Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.C(O)(C)(C)C.[CH3:14][C:15]1([CH3:42])[C@@H:17](/[CH:18]=[CH:19]\[C:20](=O)[OH:21])[C@H:16]1[C:23]([O:25][C@H:26]([C:40]#[N:41])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1)=[O:24]>C(Cl)Cl>[CH3:14][C:15]1([CH3:42])[C@@H:17](/[CH:18]=[CH:19]\[C:20](=[O:21])[Cl:1])[C@H:16]1[C:23]([O:25][C@H:26]([C:40]#[N:41])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1)=[O:24]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A solution of 0.25 ml of 1-chloro-N,N,2-trimethyl-propenylamine, 7.5 ml of methylene chloride and 1.5 ml of tert.-butanol was added to a solution of 0.5 g of (S)α-cyano -3-phenoxy-benzyl (IR,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy -1-propenyl]-cyclopropane-carboxylate in 7.5 ml of methylene chloride and the mixture was stirred at 20° C. for 48 hours. The mixture was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 hexane-ether mixture to obtain 0.43 g of (S)α-cyano-3-phenoxy-benzyl (IR,cis,Z) 2,2-dimethyl -3-[3-oxo-3-chloro-1-propenyl]-cyclopropane-carboxylate melting at 86° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23]S[C:21]4[N:25]=[CH:26][C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:28][C:20]3=4)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O.OO.[OH:38][S:39]([O-:41])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][S:39](=[O:41])(=[O:38])[C:21]4[N:25]=[CH:26][C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:28][C:20]3=4)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CCSc2ncc(N3CCOCC3)cc21
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CCS(=O)(=O)c2ncc(N3CCOCC3)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine (40 mg, 0.084 mmol) in EtOAc (2.5 mL) was added disodium tungstate (24.8 mg, 0.084 mol) and water (0.3 mL). The reaction was cooled at 0° C. and then H2O2 (25.9 μL, 0.84 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (7 mg) was added followed by H2O2 (0.4 mL, 30%) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (15 mL). The separated organic layer was washed with brine (15 mL), dried over MgSO4, filtered and evaporated in vacuo to give 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.64-8.81 (1H, m), 7.87-7.95 (4H, m), 7.74 (1H, dd, J=9.1, 5.8 Hz), 7.36-7.45 (2H, m), 5.59 (1H, s), 4.21-4.26 (2H, m), 3.63-3.72 (6H, m), 2.88-3.01 (4H, m), 2.46 (3H, s). Mass Spectrum (ESI) m/e=506.0 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH2:15][C:16]1[CH:24]=[C:23]([CH3:25])[C:22]2[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=2)[CH:17]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:42][N:3]2[CH:4]=[CH:5][N:1]=[C:2]2[CH:6]([CH2:15][C:16]2[CH:24]=[C:23]([CH3:25])[C:22]3[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[N:21]=3)[CH:17]=2)[CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1cc(CC(CC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(CC(CC(=O)OC(C)(C)C)c2nccn2Cc2ccc(C(C)(C)C)cc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-(1H-imidazol-2-yl)-4-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)butanoate (0.16 mmol), 4-tert-butylbenzyl bromide (1.0 equiv), and potassium carbonate (1.0 equiv) in dimethylformamide (2 mL) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with water (3×5 mL). The ethyl acetate layer was dried, filtered and concentrated in vacuo. The product was obtained by flash chromatography using 0% to 50% ethyl acetate/hexane (65%). 1H-NMR (400 MHz, CDCl3) δ 7.93 (1H, s), 7.23 (2H, m), 7.03 (2H, m), 6.82 (2H, m), 6.63 (1H, s), 6.49 (1H,s), 5.68 (2H, s), 4.82 (2H, d, J=4.0 Hz), 3.60 (2H, t, 8.0 Hz), 3.41 (1H, m), 2.86 (2H, d, J=8.0 Hz), 2.79 (1H, dd, J1=8.0 Hz, J2=16 Hz), 2.61 (1H, dd, J1=8.0 Hz, J2=16 Hz), 2.49 (3H, s), 1.31 (9H, s), 1.25 (9H, s), 0.91 (2H, t, J=8.0 Hz), −0.06 (9H,s). MS(ESI)[M+H]+=617.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[Cu](C#N)[C:10]#[N:11].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: Clc1ccc(I)nn1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(Cl)nn1
Yield: 89 %

Procedure:
A mixture of 3-chloro-6-iodo-pyridazine (CAS 135034-10-5, 5.5 g, 22.9 mmol; Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron (1999), 55 (52), 15067-15070) and copper cyanide (4 g, 44.7 mmol) in acetonitrile (30 ml) was stirred for 30 min. at 160° C., under microwave irradiation (Milestone MW-oven). The mixture was then poured into dichloromethane (200 ml), filtered over celite, and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane/heptane 1:1 to 7:3) to yield D4 (2.84 g, 89%), as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](=O)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH3:26][C:27]1[C:28]([NH2:32])=[N:29][O:30][CH:31]=1.[B][B][B][B][B][B][B][B][B][B]>CO.C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][CH:16]([O:19][CH2:20][CH:21]([NH:32][C:28]5[C:27]([CH3:26])=[CH:31][O:30][N:29]=5)[CH3:22])[CH2:17][CH2:18]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1conc1N
Reactant: CC(=O)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1conc1NC(C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-one (50 mg) and 4-methylisoxazol-3-amine (21.4 mg) in methanol (1 mL) and acetic acid (50 μL) was added decaborane (26.6 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate). 1M Hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (42.1 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:17][C:15]1[NH:14][C:13]([CH:18]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:12]([CH3:11])[CH:16]=1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Temperature: 90 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 147.8 mg of the 3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 136.7 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41]O)[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1.CCN(S(F)(F)[F:53])CC>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:13]=[C:12]([C:15]5[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]6[O:22][C:21]([C:23]7[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=7)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=6[CH:34]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH:7]([CH2:41][F:53])[N:6]3[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CO)C4)cc12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CF)C4)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
5-(11-fluoro-6-(hydroxymethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, 0.062 mmol) was dissolved in DCM (2 ml) and cooled to 0° C., followed by addition of DAST (0.025 ml, 0.187 mmol). The mixture was stirred at 0° C. for 1 h, then at RT for 30 min and then concentrated in vacuo. Preparative TLC (50% DCM in ethyl acetate) gave 5-(11-fluoro-6-(fluoromethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (14 mg, yield: 35%). MS (M+H)+: 645.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28].C(=O)(O)[O-]>CN(C=O)C.[Cu]I.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.CO>[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[C:32][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)=[O:28]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 5-iodo-2′-deoxyuridine (1.05 g, 2.96 mmol) and CuI (114 mg, 0.60 mmol) in dry DMF (21 ml) was added triethylamine (0.9 ml). After stirring for 5 min trifluoro-N-prop-2-ynyl-acetamide (1.35 g, 9.0 mmol) and Pd(PPh3)4 (330 mg, 0.29 mmol) were added to the mixture and the reaction was stirred at room temperature in the dark for 16 h. Methanol (MeOH) (40 ml) and bicarbonate dowex added to the reaction mixture and stirred for 45 min. The mixture was filtered and the filtrate washed with MeOH and the solvent was removed under vacuum. The crude mixture was purified by chromatography on silica (ethyl acetate (EtOAc) to EtOAc:MeOH 95:5) to give slightly yellow crystals (794 mg, 71%). 1H NMR (d6 dimethylsulfoxide (DMSO)) δ 2.13-2.17 (m, 2H, H-2′), 3.57-3.65 (m, 2H, H-5′), 3.81-3.84 (m, 1H, H-4′), 4.23-4.27 (m, 3H, H-3′, CH2N), 5.13 (t, J=5.0 Hz, 1H, OH), 5.20 (d, J=4.3 Hz, 1H, OH), 6.13 (t, J=6.7 Hz, 1H, H-1′), 8.23 (s, 1H, H-6), 10.11 (t, J=5.6 Hz, 1H, NH), 11.70 (br s, 1H, NH). Mass (−ve electrospray) calcd for C14H14F3N3O6 377.08, found 376.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])C(=O)[NH:7]2.[OH-:16].[Na+].OO.Cl>C(O)(=O)C>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([NH2:7])[C:4](=[C:3]([O:2][CH3:1])[CH:11]=1)[C:5]([OH:15])=[O:16]
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(N)c(C(=O)O)c(OC)c1
Temperature: 100 °C
Yield: 50 %

Procedure:
To a heated mixture (in an oversized flask) of 13 g (63 mmol) 4,6-dimethoxyindole-2,3-dione prepared in Example 1 and 108 ml of 33% NaOH solution was carefully added 20 ml of a 30% solution of H2O2. A vigorous exothermic reaction occurs. After all H2O2 was added, the reaction mixture was maintained at 100° C. for an additional 10 min. The pH of the solution was brought to 8 with concentrated HCl and acidified to pH 5-6 with acetic acid. The solid was filtered, washed with water and dried to yield 6.2 g of 4,6-dimethoxyanthranilic acid as a pale brown solid (50% yield).
Reaction SMILES: [CH:1](O)=[O:2].[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([NH2:54])([C:16](=[O:53])[NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([C:16](=[O:53])[NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)([NH:54][CH:1]=[O:2])[CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: O=CO
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccncc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(NC=O)(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
Formic acid (17 mg, 0.36 mmol) was added to a solution of 3-Amino-3-[3-(4-fluoro-phenyl)-1 trityl-indazol-5-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1P) 250 mg, 0.367 mmol); 2-Chloro-4,6-dimethoxy-1,3,5-triazine (77 mg, 0.44 mmol); DMAP (10 mg) and NMM (50 mg, 0.49 mmol) in MeCl2 (3 ml) at room temperature. The solvent was evaporated and residue chromatographed on silica gel eluting with 3% v/v MeOH/MeCl2 yielding 4P as a white solid (210 mg, 80%) ESMS (MH 710).
Reaction SMILES: [NH2:1][C:2]1[C:11](C)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=O.[CH3:13][Mg]Br.CC[O:18][CH2:19][CH3:20]>>[NH2:1][C:2]1[C:3]([CH3:4])=[CH:8][CH:9]=[CH:10][C:11]=1[C:19]([OH:18])([CH3:20])[CH3:13]
Reactant: COC(=O)c1cccc(C)c1N
Reactant: C[Mg]Br
Reactant: CCOCC
Product: Cc1cccc(C(C)(C)O)c1N

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from methyl 2-amino-3-methylbenzoate and methyl magnesium bromide (3 M in diethyl ether) in ether to afford 2-(2-amino-3-methylphenyl)propan-2-ol.
Reaction SMILES: O[CH:2]1[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl.O>[CH3:19][C:16]([CH3:17])([CH3:18])[CH2:15][C:14]([NH:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2[O:4][C:3]([CH3:22])([CH3:23])[CH:2]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:6]=2[C:7]=1[CH3:21])=[O:20]
Reactant: C1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(N1CCCCC1)C(C)(C)O2
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of N-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (450 mg, 1.41 mmol) obtained in Example 234 in dichloromethane (3 mL) was added triethylamine (0.79 mL, 5.64 mmol), and then added dropwise with ice-cooling methanesulfonyl chloride (0.22 mL, 2.82 mmol). The reaction solution was stirred for 30 minutes, and to the reaction solution was added piperidine (0.70 mL, 7.05 mmol), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=20:1) to obtain 270 mg (yield: 50%) of the title compound. Melting point: 229-230° C. (ethyl acetate-hexane).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([N:9]3[C@@H:8]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[C@H:7]([CH2:6][S:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:11][C:10]3=[O:12])=[CH:14][CH:15]=2)=[CH:21][CH:22]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1cccc(F)c1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1O[C@@H](CSc2ccccc2)[C@H](c2cccc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 75 °C

Procedure:
((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (0.3 mmol, prepared by the methods described in example 34) was dissolved in ethanol (1.5 mL) and treated with benzenethiol (0.6 mmol) and triethylamine (0.6 mmol). The reaction mixture was heated to 75° C. for 8 h, then was cooled to room temperature, diluted with ethyl acetate, washed with 1M HCl and then purified on silica gel (10-30% ethyl acetate/hexanes) to give the title compound as a colorless oil. 1H NMR (CDCl3) δ (ppm) 7.31-7.37 (m, 5H), 7.24-7.29 (m, 5H), 7.08 (d, 1H, J=7.7 Hz), 6.97-7.04 (m, 2H), 6.86-6.91 (m, 4H), 5.21 (d, 1H, J=4.0 Hz), (ddd, 1H, J=8.4, 4.0, 4.0 Hz), 3.46 (dd, 1H, J=14.2, 3.9 Hz), 3.22 (dd, 1H, J=14.2, 8.7 Hz). HPLC-MS calculated C28H21ClFNO3S (M+H+): 506.1, found 506.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:6]([CH3:24])=[N:5][N:4]=1.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>N1C=CC=CC=1>[S:25]([O:1][CH2:2][C:3]1[N:7]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:6]([CH3:24])=[N:5][N:4]=1)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2COS(=O)(=O)c2ccc(C)cc2)s1
Reaction time: 8 h

Procedure:
To a solution of 4.5 g of 3-hydroxymethyl-4-(3 -o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole in 50 ml of pyridine is added 2.5 g of tosyl chloride, and the mixture is allowed to stand at room temperature overnight. The solvent is distilled off, and the residue to which water is added is made alkaline with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer is dried over anhydrous sodium sulfate and the solvent is distilled off to give 3-tosyloxymethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole as a yellowish oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:13])[C:8](OCC)=[O:9])[CH2:3][CH2:2]1.O.[NH2:15][NH2:16]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:13])[C:8]([NH:15][NH2:16])=[O:9])[CH2:3][CH2:2]1
Reactant: NN
Reactant: CCOC(=O)C(=O)N1CCOCC1
Solvent: CCO
Solvent: O
Product: NNC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
Ethyl 2-morpholino-2-oxoacetate (1.0 g, 5.34 mmol) was dissolved in ethanol (7 mL) and hydrazine hydrate (0.267 g, 5.34 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give 0.9 g of the crude product, which was used without further purification in the following step. Crude yield 90%. 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 4.43-4.48 (m, 2H), 3.56-3.61 (m, 4H), 3.40-3.48 (m, 4H). LCMS m/z 174.16 [M+H]+, tR=2.031 min.
Reaction SMILES: [N+]([O-])([O-])=O.[Li+].[C:6]([O:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[CH2:13]=[CH:14][CH:15]=[CH2:16].O=O.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:13][CH:14]([O:9][C:10](=[O:12])[CH3:11])[CH:15]=[CH2:16])(=[O:21])[CH3:20].[C:19]([O:22][CH2:15][CH:16]=[CH:11][CH2:10][O:9][C:6](=[O:8])[CH3:7])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: C=CC=C
Agent: O=O
Agent: O=[N+]([O-])[O-]
Agent: [Li+]
Product: C=CC(COC(C)=O)OC(C)=O
Product: CC(=O)OCC=CCOC(C)=O

Procedure:
Another control run was carried out, employing the same reaction vessel as that utilized in Examples I and II above. In this run, the reactor was charged with 3.9 grams (50 mmoles) of lithium nitrate, 50 ml of acetic acid, 25 ml of acetic anhydride, and 11.0 grams (204 mmoles) of butadiene charged from the vapor phase. The reactor was placed in an oil bath and pressured to 30 psig with oxygen, and heated to 140° C for 3 hours. Oxygen was added to the reactor intermittently in the same manner as in Example I. At the end of the reaction period, the reactor was vented and the contents fractionally distilled through an 18 inch Vigreaux column, fraction 1 boiling at 46° - 51° C at 55 mm Hg, weighed 88.4 grams while fraction 2 boiling at 74° - 78° C at 6 mm Hg, weighed 2.1 grams and the distillation residue fraction 3 weighed 17.7 grams and was a thick black tar. Fractions 1 and 2 were analyzed by gas-liquid phase chromatography, which indicated that there was obtained 1.16 grams (6.7 mmoles) of 1,2-diacetoxy-3-butene and 0.43 grams (2.5 mmoles) of 1,4-diacetoxy-2-butene for a total yield of 9.2 mmoles of the diacetoxy butenes. This represents a yield of 4.5% based on the butadiene charged. This result shows that a much lower yield of diacetoxy butenes was obtained when the bismuth catalyst component is omitted from the reaction mixture.