Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].CCN(CC)CC.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CCCCCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of methyl-9-hydroxy-nonanoate (0.838 g, 4.46 mmol, 1.0 equiv: Aldrich) in CH2Cl2 (15 mL, 0.3 M) was treated successively with Et3N (0.75 mL, 5.38 mmol, 1.2 equiv), t-butylchlorodiphenylsilane (1.28 mL, 4.93 mmol, 1.1 equiv), and DMAP (0.180 g, 1.48 mmol, 0.33 equiv), and the reaction mixture was stirred at 25° C. for 12 h. Saturated aqueous NH4Cl was added to the reaction mixture and the mixture was partitioned between CH2Cl2 (100 mL) and H2O (100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Chromatography (SiO2, 5 cm×15 cm, 0-5% EtOAc-hexanes gradient elution ) afforded the intermeidate as a clear, colorless oil (1.22g, 1.831 theoretical, 64.1%): 1H NMR (CDCl3, 250 MHz) δ 7.66 (m, 4H, ArH), 7.38 (m, 6H, ArH), 3.67-3.62 (m, 5H, C(O)OCH3 and CH2OTBDPS), 2.30 (t, 2H, J=7.4 Hz, CH2C(O)OCH3), 1.58 (m, 4H, CH2CH2OTBDPS and CH2CH2C(O)OCH3), 1.28 (b s, 8H, alkyl protons), 1.05 (s, 9H, C (CH3)3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])([O-])=O.[K+].[K+].[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: Sc1ccccc1Br
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CSc1ccccc1Br
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromobenzene thiol (10.0 g, 52.8 mmol, 1.0 eq.) in DMF (250 mL) was added K2CO3 (17.5 g, 126.7 mmol, 2.4 eq.) and isobutyl iodide (7.3 mL, 63.36 mmol, 1.2 eq). The reaction was warmed to about 40° C. and stirred overnight. The mixture was diluted with EtOAc (300 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was extracted with EtOAc(2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 1-bromo-2-isobutylsulfanyl-benzene (12.94 g, 52.8 mmol, 100%), which is then taken to the next step without any further purification. GCMS (EI): 244.0
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:18][S:19][CH2:20][C:21]([NH2:23])=[S:22]>C1CCCCC1.C(OCC)(=O)C>[CH3:18][S:19][CH2:20][C:21]1[S:22][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH3:16])[N:23]=1
Reactant: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CSCC(N)=S
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCc1nc(CSC)sc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
A mixture of 5 g of 2-chloro-1-(4-nitrophenyl)-hexan-3-one (0.02 mol) and 2.6 g of (methylthio)thioacetamide (0.022 mol) is heated at 60° C. for 24 h. The reaction is followed by TLC (7/3 cyclohexane/ethyl acetate). The reaction medium is then treated according to the process of Example 45 to give 5.6 g of 2-methylthiomethyl-5-(4-nitrobenzyl)-4-propylthiazole in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[CH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]#[C:14][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccccn1
Reactant: C#Cc1c(-c2ccc(Cl)cc2)noc1C
Product: Cc1onc(-c2ccc(Cl)cc2)c1C#Cc1ccccn1
Yield: 87 %

Procedure:
As described for example 11c, 3-(4-chloro-phenyl)-4-ethynyl-5-methyl-isoxazole (109 mg, 0.50 mmol) instead of 4-ethynyl-5-methyl-3-phenyl-isoxazole was converted (using 2-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 129 mg, 87%) which was obtained as a light brown solid. MS: m/e=295.1 [M+H]+.
Reaction SMILES: [Si]([O:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:59]2[C:54](=[CH:55][N:56]=[C:57]([CH3:60])[CH:58]=2)[CH:53]=[C:52]([C:61]2[CH:62]=[C:63]([NH:68]/[C:69](/[NH2:72])=[N:70]/O)[CH:64]=[CH:65][C:66]=2[CH3:67])[C:51]1=[O:73]>CN(C=O)C>[OH:8][C@@H:9]([C:10]1[O:12][N:70]=[C:69]([NH:68][C:63]2[CH:64]=[CH:65][C:66]([CH3:67])=[C:61]([C:52]3[C:51](=[O:73])[N:50]([CH3:49])[C:59]4[C:54]([CH:53]=3)=[CH:55][N:56]=[C:57]([CH3:60])[CH:58]=4)[CH:62]=2)[N:72]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc([C@H](O)C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid (83 mg, 0.35 mmol) in DMF (2 mL) were added DIPEA (52 μL, 0.3 mmol) and HATU (0.11 g, 0.3 mmol). After stirring at rt for 15 min, 17 (0.10 g, 0.3 mmol) was added as a solution in DMF (1 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 1 h. Subsequently, the reaction was cooled to rt, partitioned with EtOAc (30 mL) and 5% aq NaHCO3 (20 mL). The aqueous layer was extracted with fresh EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and reduced to dryness. The crude material was dissolved in THF and was added TBAF (2.7 mL of a 1.0 M solution in THF). The mixture was stirred at rt for 2 h. Subsequently the reaction was diluted with EtOAc (20 mL) and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by preparative LCMS to give (R)-3-(5-(5-(1-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A92). 1H NMR (400 MHz, d6-DMSO) δ 9.87 (s, 1H), 8.81 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 7.39 (dd, J=8, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.02 (d, J=6 Hz, 1H), 4.48 (bt, J=6 Hz, 1H), 3.67 (s, 3H), 2.61 (s, 3H), 2.07 (s, 3H) 0.94 (d, J=6 Hz, 3H), 0.87 (d, J=6 Hz, 3H). MS m/z 420.4 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:29]=[CH:28][C:15]([CH2:16][N:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:19][CH2:18]4)=[CH:14][CH:13]=3)OCC[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:7]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:21][CH2:22]2)=[CH:28][CH:29]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)CN1CCN(Cc2ccc(C3(c4ccccc4)OCCO3)cc2)CC1
Agent: Cl
Solvent: CO
Product: NNC(=O)CN1CCN(Cc2ccc(C(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a stirred solution of 15 (1.82 g, 4.57 mmol, 1.0 equiv.) in MeOH (14 mL, 0.33 M) was added 10% aqueous HCl (14 mL). The reaction mixture was stirred overnight at room temperature. The MeOH was evaporated, and the resulting aqueous solution was made basic (pH>12) by the addition of 1M NaOH. The aqueous solution was extracted with DCM (4×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to yield 1{31} (726 mg, 45%) as a yellow oily solid, which was used without further purification. 1H-NMR (500 MHz, CDCl3): δ 8.16 (br s, 1H), 7.75-7.71 (m, 4H), 7.53 (t, 1H, J=7.5 Hz), 7.42 (t, 2H, J=7.5 Hz), 7.38 (d, 2H, J=8.0 Hz), 3.85 (br s, 2H), 3.53 (s, 2H), 3.03 (s, 2H), 2.51 (br s, 4H), 2.45 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 196.2, 170.2, 142.9, 137.4, 136.2, 132.2, 130.0, 129.8, 128.6, 128.1, 62.2, 60.4, 53.4, 52.9.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: N#Cc1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1OCC(=O)N1CCOCC1
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzonitrile, (685 mg, 5 mmol) in dimethylformamide (8 mL, Sure Seal; Aldrich) was added NaH (200 mg, 5 mmol; 60% oil dispersion; Aldrich), and the mixture stirred for 5 min under an anhydrous nitrogen atmosphere. To this was added 4-(2-chloroacetyl)morpholine (900 mg, 5.5 mmol, 1.1 eq.; Avocado Organics), and stirring continued at room temperature for 21 hrs. The reaction was quenched by careful addition of water (30 mL). The resulting mixture was extracted with CH2Cl2 (25 mL×2). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was triturated to obtain 1.10 g (4.17 mmol, Yield 83%) of the title compound as a white solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.63 (2H, t, J=4 Hz, NCH2), 3.67 (1H, m, OCH), 3.72 (1H, m, OCH), 4.86 (2H, s, OCH2), 6.80-6.86 (2H, m, Ar—Hs), 7.61 (1H, dd, J=8.5 Hz, 6.1 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δppm: 42.63, 46.04, 66.80, 68.33, 98.45, 98.47, 101.57, 101.79, 109.56, 109.74, 115.42, 135.48, 135.57, 161.26, 161.35, 114.79, 165.23, 167.28. HRMS calcd for C13H14N2O3F (M+H) 265.0988, found 265.0998.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:14]([CH:15]=1)=[N:13][CH:12]=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:14]([CH:15]=1)=[N:13][CH:12]=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(O)cc2ncc3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(OCc2ccccc2)cc2ncc3ccccc3c12
Temperature: 60 °C

Procedure:
The hydrobromide salt 4d (100 mg, 0.34 mmol) was dissolved in 3 mL DMF. Potassium carbonate (100 mg) and benzyl bromide (60 μL, 0.50 mmol) were added to the solution and the mixture was heated to 60° C. for 14 h. The solvent was removed in vacuo and the residue was washed with water (5 mL) and boiling MeOH (10 mL) and filtered. The solid 4e (47 mg, 46%) was pure while the filtrate contained a mixture of isomers. Mp=271-276° C. 1H NMR (d6-DMSO) δ 11.68 (bs, 1H), 8.71 (d, 1H), 8.30 (d, 1H), 7.93 (t, 1H), 7.74 (m, 2H), 7.55 (d, 2H), 7.40 (t, 2H), 7.32 (t, 1H), 7.09 (d, 1H), 5.54 (s, 2H). Anal Calcd. for C19H14N2O2(H2O): C, 71.24; H, 5.03; N, 8.74. Found: C, 71.28; H, 4.83; N, 8.38.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[C@@H:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:3]1.[N+]([O-])(O)=O.[N+:20]([O:23][CH2:24][CH2:25][NH2:26])([O-:22])=[O:21]>>[N+:20]([O:23][CH2:24][CH2:25][NH:26][C:7]([C@@H:5]1[C@@H:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:22])=[O:21]
Reactant: O=C1N[C@H](C(=O)O)[C@@H](c2ccccc2)O1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])[C@@H](c2ccccc2)O1
Yield: 38.9 %

Procedure:
A procedure similar to that described in Example 19 was repeated, but using 130 mg of (4S,5R)-2-oxo-5-phenyloxazolidine-4-carboxylic acid and 127 mg of N-(2-nitrooxyethyl)amine nitrate, to obtain 72 mg of the title compound as colorless plates, melting at 122°-124° C.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:17]4=[N:18][CH:19]=[C:20]([C:22]([O:24]C)=[O:23])[CH:21]=[C:16]4[N:15]=3)[C:5]2=[O:32])[CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:26]([CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[C:17]4=[N:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[CH:21]=[C:16]4[N:15]=3)[C:5]2=[O:32])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc2c(c1)nc(Cn1c(=O)n(C3CC3)c3ccncc31)n2CCC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 26 (0.84 g, 1.89 mmol) was dissolved in THF (15 mL) and lithium hydroxide (544 mg, 22.7 mmol) dissolved in water (10 mL) was added. The resulting mixture was stirred at room temperature overnight. The pH of the resulting mixture was adjusted to pH=4 by addition of a 1 M solution of hydrochloric acid. Then the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The title compound 28 was isolated as a white powder (690 mg, 84%). m/z=421 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:17][CH:14]([CH3:16])[CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CC(C)N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)cc1NC(C)C

Procedure:
A stirred solution of ethyl 4,6-dichloronicotinate (1) (10 g, 43.4 mmol), isopropyl amine (8 mL) and DIPEA (8 mL) in DMA (50 mL) were heated at 120° C. in a sealed tube for 3 h. The reaction mixture was concentrated to dryness to remove excess of DMA from the reaction mass. The crude material obtained was purified by column chromatography through silica gel and EtOAC:pet. Ether as eluent to obtain the title compound (2). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.90 min; LCMS (ES-API), m/z 243.7 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15])=[O:5])[CH3:2].[BH4-].[Na+].CO>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:36])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1O
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
The compound of step 1 (0.439 g, 0.900 mmol) was dissolved in THF (4 ml). The mixture was cooled to −30° C. and sodium borohydride (35 mg, 0.90 mmol) was added followed by dropwise addition of methanol. After 30 min, the mixture was partitioned between diethyl ether and 2 N hydrochloric acid, the aqueous phase was extracted with diethyl ether, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound as a mixture of stereoisomers.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][CH:12]=[CH:11][C@H:10]1[O:24][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13][CH:12]=[CH:11][C@H:10]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C=CO[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H]1C=CO[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4,6-Di-O-benzyl-3-O-tert-butyldimethylsilyl-D-glucal (3 mmol) was dissolved in THF (35 mL). Tetrabutyl fluoride (1M solution in THF) (3.5 mL) was added and the reaction mixture was stirred at room temperature overnight, then water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). Combined organic extracts were washed with water until neutral, and dried over anhydrous sodium sulfate. Solids and solvents were removed and crude product was purified by column chromatography (SilicaGel 60) using hexanes:ethyl acetate as eluents. Pure 4,6-di-O-benzyl-D-glucal (2.61 mmol, yield 87%) was obtained. mp 53° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C=O.[C:14]1(B(O)O)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[CH2:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: OB(O)c1ccccc1
Agent: C=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=C1Cc2ccc(Br)cc2C1=O
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of 6-bromo-2,3-dihydro-1H-inden-1-one (0.3 g, 1.36 mmol), paraformaldehyde (0.4 g, 13.6 mmol), phenylboronic acid (0.2 g, 1.64 mmol) and trifluoroacetic acid (0.1 mL, 0.15 g, 1.36 mmol) in dry toluene (10 mL) was refluxed for 5 hours. When starting material was totally consumed, the crude mixture was cooled to room temperature, neutralized with saturated aqueous Na2CO3, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, petroleum ether-ethyl acetate, 95:5) to give compound 6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one (89 mg, 30%) as a white solid. 1H NMR (CDCl3, 400 MHz): 3.71 (s, 2H), 5.68 (s, 1H), 6.39 (s, 1H), 7.38-7.40 (d, 1H), 7.70-7.72 (d, 1H), 7.99 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:19]([F:22])([F:21])[F:20])[O:8][C:9]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=2[C:11]=1[CH:12]=[CH2:13])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:19]([F:20])([F:22])[F:21])[O:8][C:9]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=2[C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: C=CC1=C(C(=O)OCC)C(C(F)(F)F)Oc2ccc(Cl)cc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1=C(CC)c2cc(Cl)ccc2OC1C(F)(F)F
Reaction time: 0.42 h
Yield: 64.8 %

Procedure:
Ethyl-6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 142,Step 5)(0.433 g, 1.30 mmol) was dissolved in methanol (10 mL). Palladium(5 wt % on activated carbon)(0.150 g) was slowly added. The reaction vessel was charged with hydrogen (25 psi) and was stirred for 25 minutes. Gas chromatographic analysis indicated that the reaction was complete. The reaction mixture was filtered through Celite and evaporated to yield a orange oil. The oil was purified by flash column chromatography(100 % hexanes) to yield the desired product as a yellow oil (0.282 g, 65%): 1H NMR (CDCl3/300 MHz) 7.43 (d, 1H, J=2.4 Hz), 7.25 (dd, 1H, J=2.4, 8.7 Hz), 6.92(d, 1H, J=8.7 Hz), 5.75 (q, 1H, J=7.0 Hz), 4.38–4.24 (m, 2H), 3.05–2.95 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.25, (t, 3H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[CH3:15][S:16][C:17]1[O:21][C:20](C(Cl)=O)=[N:19][N:18]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:20]1[O:21][C:17]([S:16][CH3:15])=[N:18][N:19]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CSc1nnc(C(=O)Cl)o1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CSc1nnc(C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)o1
Yield: 44.2 %

Procedure:
Using the procedure of Example 32, a 30 ml N,N-dimethylformamide solution of 958 mg (4.55 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.50 g (12.28 mmoles) of 4-(N,N-dimethylamino)pyridine was reacted with 975 mg (5.46 mmoles) of 5-methylthio-1,3,4-oxadiazol-2-carbonyl chloride (U.S. Pat. No. 4,001,238). After acidic workup a crude orange solid (1.25 g, 78% Z0 yield) was obtained. Suspension in hot glacial acetic acid followed by filtration furnished the pure title compound (710 mg, 2.01 mmole, 44%) as a bright yellow solid, m.p. 297°-9° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])O.[Na+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>C(O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Nc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.19 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (295 mg, 2.32 mmol) and p-anisidine (357 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, the precipitated crystals were filtered off, and after washing with water and ethanol the crystals were dried to yield the title compound (359 mg, 86% yield) as orange crystals.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[C:6]([SiH2:10][O:11][C:12]([CH3:23])([CH3:22])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O)([CH3:9])([CH3:8])[CH3:7].[BH4-].[Na+]>CO>[C:6]([SiH2:10][O:11][C:12]([CH3:23])([CH3:22])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][NH:4][CH2:3][CH:2]([F:5])[F:1])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=O)ccc1Cl
Reactant: NCC(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNCC(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
2,2-Difluoroethylamine (660 mg, 7.90 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzaldehyde (1.50 g, 5.27 mmol) in MeOH (53 mL). The mixture was heated to reflux for 4 h, and was allowed to cool down to rt. NaBH4 (300 mg, 7.90 mmol) was added carefully by portions, and the mixture was stirred for 1 h. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc. The mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-(2,2-difluoro-ethyl)-amine (1.86 g) as a clear crude oil that was used further directly. This crude material was dissolved in CH2Cl2 (53 mL), and DIPEA (2.7 mL, 15.6 mmol) was added, followed by Boc2O (1.70 g, 7.90 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with CH2Cl2 (50 mL), and washed with aq. 1M HCl, aq. sat. NaHCO3, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 5:95) yielded the title compound (2.27 g, 96%). LC-MS: tR=1.22 min.