Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:16])[C:12](I)=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>C(#N)C.O.O>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:31]=3)[CH2:14][CH:13]=[CH:12][N:11]2[CH3:16])[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: CC1(C)OB(c2cccc(OCCC3CCCCC3)c2)OC1(C)C
Reactant: Cn1c(I)ccc1CC[C@]1(C)COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CC#N
Product: CN1C=CCC1(CC[C@]1(C)COC(=O)N1)c1cccc(OCCC2CCCCC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 10.8 %

Procedure:
(4R)-4-Methyl-4-[2-(5-iodo-1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (0.3101 g, 0.92 mmol) obtained in Example (40a), 2-[3-(2-cyclohexylethyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4646 g, 1.41 mmol), dichlorobis(triphenylphopsphine)palladium(II) (63.1 mg, 0.09 mmol) and cesium carbonate (0.6006 g, 1.81 mmol) were suspended in a mixed solvent of dimethoxyethane (8 ml) and water (2 ml) and stirred at 80° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:2) as the eluent to afford the crude product. Furthermore, the crude product thus obtained was purified using a preparative reversed phase HPLC column (Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (41.1 mg, yield: 11%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[CH3:39][O:40]C1C=C(CC(=O)C(OCC)=O)C=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:40][CH3:39])[CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1cccc(OC)c1
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(OC)c1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 22 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-methoxyphenyl)-2-oxopropanoate B9 (100 mg, 0.369 mmol), sodium hydride (11.88 mg, 0.495 mmol) and 2,3,4,6 tetra-O-acetyl-α-D-glucose bromide (185 mg, 0.450 mmol). The resulting compound was isolated in the form of white solid in 22% yield.
Reaction SMILES: [O:1]([CH2:8][CH:9]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([S-:34])#[N:33].[K+].BrBr>C(O)(=O)C>[O:1]([CH2:8][CH:9]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)[CH:10]([OH:11])[C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:32]([NH2:33])[S:34][C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(O)C(COc2ccccc2)N2CCC(Cc3ccccc3)CC2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(O)C(COc3ccccc3)N3CCC(Cc4ccccc4)CC3)cc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of 1.5 g of (+) three 1-phenoxymethyl-1-(4-benzylpiperidin-1-yl)-2-p-aminophenyl-2-hydroxy-ethane and 1.43 g of KSCN in 20 ml of glacial acetic acid was added dropwise a solution of 0.58 g of Br2 in 5 ml of glacial acetic acid at room temperature. After stirring for 2 h., the yellow sospension was filtered and the solution was poured into 70 ml of concentrated ammonium solution. The cloudy basic solution was extracted with ethyl acetate dried and evaporated. The resulting yellow residue was chromatographed on silica gel eluting with ethylacetate/cycloexane ⅓, furnishing after crystallization from ethanol 0.9 g of the title compound, m.p. 210-214° C., [α]20D=−2.1±0.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:29][CH3:28])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: CN
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1CCN2c1ccc(F)cc1C
Temperature: 190 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in aqueous solution of methylamine(40%, 10 ml) in the pressure tube, and the reaction mixture was refluxed at 190° C. for 3 hours. The solvent was removed by distillation under reduced pressure, and the residue was diluted in dichloromethane(20 ml), then washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent to obtain 380 mg of desired compound as solid in 72% of yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:22](N)([CH3:24])[CH3:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([CH:22]([CH3:24])[CH3:23])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(OC)c1
Reactant: CC(C)N
Product: COc1cc(NC(=C(C#N)S(C)(=O)=O)C(C)C)cc(OC)c1

Procedure:
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile (0.263 g, 0.8 mmol) was stirred in isopropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) to give the title compound syrup, 209 mg (77%). Mp 135-136.5° C. 1H NMR (200 MHz, CDCl3): δ=1.15 (s, 6H), 3.10 (s, 3H), 3.5 (m, 1H), 3.78 (s, 6H), 6.25 (br s, 2H), 6.33 (br s, 1H); Analysis: calc. for C15H21N3O4S: C, 53.08%; H, 6.24%; N, 12.38%. Found: C, 53.38%; H, 6.26%; N, 12.31%.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([C:24]([CH3:26])=[CH2:25])[CH2:8][CH2:9]/[C:10](/[CH3:23])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:22])=[CH:15][C:16](OC(C)C)=[O:17])([CH3:4])([CH3:3])[CH3:2].COCCO[AlH2-]OCCOC.[Na+].O.S(=O)(=O)(O)O>CCCCCC>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][CH:7]([C:24]([CH3:26])=[CH2:25])[CH2:8][CH2:9]/[C:10](/[CH3:23])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:22])=[CH:15][CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C(CC/C(C)=C/CCC(C)=CC(=O)OC(C)C)O[Si](C)(C)C(C)(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: C=C(C)C(CC/C(C)=C/CCC(C)=CCO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C

Procedure:
24.5 ml of sodium dihydro-bis(2-methoxyethoxy)-aluminate (70% solution in toluene, "Vitride") are slowly added dropwise at 0° to a solution of 32.6 g of isopropyl (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrienoate in 80 ml of hexane. After stirring at room temperature for 2 hours a further 2.5 ml of "Vitride" are added dropwise. The reaction mixture is stirred for a further hour and then treated cautiously with 20 ml of water, whereupon the mixture is poured into ice-water. After adding 70 ml of 50% sulphuric acid the mixture is extracted twice with hexane. The combined extracts are washed with 2N sulphuric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with hexane-ethyl acetate-triethylamine 80:20:0.1, whereby (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrien-1-ol is obtained as a colourless oil. NMR (80 MHz, CDCl3); 5.45 (t, J=7.1 olefin. H); 5.15 (m, 1 olefin. H); 4.95-4.75 (m, 2H-C(12)); 4.2 (d, J=7, 2H-C(1)); 4.05 (t, J=6.5, H-C(10)); 2.2-1.3 (m, 4CH2, 3CH3); 0.9 (s, SiC(CH3)3); 0.05 and 0.0 (2s, Si(CH3)2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.C(N(C(C)C)C(C)C)C.[C:48]([Si:50]([CH3:53])([CH3:52])[CH3:51])#[CH:49]>CN(C=O)C.[Cu]I>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:49]#[C:48][Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:10][CH:9]=2)[C:5]([C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)=[N:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C#C[Si](C)(C)C)cc34)n2)C1
Temperature: 160 °C
Yield: 99.9 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (579 mg, 0.991 mmol), copper(I) iodide (37.7 mg, 0.198 mmol), PdCl2(Amphos) (70.1 mg, 0.099 mmol), N-ethyl-N-isopropylpropan-2-amine (530 μL, 2.97 mmol), and ethynyltrimethylsilane (208 μL, 1.486 mmol) in DMF (9906 μL) was heated in the microwave for 15 min at 160° C. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 20% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (596 mg, 0.990 mmol, 100% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 602.3 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]3[N:22]=[C:21]4[C:16]([C:17](=[O:30])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][N:20]4[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:15][C:14]=3[F:31])[CH2:8]2)C=CC=CC=1.[CH3:32]S([O-])(=O)=O>>[CH3:1][CH:7]1[N:12]([CH3:32])[CH2:11][CH2:10][N:9]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:30])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][N:20]3[C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:15][C:14]=2[F:31])[CH2:8]1
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccccc4)C3)nc21
Reactant: CS(=O)(=O)[O-]
Product: CC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C(C)(C)C)CCN1C

Procedure:
7-(3-phenyl-1-piperazinyl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].C[N:16](C)C=O>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:16])(=[O:14])=[O:12]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C

Procedure:
2-chloro-5-nitrobenzenesulfonic acid (44 mmol) was heated at reflux for 3.5 hours in a mixture of thionyl chloride (22 mL) and dimethylformamide (2 mL). After cooling the reaction mixture to room temperature, the solvents were removed under high vacuum. The crude solid was azeotroped with toluene (3×100 mL) to dryness under vacuum. The final residue was taken up in a mixture of toluene (20 mL) and tetrahydrofuran (50 mL) then cooled to 0° C. Ammonia (50 mL) was added to the stirred reaction mixture, then allowed to warm to room temperature overnight. The solution was acidified using 6 M HCl (pH ˜4) and extracted with ethyl acetate (3×100 mL). The combined organics were dried over MgSO4, filtered and then concentrated to dryness under vacuum to yield 2-Chloro-5-nitrobenzenesulfonamide as a light brown solid (3.91 g, 38% over 2 steps).
Reaction SMILES: [CH2:1]([C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH-].[Na+:14]>O>[CH2:1]([C:4]1([C:10]([O-:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH:2]=[CH2:3].[Na+:14]
Reactant: C=CCC1(C(=O)O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCC1(C(=O)[O-])CCCCC1

Procedure:
170 g of 1-allyl-1-cyclohexyl-carboxylic acid (Example 1) were added gradually to a stirred solution, at ambient temperature, of 40 g of sodium hydroxide in 500 g of water in such a way that, at the end of the neutralisation, an aqueous solution of sodium 1-allyl-1-cyclohexyl-carboxylate having a pH of 8 was obtained. 4 g of CECA 2 S charcoal were then added and the mixture was stirred for 1/2 hour.
Reaction SMILES: C([O:8][C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]([C:28]([N:30]2[CH2:47][CH2:46][CH2:45][C@H:31]2[C:32]([NH:34][CH:35]([CH:42]([CH3:44])[CH3:43])[C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[O:33])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:17][CH:16]=1)=[O:14])=[O:10])C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][C@H:24]([C:28]([N:30]2[CH2:47][CH2:46][CH2:45][C@H:31]2[C:32]([NH:34][CH:35]([CH:42]([CH3:43])[CH3:44])[C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[O:33])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:19][CH:20]=1)=[O:14])([OH:10])=[O:8]
Reactant: [H][H]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)O)cc1)C(C)C)C(=O)C(F)(F)F
Yield: 100.9 %

Procedure:
A solution of 3(RS)-[[4-[(benzyloxycarbonyl)methylaminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (70 mg) in a mixture of methanol (10 ml) and water (1 ml) was hydrogenated over 10% palladium on carbon (1.0 g) at 3 atmosphere pressure of hydrogen for 3 hours at room temperature. After the catalyst was removed by filtration, the filtrate was evaporated under reduced pressure to give 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (61 mg).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:18]([O:36][CH3:37])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:38]([C:17]1[C:18]([O:36][CH3:37])=[C:19]([NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([NH:30][CH2:31][C:32]([F:35])([F:33])[F:34])=[CH:28][CH:29]=2)=[O:23])[CH:20]=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: COc1c(NC(=O)c2ccc(NCC(F)(F)F)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)nn2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 3—To a solution of 314 (0.029 g, 0.1 mmol) in MeOH (5.0 mL) and EtOAc (4.0 mL) was added Pd(OH)2 (0.005 g). The solution was stirred under 1 atm of H2. After 18 h the mixture was filtered through a pad of CELITE and the filtrate concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (1% to 10% MeOH) to 0.018 g (74%) of I-248 as an oil: MS (CI) mz/=476 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:12][C:13]2[N:17]=[C:16]([C:18]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])([CH:20]3[CH2:32][C:23]4[NH:24][C:25]5[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][C:30]=5[C:22]=4[CH2:21]3)[F:19])[O:15][N:14]=2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:36]1([S:33]([C:18]([CH:20]2[CH2:32][C:23]3[NH:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][C:30]=4[C:22]=3[CH2:21]2)([F:19])[C:16]2[O:15][N:14]=[C:13]([CH2:12][NH:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=3)[N:17]=2)(=[O:35])=[O:34])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(CNCc2noc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3ccccc3)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)C(F)(c1nc(CNCc2ccc(CO)cc2)no1)C1Cc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 27 mg (0.04 mmol) of (RS,SR)-4-[({5-[-benzenesulfonyl-(-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester (example 129.3) in 2 mL THF at 0° C., 40 μl (0.04 mmol, 1 eq) lithium aluminum hydride (1M solution in THF) were added. The reaction mixture was stirred at 0° C. for 1 hour and then at RT for 30 minutes. The reaction was quenched with a saturated NaHCO3 aqueous solution, and the crude product extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 2:8) yielded 12 mg (48%) of (RS,SR)-{4-[{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-phenyl}-methanol as a light yellow powder, MS: 581 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]([F:25])([F:24])[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.Br[CH2:27][C:28]([CH2:30][CH2:31][Cl:32])=[CH2:29]>C1COCC1.CCOC(C)=O.C(Cl)(Cl)Cl>[Cl:32][CH2:31][CH2:30][C:28](=[CH2:27])[CH2:29][CH:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]([F:24])([F:25])[F:11])=[CH:19][CH:18]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: C=C(CBr)CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=C(CCCl)CC(C(=O)O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
Step AAJ (1): NaHMDS 2.0 M in THF (10.2 mL, 20.4 mmol) was added to a solution of 2-(4-(trifluoromethoxy)phenyl)acetic acid (2.00 g, 9.08 mmol) in THF (18.2 mL) at 0° C. The resulting mixture was stirred for 20 min at 0° C., then neat 2-(bromomethyl)-4-chlorobut-1-ene (1.83 g, 9.99 mmol, from Step AAI (3)) was added. The mixture was quenched at 0° C. after 10 min with water (5 mL) and concentrated in vacuo. The mixture was diluted with EtOAc and the organic layer was extracted with 1N HCl, then brine, dried over sodium sulfate, and concentrated in vacuo to afford after purification by silica gel column chromatography (60-100% EtOAc/chloroform), 6-chloro-4-methylene-2-(4-(trifluoromethoxy)phenyl)hexanoic acid (2.21 g, 6.85 mmol, 75% yield) as a pale-yellow oil. LC-MS (M−H)− 321.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.35-7.44 (2 H, m), 7.20 (2 H, d, J=8.5 Hz), 4.89-4.97 (2 H, m), 3.81-3.93 (1 H, m), 3.55-3.66 (2 H, m), 2.86 (1 H, dd, J=15.3, 8.9 Hz), 2.39-2.57 (3 H, m).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]=[CH:2]2.ClS([N:12]=[C:13]=[O:14])(=O)=O.S([O-])([O-])=O.[Na+].[Na+].O.[OH-].[Na+]>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[CH:2]2[NH:12][C:13]1=[O:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C1=CC2C=CC1C2
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C1NC2C3C=CC(C3)C12
Temperature: -5 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
In a 500 mL RBF, fit with dropping funnel and stir bar, under N2 was charged with Methylene chloride (100 mL) and 2,5-Norbornadiene (25 mL, 0.24 mol). The mixture was cooled in an ice/NaCl bath (ca. −5° C.). The dropping funnel was charged with Chlorosulfonyl Isocyanate (21.4 mL, 0.246 mol) and Methylene chloride and this mixture was added dropwise slowly to the reaction over about 1 hour. The mixture was held at −5° C. for about 1 hour further with stirring then warmed to room temp by removal of the ice bath. This warming occurred over about 2 h. The mixture was quenched with water (60 mL) and stirred for 10 min. The org layer was separated, washed with brine, dried (sodium sulfate) and concentrated to give a pale yellow oil. The pale yellow oil was dissolved in Methylene chloride (100 mL, 2 mol) and added dropwise to a −5° C. (Ice/NaCl bath) solution of Sodium sulfite (24.5 g, 0.194 mol), Methylene chloride (30 mL, 0.5 mol), and Water (70 mL, 4 mol) in a two neck 500 mL RBF. During the addition, the pH of the mixture was kept between 7 and 10 (monitor by pH paper) by addition of 10% NaOH. The addition took about 1 h. Following the complete addition, the pH was adjusted to 8.5 and the milky white solution was stirred for 1 h at −5° C. The mixture was diluted with about 400 mL of methylene chloride and the mixture stirred vigorously overnight. The stirred mixture was transferred to a 1 L separatory funnel and the layers separated. The aq was extracted 2× further with dichloromethane (200 mL each) and the combined organics washed with brine, dried (MgSO4), filtered through a bed of Celite and concentrated to give 3-Aza-tricyclo[4.2.1.0(2,5)]non-7-en-4-one a white solid. (21.6 g) (65% yield); MP: 94-97° C.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[CH2:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[O:14][C:15]2[C:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11].Cl>O1CCOCC1.CN(C)C=O>[CH3:1][O:2][CH2:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[O:14][C:15]2[C:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11]
Reactant: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3o2)ccn1
Temperature: 50 °C
Yield: 67.1 %

Procedure:
To a stirred solution of 0.05 ml (1.24 mmol) methanol in 5 ml dioxane and 1 ml N,N-dimethylformamide at room temperature was added 27 mg (0.62 mmol) sodium hydride (55% dispersion in mineral oil), and the mixture heated at 50° C. for 1 hour. 50 mg (0.12 mmol) 2-chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide was then added, and the mixture heated at 50° C. for 20 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was acidified with 1 N aq. hydrochloric acid and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (dichloromethane) followed by trituration in ether afforded 32 mg (65%) 2-methoxymethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 398 (M+H+, 100).