Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c(OC2CCCCO2)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OC2CCCCO2)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 6-chloro-5-((tetrahydro-2H-pyran-2-yl)oxy)nicotinate (546 mg) in toluene (6.7 mL) were added 2-fluoro-5-methoxyphenylboronic acid (512 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (132 mg), tris(dibenzylideneacetone)dipalladium(0) (74 mg) and 2.0 M aqueous sodium carbonate (3.0 mL) solution, and the mixture was stirred at 100° C. for 20 hr. The reaction mixture was poured into water, 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, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (466 mg) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]([CH3:19])[CH2:3][CH2:4][CH:5]([C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:12])C(OCC)=O.N1C=CC(C2CCCC(=O)C=2)=CC=1>>[N:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:19])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(CCC(C)=O)C(=O)c1ccncc1
Agent: O=C1C=C(c2ccncc2)CCC1
Product: CC(=O)CCCC(=O)c1ccncc1

Procedure:
Gelotte et al. U.S. Pat. No. 4,111,946, issued Sept. 5, 1978, shows two sequences for converting ethyl 5-oxo-2-[(4-pyridinyl)carbonyl]hexanoate to 3-(4-pyridinyl)-2-cyclohexen-1-one: (1) heating ethyl 5-oxo-2-[(4-pyridinyl)-carbonyl]hexanoate under aqueous acidic conditions thereby hydrolyzing and decarboxylating it to produce 1-(4-pyridinyl)-hexan-1,5-dione and then reacting said hexan-1,5-dione with a basic condensing agent to produce 3-(4-pyridinyl)-2-cyclohexen-1-one; and, (2) reacting ethyl 5-oxo-2-[(4-pyridinyl)-carbonyl]hexanoate with a basic condensing agent to produce ethyl 3-(4-pyridinyl)-2-cyclohexen-1one-4-carboxylate and then heating said 4-carboxylate under aqueous acidic conditions to hydrolyze and decarboxylate it to produce 3-(4-pyridinyl)-2-cyclohexen-1-one. The 3-(4-pyridinyl)-2-cyclohexen-1one was then reacted with hydroxylamine to convert it into its oxime, an intermediate for preparing 3-(4-pyridinyl)aniline, in turn, an intermediate for preparing rosoxacin, an antibacterial agent, namely 1 -ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CBr
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Yield: 68.3 %

Procedure:
Using the procedure described in Example 1, Part E, 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56g, 6.2 mmol) was treated with 248 mg (6.2 mmol) of 60% NaH/mineral oil and then 0.6 mL (6.2 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.37 g (69% yield) of [[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 89-92° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:34][C:33]4[C:28](=[CH:29][C:30]([O:37][CH2:38][CH2:39][N:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)=[C:31]([O:35][CH3:36])[CH:32]=4)[C:17]=3[N:18]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[CH3:36][O:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C:17]1[N:18]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:25])[CH3:26])[N:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16]=1[CH2:34]2
Reactant: COc1cc2c(cc1OCCN1CCCCC1)-c1c(c(-c3ccc(OCc4ccccc4)cc3)nn1COCC[Si](C)(C)C)C2
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCN1CCCCC1)-c1c(c(-c3ccc(O)cc3)nn1COCC[Si](C)(C)C)C2
Yield: 84.9 %

Procedure:
The mixture of Example 301D (5.50 g, 8.79 mmol) and 10% Pd/C (1.15 g, 1.09 mmol) in THF (100 mL) was treated with H2 (60 psi) at room temperature for 2 days. The mixture was filtered. The solution was concentrated, and purified by flash chromatography to give the desired product (4.0 g, 85%). MS (ESI) m/z 536 (M+H)+.
Reaction SMILES: FC(F)C1N(C)C=C(O)C(=O)C=1.F[CH:14](F)[C:15]1[N:20](C)[C:19]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])=[C:18]([OH:28])[C:17](=[O:29])[CH:16]=1.C(O)C(N)(CO)CO.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CC#N>[OH:28][C:18]1[C:17](=[O:29])[CH:16]=[C:15]([CH3:14])[NH:20][C:19]=1[CH:22]([OH:27])[C:23]([F:26])([F:24])[F:25]
Reactant: Cn1c(C(F)F)cc(=O)c(O)c1C(O)C(F)(F)F
Agent: Cn1cc(O)c(=O)cc1C(F)F
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CC#N
Product: Cc1cc(=O)c(O)c(C(O)C(F)(F)F)[nH]1

Procedure:
Proceeding in a similar manner as A, 2-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one was converted to 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one. 1H NMR (DMSO-d6+1 drop of D2O) δ ppm: 7.12 (t, J=52.8 Hz, 1H), 6.56 (s, 1H), 5.83 (b, 1H), 3.79 (s, 3H). 19F NMR (DMSO-d6+1 drop of D2O) δ ppm: −73.3 (3F), −117.8 (2F). MS (m/z) 274.1 [M+1]+. HPLC conditions: Column: XTerra MS C18 5 μm 4.6×250 mm. Mobile phase: A=the aqueous phase: 4 mM Tris, 2 mM EDTA, pH 7.4; B=the organic phase: CH3CN. The gradient program: B %: 0 min. 5%, 15 min. 55%, 25 min. 55%, 25.05 min. 5%, 30 min. 5%. Flow rate=1 ml/min.; injection volume=5 μL; wavelength: 220, 254, 280, 450 nm. Retention time of 2-Difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one=6.7 min. Retention time of 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one=11.4 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[CH:4][C:5](I)=[C:6]([NH:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:10])[CH:7]=1>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd+2].O1CCOCC1>[Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[CH:4][C:5]2[N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:10])[NH:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2cc(Cl)c(C(F)(F)F)cc2I)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)c(C(F)(F)F)cc32)CC1
Temperature: 80 °C

Procedure:
Under an argon atmosphere, dry 1,4-dioxane (5 ml), palladium 1,1′-bis(diphenyl-phosphino)ferrocene dichloride (10% mol, 0.268 mmol, 220 mg), NatBuO (2 eq., 5.36 mmol, 520 mg) were mixed together and sonicated at room temperature for 10 minutes; 1,1-dimethylethyl 4-[({[5-chloro-2-iodo-4-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-piperidinecarboxylate D11 (2.68 mmol, 1.5 g) was then added at room temperature and the mixture was heated to 80° C. overnight. The reaction mixture was cooled to room temperature, quenched with NH4Cl (saturated solution) and the aqueous solution obtained was extracted with ethyl acetate; the organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (methanol-NH3-dichloromethane) to yield the title compound, 115 mg, 10%, M+−H=418.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>CCCCC>[CH3:1][C:2]([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH3:3]
Reactant: CC(C)=CC(=O)C=C(C)C
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: CC(C)(C)OOC(C)(C)CC(=O)CC(C)(C)OOC(C)(C)C
Temperature: 10 °C

Procedure:
A mixture of 6.9 g. (0.05 mole) of phorone and 23.2 g. (0.2 mole) of anhydrous 81% t-butyl hydroperoxide was diluted with 50 ml of pentane and the mixture stirred at 10° C., while 5.7 g. of 77% sulfuric acid solution was slowly added over a thirty minute time period. The mixture was then allowed to warm slowly to 25° C. and stirred for 72 hours. After the reaction mixture was washed with water and sodium bisulfite solution, it was dried over anhydrous magnesium sulfate, the drying agent separated and the pentane removed under reduced pressure. The product weighed 11.4 g. (71.7% of the calculated amount). The infrared spectrum showed a strong absorption in the 880 cm-1 region, usually associated with t-butylperoxy groups and no absorption in the regions ascribed to hydroxyl or olefin. A GLC scan showed one large major peak for the expected product. By active oxygen assay, the purity of the product was estimated at 93%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.[C:14]1([CH2:20]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12
Reactant: O=C(O)c1cnc2[nH]ccc2c1Cl
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-Carboxylic acid (343 mg) in N,N-dimethylformamide (4 ml) was added phenylmethanol (375 μl) 4-dimethylaminopyridine (428 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (676 mg). After stirring at ambient temperature for 3 days, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform to give benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (200 mg) as a yellow powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:32])[CH:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:31])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:34])[CH3:33].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:31][C@:8]12[C@@:7]3([CH3:32])[CH:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:33])([CH3:34])[C:2](=[O:1])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:21]([C:24]([CH3:26])=[CH2:25])[CH2:22][CH2:23][C@:11]1([C:27]([O:29][CH3:30])=[O:28])[CH2:10][CH2:9]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OC)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OC)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.4 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-methyl 9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (4 g, 8.50 mmol) in CH2Cl2 (100 mL) was added PCC (5.50 g, 25.5 mmol). The reaction mixture was stirred for 15 hours at room temperature. TLC indicated starting material was consumed and a new compound was generated. The reaction mixture was concentrated under reduced pressure and the residue was purified by biotage using ethyl acetate/hexanes (0-20%) to give the desired product (1R,3aS,5aR,5bR,7aR,11aR,13aR,13bR)-methyl 5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate as a white solid (4 g, 100%). 1H NMR (500 MHz, DMSO-D6) δ ppm 0.85 (s, 3H), 0.88 (s, 3H), 0.93 (s, 3H), 0.95 (s, 3H), 0.98 (s, 3H), 1.00-1.64 (m, 17H), 1.65 (s, 3H), 1.73-1.84 (m, 3H), 2.07-2.23 (m, 2H), 2.28-2.39 (m, 1H), 2.39-2.48 (m, 1H), 2.86-3.00 (m, 1H), 3.56-3.63 (s, 3H), 4.58 (s, 1H), 4.71 (d, J=1.83 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:3]=1.BrC1C=CC(C(O)=O)=C(S(C)(=O)=O)C=1.N1(C2CCNCC2)CCCC1.BrC1C(C)=C(C(N2CCC(N3CCCC3)CC2)=O)C=CC=1.[F:71][C:72]([F:83])([F:82])[C:73]1[CH:74]=[C:75](B(O)O)[CH:76]=[CH:77][CH:78]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][S:21]([C:4]1[CH:3]=[C:2]([C:77]2[CH:76]=[CH:75][CH:74]=[C:73]([C:72]([F:83])([F:82])[F:71])[CH:78]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])(=[O:23])=[O:22]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Pd]
Agent: C1CCN(C2CCNCC2)C1
Agent: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(-c2cccc(C(F)(F)F)c2)ccc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described in example 1, (4-bromo-2-methanesulfonyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared from 4-bromo-2-methanesulfonyl-benzoic acid and 4-pyrrolidin-1-yl-piperidine in analogy to the procedure described for the preparation of intermediate 2) was reacted with 3-trifluoromethyl-phenyl boronic acid, potassium phosphate solution and tetrakis-(triphenylphosphine)-palladium in DMF at 80° C. to give the title compound as light yellow oil. MS: 481.2 (MH+).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][Cl:5].[Cl:6][CH2:7][CH2:8][OH:9]>ClCCCl>[Cl:6][CH2:7][CH:8]([OH:9])[CH2:1][O:3][CH2:2][CH2:4][Cl:5]
Reactant: ClC[C@H]1CO1
Reactant: OCCCl
Solvent: ClCCCl
Product: OC(CCl)COCCCl
Temperature: 45 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
step 1—To a solution of R-(−)-epichlorohydrin (7 mL, 89.27 mmol) and DCE (280 mL) was added 2-chloroethanol (6.3 mL, 93.74 mmol) followed by a solution of BF3 Et2O (1.1 mL, 8.927 mmol) and DCE (20 mL). The pale yellow solution was stirred at 45° C. for 2 h. The reaction mixture was allowed to cool to RT, evaporated and dried in vacuo overnight (yield>95%) to afford 1-chloro-3-(2-chloro-ethoxy)-propan-2-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#N)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[NH:27][C:28]1C2C(=CC=CC=2)C(C=O)=CC=1)(C)(C)C.C1(C)C(S([N+]#[C-])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:25][CH:26]=[N:27][CH:28]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)c2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [C-]#[N+]S(=O)(=O)c1ccccc1C
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnco2)c2ccccc12
Yield: 44 %

Procedure:
The above mixture of compounds 503A & 503B (3.37 g, 10.0 mmol; corrected for presence of compound 503A), toluene-sulfonylisocyanide (2.15 g, 11.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 50 mL of methanol was refluxed for 4 h. The reaction mixture was partitioned between water (200 mL) and chloroform (200 mL). After extracting the aqueous layer with chloroform (100 mL), the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a gradient of 10-40% ethyl acetate in hexane to give 1.35 g (44%) of compound 503C as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.57 (s, 1H), 8.20 (m, 2H), 7.76 (m, 2H), 7.64 (s, 1H), 7.62 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:7](=[O:24])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[OH-].[K+].Cl.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]Cl)=[CH:39][CH:38]=1>CO.C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:43][C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)([CH2:25][C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)[C:7](=[O:24])[N:8]2[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(=Cc3ccncc3)c3ccc(Br)cc32)cc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)c3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
4-(6-Bromo-2-oxo-3-pyridin-4-ylmethylene-2,3-dihydro-indol-1-ylmethyl)-N,N-dimethyl-benzenesulfonamide (1.45 g, 2.92 mmol) was dissolved in a previously degassed solution of 50 ml of methanol and 50 ml of THF under an atmosphere of dry N2. To this solution was added sodium borohydride (177 mg, 4.67 mmol). The reaction was stirred at ambient temperature for 1.5 hours after which time 11.7 ml of aqueous 1.0 N potassium hydroxide (KOH) was added followed by the addition of 4-picolyl chloride hydrochloride (520 mg, 3.08 mmol). The reaction mixture was then stirred at ambient temperature for 2 hours after which time the reaction mixture was concentrated under vacuum to give a dark oil. The dark oil was partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was then washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give a dark oil which was chromatographed on flash silica gel eluting with a gradient from EtOAc/hexanes (60:40) to EtOAc/Hexanes (80:20) to give 650 mg of the titled compound as a pink solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[O-:10][C:11]#[N:12].[Na+]>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([NH2:12])=[O:10])=[CH:5][CH:4]=1
Reactant: N#C[O-]
Reactant: CSc1ccc(N)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(NC(N)=O)cc1
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 30 g (170 mmol) of 4-(methylmercapto)aniline dissolved in 83 ml of acetic acid and 165 ml of water was heated to 40° C. Once warmed to 40° C. a solution of sodium cyanate (22.2 g; 340 mmol) in 150 ml of water was slowly added. The resulting suspension was stirred for 15 minutes and then allowed to sit for 2 hours. Filtration of the suspension provided 29.98 g of title compound. m.p. 155°-159° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccsc3)n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2cccc(-c3ccsc3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 2, but starting from 5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A1), 82 mg; 0.38 mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride (55 mg; 0.3 mmol; 1.2 eq.) as a beige solid (21 mg, 26%). HPLC, Rt: 2.15 min. (purity 97.3%). LC/MS, M+(ESI): 322.0, M−(ESI): 320.0.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11](Cl)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].N1C=CC=CC=1>CC(C)=O>[C:1]([O:9][CH2:10][C:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: O=C(Cl)COC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(OCC(=O)N1CCCC1=O)c1ccccc1
Yield: 64.7 %

Procedure:
A mixture of (benzoyloxy)acetyl chloride (1.98 g, 0.01 mole), pyrrolidone (0.85 g, 0.01 mole) and pyridine (0.8 g, 0.01 mole) in acetone (10 ml) was refluxed for 3 h. The cooled mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and the solution washed with a 2% aqueous solution of sodium bicarbonate, 2M hydrochloric acid and water. After drying over anhydrous sulphate, the organic phase was evaporated under reduced pressure to give a residue which crystallized by addition of ether. Recrystallization from ether-petroleum ether yielded 1.6 g (65%) of the title compound. Mp 83°-84° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-])=O)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C.[OH-].[Na+]>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)c1cc(Cl)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC[C@H](NC(=O)c1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a stirred solution of (S)-2-(5-chloro-2-nitro-benzoylamino)-butyric acid-tert-butyl ester (5.72 g,) in ethanol (250 ml) at ambient temperature was added tin(II) chloride bis-hydrate (18.8 g). The mixture was stirred at ambient for 16 hours. The volume was reduced to approximately 50 ml under reduced pressure, and reaction mixture was then diluted with 1M NaOH until the precipitate formed re-dissolved (400 ml). The aqueous was then extracted with diethyl ether (3×100 ml). The organic extracts were combined and washed with brine, dried (MgSO4), and concentrated to give the sub-titled compound as a yellow solid (4.60 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.4 (1H, s), 7.2 (1H, d), 6.6 (2H, m), 5.5 (2H, m), 4.6 (1H, m), 2.0 (1H, m), 1.85 (1H, m), 1.5 (9H, s), 0.95 (3H, t) ppm.