 g, 15.16 mmol) in anhydrous tetrahydrofuran (40 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, 2-lithiothiophene (15.16 mL of a 1M solution in tetrahydrofuran, 15.16 mmol) and stir at -78° C. for 1.5 hours. Quench with saturated ammonium chloride, separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl acetate/hexane) and recrystallize (cyclohexane) to give the title compound as a white crystalline solid; mp 143°-144° C.
Reaction SMILES: B.C1COCC1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])=O>C1COCC1>[C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][CH2:16][CH2:15][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])([OH:23])=[O:22]
Reactant: O=C(CNc1ccccc1F)Nc1ccccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1NCCNc1ccccc1F
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 24.2 %

Procedure:
To a solution of BH3.THF (1.00M, 10.0 mL 300 mol %) at 5° C. was added a solution of 2-(2-(((2-fluorophenyl)amino)acetylamino)benzoic acid from Example 2 (1.0 g, 3.47 mmol) in anhydrous THF (10 mL). After stirring for 5 min at 10° C., the reaction mixture was refluxed for 2.5 h and then cooled to rt. The reaction mixture was quenched with 25% (w/v) NaOH (4 mL) and then the solution was refluxed for 4 h. After cooling to rt, the reaction mixture was stirred for 20 h, water (50 mL) was added, and then the mixture was extracted with ether (3×100 mL). The water layer was acidified with 1N HCl to pH=3-4 and then the light crystalline product which crystallized was filtered and washed several times with cold water. After drying in a vacuum oven at 50° C. for 5 h, 0.23 g (24%) of the title compound was obtained which contained ca 5% of an impurity by 1H NMR: mp 127°-128° C. Further purification by LPLC (EtOAc-hexane 1:2), afforded, after drying in vacuo, 176 mg (19%) of the title compound: mp 135.7°-136.2° C.; 1H NMR (CDCl3) δ8.00 (d, 1H, J=8, NH), 7.42 (t, 2H, J=6.8), 7.05-6.97 (m, 2H), 6.80-6.65 (m, 4H), 3.55 (d, 2H, J=4.8), 3.51 (d, 2H, J=4); 13C NMR (CDCl3) δ173.37, 151.72 (d, J=238), 151.38, 135.63, 132.83, 124.60 (d, J=3.8), 117.27 (d, J=6.8), 115.30, 114.73, 114.54, 112.32, 111.33, 109.25, 42.75, 42.12; MS (EI, m/z) 274 (M+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([O:30]C)[CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[S:8][C:7]=2[CH:40]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:8][C:7]=2[CH:40]=1
Reactant: CCCCCCNCC(COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CCCCCNCC(O)COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 63.8 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(2-methoxy-3-hexylaminopropoxy)phenyl]methanone (340 mg, 0.62 mmol) was converted to 200 mg of the title compound by the procedure of Example 32 using 0.23 mL (3.1 mmol) of ethanethiol 660 mg (5.0 mmol) of aluminum chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(F)cc3)cc2sc1=O

Procedure:
7-(4-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 4-fluorophenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.27 (s, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.60-7.50 (m, 4H), 7.21-7.17 (m, 2H), 4.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH:3]1[N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:5](=[O:11])[O:4]1.[Li+].[CH3:15]C([N-]C(C)C)C.C1COCC1.CCCCCCC.ICI>C1COCC1>[CH3:15][C@:6]12[CH2:10][CH2:9][CH2:8][N:7]1[CH:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[O:4][C:5]2=[O:11]
Reactant: O=C1OC(C(Cl)(Cl)Cl)N2CCC[C@H]12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ICI
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C[C@]12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of (7aR)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (D1) (0.2 g, 0.82 mol) in THF (10 ml) cooled at −78° C. LDA 2M sol in THF/heptane (0.58 ml, 1.17 mol) was added and the mixture stirred 30 min. Diiodomethane (0.185 ml, 2.97 mol) was added and the temperature was allowed to warm to −40° C. over a period of 2 hrs then left at this temperature for an additional hour. The resulting mixture was partitioned between DCM and H2O. The aqueous phase was extracted with DCM (2×10 ml); the organic phases were collected, dried over Na2SO4 and evaporated in vacuo. The residue was purified by SPE-Si cartridge (25 g) eluting with DCM. Collected fractions after solvent evaporation afforded title compound (D2) in mixture (4:1) with starting material (110 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].[CH3:10]CCCCC.C[Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:10][O:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[CH2:3][CH2:2][OH:1]
Reactant: CC(C)(CCO)C(=O)O
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)(C)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Step B To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid (2.2 g, 16.6 mmol) in ethyl ether (16 mL) and methanol (24 mL) at 0° C. was added a hexane solution (2.0 M) of trimethylsilyldiazomethane (Aldrich) (12.5 mL, 25 mmol). The reaction mixture was stirred at 0° C. for 1 h. The solvents were evaporated. The residue was taken up in ethyl acetate, washed with diluted aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give 4-hydroxy-2,2-dimethyl-butyric acid methyl ester as a colorless oil (1.5 g, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=1[S:52](Cl)(=[O:54])=[O:53]>C(#N)C>[CH3:42][O:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=1[S:52]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:53])=[O:54]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c(OC)c1
Yield: 28.2 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0289 g, 0.0626 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,4-dimethoxybenzenesulfonyl chloride (0.0462 g, 0.195 mmol) to obtain 4-(2,4-dimethoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0117 g, yield 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35](Cl)(=[O:37])=[O:36])[CH:34]=1>O1CCCC1>[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:37])=[O:36])[CH:34]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 14, 40.6 g, 0.1619 mol) in anhydrous tetrahydrofuran (600. mL), cooled to −70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 161.9 mL, 0.161.9 mol) drop wise. The reaction mixture was warmed to room temperature and stirred for 1 hour before cooling to −70° C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (40 g, 0.1619 mol) in tetrahydrofuran (200.0 mL) was added dropwise. After complete addition, the reaction mixture was gradually warmed to room temperature and stirred for 1 hour. Reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with water and saturated aqueous sodium chloride solution. Crude residue was purified by column chromatography eluting with ethyl acetate:hexane (gradient 1:19 to 3:17, by volume) to afford the title compound as a white solid, 46 g.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[CH:31]=O)[O:24][C:23]2=[O:36])=[C:4]([O:37][CH3:38])[CH:3]=1.[CH3:39][NH:40][CH3:41].[BH4-].[Na+]>CCO.CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:39][N:40]([CH2:31][C:30]1[CH:29]=[C:28]([C@H:25]2[O:24][C:23](=[O:36])[N:22]([CH2:21][C:12]3[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=3[C:5]3[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]([F:1])=[CH:3][C:4]=3[O:37][CH3:38])[C@H:26]2[CH3:27])[CH:35]=[CH:34][CH:33]=1)[CH3:41]
Reactant: CNC
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C=O)c2)[C@@H]1C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(CN(C)C)c2)[C@@H]1C
Reaction time: 8 h

Procedure:
To a solution of 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde (15 mg, 0.028 mmol) in EtOH (1 mL) was added dimethylamine (140 μL of a 2.0 M solution in MeOH) and titanium isopropoxide (79 μL, 0.28 mmol). The resulting white suspension was stirred overnight. Sodium borohydride (7.1 mg, 0.188 mmol) was added and the mixture was stirred overnight. The reaction was quenched by pouring the mixture into 2N aqueous ammonia (2 mL). The resulting inorganic precipitate was filtered and washed with dichloromethane. The combined filtrates were extracted with dichloromethane (2×15 mL). The extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si) to give (4S,5R)-5-{3-[(dimethylamino)methyl]phenyl}-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=559.25; found=559.4 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.74 (s, 0.5 H); 7.67 (s, 0.5 H); 7.64 (s, 0.5 H); 7.62 (s, 0.5 H); 7.37-7.29 (m, 3 H); 7.18 (s, 1 H); 7.16 (s, 0.5 H); 7.13 (s, 0.5 H); 7.01 (d, J=8.4 Hz, 0.5 H); 6.99 (d, J=8.5 Hz, 0.5 H); 6.71 (d, J=3.0 Hz, 0.5 H); 6.68 (d, J=2.9 Hz, 0.5 H); 5.52 (d, J=8.1 Hz, 0.5 H); 5.37 (d, J=8.0 Hz, 0.5 H); 4.82 (d, J=15.9 Hz, 0.5 H); 4.77 (d, J=16.0 Hz, 0.5 H); 4.15 (d, J=16.0 Hz, 0.5 H); 3.91 (d, J=15.9 Hz, 0.5 H); 3.76 (s, 3 H); 3.80-3.73 (m, 0.5 H); 3.72-3.68 (m, 0.5H); 3.43 (s, 2H); 3.25-3.18 (m, 1 H); 2.23 (s, 6 H); 1.27 (m, 4.5 H); 1.19 (d, J=6.9 Hz, 1.5 H); 0.53 (d, J=6.5 Hz, 1.5 H); 0.39 (d, J=6.6 Hz, 1.5 H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[S:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:31][N:32]=1>>[S:33]([C:30]1[S:29][C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:32][CH:31]=1)(=[O:35])(=[O:34])[NH2:36]
Reactant: Nc1ncc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cnc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-thiazole-5-sulfonic acid amide [CAS-No. 63735-95-5] according to general procedure II. Yellow solid. MS (ISP) 535.2 [(M−H)−]; mp 309° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[C:33](O)(=[O:35])[CH3:34].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][N:29]([C:33](=[O:35])[CH3:34])[CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCNC5)s4)c(Cl)cnc32)cc1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(O)(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ambient solution of 3-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)pyrrolidin-3-ol (Example 117D) (180 mg, 0.300 mmol) in N,N-dimethylformamide (10 mL) was added acetic acid (36 mg, 0.599 mmol), triethylamine (0.125 mL, 0.899 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (137 mg, 0.359 mmol). The reaction was stirred at room temperature for 3 hours and was quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purifed by flash column chromatography on silica gel, eluting with a gradient of 0 to 5% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 643.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:21])[NH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[C:11]1[C:12](=[O:21])[N:13]([CH3:22])[C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][N:16]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
First, 2.20 g of 3-(2,4-dichloro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazin (compound 1-1009) was dissolved in 12 ml of N,N-dimethylformamide, to which 1.34 g of potassium carbonate and 0.81 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 1.11 g (yield, 48%) of 3-(2,4-dichloro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-358; m.p., 130.6° C.).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>CO.[Pt]=O>[NH2:11][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CO
Product: Cc1c(N)cccc1C(=O)O

Procedure:
A solution of 2-methyl-3-nitrobenzoic acid (mp. 182°-184° C., 22 g, 0.12 mol) in 400 mL of methanol was hydrogenated over platinum oxide (100 mg) for 45 minutes at 55 pounds per square inch (psi), whereupon the catalyst was filtered off through a bed of Celite® (50 g), and the solvent evaporated under reduced pressure to give 3-amino-2-methylbenzoic acid (mp. 178°-181° C.) in quantitative yield (18.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II)dichloride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).