Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].N.CO.Cl.C([N:41]=C=NCCCN)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH2:41])=[O:31])=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2]
Reactant: CCN=C=NCCCN
Reactant: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(N)=O)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 27 h
Yield: 79.9 %

Procedure:
A mixture of 3-(4-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}-2-fluorophenyl)propanoic acid (0.233 g, 0.500 mmol), 7 M ammonia/methanol (0.4 mL, 2.80 mmol) solution, 1-ethyl-3-(3-aminopropyl)carbodiimide hydrochloride (2.88 g, 1.50 mmol), 1-hydroxybenzotriazole (0.230 g, 1.50 mmol), 1,8-diazabicyclo[5.4.0]-7-undecene (0.448 mL, 3.00 mmol), triethylamine (0.502 mL, 3.60 mmol) and acetonitrile (3 mL) was stirred at room temperature for 27 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) to give the title compound (0.186 g, yield 80%) as a colorless oil.
Reaction SMILES: C(NCC)C.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22]I)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>[Cu](I)I.O>[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#CI)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(C#CC#C[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of dichlorobistriphenylphosphine palladium (4.2 mmol) and copper iodide (0.64 mmol) was added diethylamine, and stirred at room temperature under argon gas atmosphere for 30 minutes. Then, 4-(trans-4-propylcyclohexyl)-1-(2-iodoethynyl)benzene (0.12 mol) was added thereto, and further stirred at room temperature for 15 minutes. To this reaction mixture was added (trimethylsilyl)acetylene (0.14 mol), and stirred at room temperature overnight. After completion of the reaction, water was added thereto and extracted with toluene twice. The organic layer thus obtained was washed with water, and then dried over anhydrous magnesium sulfate. After it was subjected to filtration, the solvent was distilled off under a reduced pressure. The residue was purified by column chromatography (silica gel/heptane) and recrystallization (ethanol) to obtain colorless crystals of 4-(trans-4-propylcyclohexyl)-1-(4-trimethylsilyl-1,3-butadiyne-1-yl)benzene. (Yield 24%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].[OH-].[Na+].[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1C=CC=CC=1>[N:22]1([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([C:11]2[C:12]3[CH:13]=[CH:14][NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCCC1
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1OCCN1CCCCC1)c1cccc2[nH]ccc12

Procedure:
3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide in 50 ml of benzene, 25 ml of acetronitrile and 50 ml of a 5N aqueous solution of sodium hydroxide were heated to 60° C. for 3 hours with stirring under an inert atmosphere with 0.4 g of 2-tetrabutylammonium hydrogensulfate and 2.2 g of 2-piperidino-1-chloroethane. After cooling, decanting, extracting with ethyl acetate and purifying by chromatography over silica (eluent:ethyl acetate--triethylamine, 9-1), 3.6 of N-[2-[2-(1-piperidinyl)ethoxy]phenyl]-1H-indol-4-carboxamide were obtained.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([CH2:26][Cl:25])[CH:28]=2)[CH:10]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
Triethylamine (2.0 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)benzamide (3.0 g), 3-chloromethylbenzoyl chloride (2.76 g), 4-dimethylaminopyridine (0.162 g) and methylene chloride (50 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under 2N aqueous hydrochloric acid solution. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. There was thus obtained the title compound (5.1 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 4.85 (s, 2H), 7.23 (d, 1H), 7.55 (m, 5H), 7.66 (d, 1H), 7.84 (s, 1H), 7.95 (m, 3H), 8.05 (s, 1H), 9.96 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M−H− 377.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.[ClH:39]>CO.CCOCC>[ClH:39].[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (82 mg, 0.16 mmol) was treated with 1.25 M HCl in MeOH (5.0 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with Et2O, and the resulting solids were collected by filtration to provide the title compound (55 mg, 76%) as a yellow solid: 298-302° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 9.30 (br s, 1H), 9.15 (t, J=1.0 Hz, 1H), 8.42-8.34 (m, 2H), 8.13 (d, J=8.0 Hz, 1H), 8.08 (d, J=7.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.13 (dd, J=7.0, 2.0 Hz, 1H), 4.39 (s, 2H), 3.74 (s, 3H), 3.60-3.51 (m, 2H), 3.15 (t, J=6.0 Hz, 2H); ESI MS m/z 426 [M+H]+; HPLC (Method A) 98.8% (AUC), tR=13.7 min.
Reaction SMILES: [N:1]1([CH:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@@H:43](O)[CH2:42]2>C1COCC1>[N:1]1([CH:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][C@@H:43]2[CH:44]3[CH2:47][CH2:48][N:41]([CH2:46][CH2:45]3)[CH2:42]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1cccs1)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1cccs1)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
A mixture of 2-(piperidin-1-yl)-2-(thiophen-2-yl)acetic acid (250 mg, 1.11 mmol), DCC (458 mg, 2.22 mmol), HOBT (300 mg, 2.22 mmol) and (R)-quinuclidin-3-ol (282 mg, 2.22 mmol) in dry THF (11.1 ml) was stirred at room temperature under nitrogen atmosphere for 24 hours. The pale pink suspension was filtered washing with THF (5 ml) and the pale pink solution was evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5+0.4% NH4OH) to obtain the title compound (132 mg, 35.6% yield) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[Si:18]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl 4-hydroxycyclohexanecaboxylate (3.44 g, 20.0 mmol) was dissolved in DMF (7 mL), and imidazole (3.40 g, 50.0 mmol) and tert-butyldimethylsilyl chloride (3.62 g, 24 mmol) were added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=10:1) to afford ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate (5.73 g, 100%).
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[NH2:9][CH:10]([CH3:13])[CH2:11][OH:12]>C(O)C>[C:1]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])(=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: CCOC(=O)C(C)O
Reactant: CC(N)CO
Solvent: CCO
Product: CC(CO)NC(=O)C(C)O
Temperature: 112.5 °C

Procedure:
3.7 g ethyl lactate and 2.1 g 2-amino-1-propanol were mixed and subsequently heated to 110-115° C. for 2.5 hours. During the reaction, the ethanol formed was distilled off. After the reaction the excess of ethyl lactate was removed by vacuum distillation (bottom temperature: 150° C., 1 mbar), using a 20 cm vigreux column. 3.9 g of residual N-lactoyl 2-amino-1-propanol (brown viscous liquid) was collected, the purity of which was confirmed by NMR analysis. The yield of the reaction was 95%
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[CH:11]=1)(=O)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[F-].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.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.C1(C)C=CC=CC=1.O>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:7]2[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[CH:11]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)OC(=O)C=C1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CC(=O)OC2(C)C)cc1
Temperature: 50 °C

Procedure:
To a 1:1 mixture of toluene/water (20 mL), were added 2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (100 mg, 0.38 mmol), 4-methoxyphenylboronic acid (87 mg, 0.57 mmol), PdCl2(PPh3)2 (27 mg, 0.038 mmol), 2M KF aqueous solution (0.95 mL, 1.9 mmol), benzyltriethylammonium chloride (8.7 mg, 0.038 mmol). The mixture was heated at 50° C. under N2 for 30 minutes, cooled to room temperature and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4. Purification through silica gel column with 10-30% EtOAc/hexanes led to the product as yellow solid. Yield: 33 mg, 40%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([C:17]([O:19][CH2:20][CH2:21][Br:22])=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)Cl>C(OCC)(=O)C.CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:24])=[C:14]([C:17]([O:19][CH2:20][CH2:21][Br:22])=[O:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)OCCBr)=CS[C@H]12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(=O)OCCBr)CS[C@H]12
Temperature: 5 °C
Yield: 53 %

Procedure:
To a cooled (5° C.) stirred solution of benzhydryl 7-(2-thienylacetamido)-3-(2-bromoethoxycarbonyl)-2-cephem-4-carboxylate (0.29 g., 0.453 mmol.) in 30 ml. chloroform was added 85% m-chloroperbenzoic acid (0.101 g., 497 mmol.) in 3 ml. chloroform. The mixture was allowed to stir with cooling for 30 minutes, and then was washed with sodium bicarbonate solution (2X) and sodium chloride solution and dried over Na2SO4. Evaporation in vacuo gave 301 mg. of the Δ3 sulfoxide. The sulfoxide was dissolved in 25 ml. dimethylformamide, cooled briefly, and then treated with 0.06 ml. (0.678 mmol., 1.5 eq.) phosphorous trichloride. The mixture was allowed to stir at ambient temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, and then it was washed successively with water (2X), aqueous sodium bicarbonate (2X), and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to dryness. The crude product was chromatographed on 5 g. of silica gel using a benzene-ethyl acetate gradient providing benzhydryl 7-(2-thienylacetamido)-3-(2-bromoethoxycarbonyl)-3-cephem-4-carboxylate (0.154 g., 53%) as a colorless solid: ir (CHCl3) 1799 cm-1 (β-lactam C = 0); nmr (DMSO-d6) 3.34 (m, 2, CH2Br), 3.76 (s, 2, side chain CH2), 3.8-4.4 (m), 5.20 (d, 1, J = 5.0 Hz, C6 --H) and 5.86 ppm (q, 1, J = 5.0 and 9.0 Hz, C7 --H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][C:9]32[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.C(=O)(O)[O-:19].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[O:19]1[CH:6]2[CH:7]1[CH2:8][C:9]1([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]1)[C:10]1[C:5]2=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=1
Reactant: O=C1NC(=O)C2(CC=Cc3ccc(F)cc32)N1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C2(CC3OC3c3ccc(F)cc32)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a slurry of 2.6 g. (0.011 mole) of 7'-fluorospiro[imidazolidine-4,1'(2'H)-naphthalene]2,5-dione in 50 ml. of chloroform was added 125 ml. of a 5% sodium bicarbonate solution followed by 3.0 g. (0.014 mole) of m-chloroperbenzoic acid. The reaction mixture was allowed to stir at room temperature for 4 hours after which an additional 1.2 g. (0.0055 mole) of m-chloroperbenzoic acid were added. After stirring overnight at room temperature the mixture was poured into 100 ml. of a 5% sodium bicarbonate solution and the mixture extracted (2×100 ml.) with chloroform and then with ethyl acetate (2×100 ml.). The organic extracts were combined, washed with water and a brine solution and dried over magnesium sulfate. Removal of the solvent gave 600 mg. (22% yield) of the desired product.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:15]([Sn](C)(C)C)[CH:14]=1>CN(C)C=O.[Cu]I>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])=[C:15]([C:2]2[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:14]=1
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: C[Sn](C)(C)c1cc(Cl)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2cc(Cl)cc3c2cnn3S(=O)(=O)c2ccccc2)o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
In 4 batches, tetra is(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g, 29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches, tetra is(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59 mmol) and copper(I) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g, 8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch, tetra is(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(I) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g, 2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated and stirred at 100° C. under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[I-:14].[K+]>C(#N)C>[I:14][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCl)cc1
Reactant: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCI)cc1

Procedure:
70 g (352.4 mmol) of methyl 4-(2-chloroethyl)benzoate [CAS Reg. No. 65787-72-6] and 146.2 g (880.9 mmol) of potassium iodide are suspended in 800 ml of acetonitrile and stirred under reflux for three days. After the reaction has gone to completion, the reaction solution is cooled and filtered and the filtrate is evaporated to dryness under reduced pressure. The resulting residue is purified by flash chromatography on silica gel (mobile phase:petroleum ether/ethyl acetate 30:1→20:1). This gives 101 g (348.3 mmol, 98.8% of theory) of a yellowish oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][CH:13]([CH3:15])[CH3:14].[CH3:19][Si](Cl)(C)C>CO>[CH3:19][O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH:1][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:10]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.50 g of L-leucine-L-leucine, under argon, is added, via a syringe, 10 ml of methyl alcohol and 0.610 ml of trimethylsilyl chloride. The reaction is stirred overnight at room temperature. The mixture is concentrated in vacuo to give 0.554 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[N:7](C(=O)C)[CH2:6][CH2:5]2.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[NH:7][CH2:6][CH2:5]2
Reactant: CNS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1cc2c(cc1Br)CCN2
Yield: 98.5 %

Procedure:
To a stirred suspension of 65.11 g (0.195 mol) of 5-bromo-6-methylsulfamoyl-N-acetylindoline in 200 ml dioxane was added 146 ml (1.75 mol) concentrated hydrochloric acid. The mixture was stirred and refluxed for 1.5 hours and allowed to cool. The mixture was then concentrated under reduced pressure, cooled in an ice bath and neutralized with 10% sodium hydroxide solution to pH 7. The resulting white precipitate was filtered, washed several times with water and allowed to dry overnight to give 55.92 g (98% by weight yield) of 5-bromo-6-methylsulfamoylindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:30]([NH2:32])=[O:31])[C:27]([NH2:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:30]([NH2:32])=[O:31])([C:27]([NH2:29])=[O:28])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Reactant: NC(=O)C(Br)(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Cc1ccc2c(c1)OC(C(N)=O)(C(N)=O)O2)N1CC(c2cccc(Cl)c2)OC1=O

Procedure:
One equivalent of 5-(3-chlorophenyl) -3-(2-(3,4-dihydroxyphenyl)-1-methylethyl )-2-oxazolidinone, prepared by the procedure of U.S. Pat. No. 5,061,727; Example 1, one equivalent of dibromomalonamide, acetonitrile, and 4 equivalents of potassium carbonate are stirred at room temperature for 18 hours. The reaction mixture is filtered and evaporated in vacuo to give 5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3 -benzodioxole-2,2-dicarboxamide.
Reaction SMILES: N[C:2]1N=C(C(O)=O)C(C)=C[CH:3]=1.[NH2:12][C:13]1[N:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15]([OH:17])=[O:16]>>[CH3:22][C:18]1[CH:19]=[CH:20][N:21]2[CH:2]=[CH:3][N:12]=[C:13]2[C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1ccnc(N)c1C(=O)O
Reactant: Cc1ccc(N)nc1C(=O)O
Product: Cc1ccn2ccnc2c1C(=O)O

Procedure:
Prepared analogous to Example 82 substituting 6-amino-3-methylpicolinic acid with 2-amino-4-methylnicotinic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2.Cl.[N:18]([O-])=[O:19].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:18]=[O:19])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2
Reactant: Cc1ccc2c(c1)CC(c1ccccc1)N2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)CC(c1ccccc1)N2N=O
Reaction time: 0.08 h
Yield: 100.5 %

Procedure:
5-Methyl-2-phenylindoline (0.7 g, 0.00334 mol) was dissolved in ethanol (5 mL), and 1N hydrochloric acid solution (3.5 mL) was added at 0° C. The resulting reaction mixture was stirred for 5 min, and then a solution of sodium nitrite (0.462 g, 0.00668 mol) in water (8.5 mL) was added at 0° C. The mixture was stirred for 1 h at RT, and after completion of reaction (monitored by TLC), the solvent was removed under reduced pressure to obtain product as a brown colored oil (0.8 g).