Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:34]=1>C1COCC1>[CH2:29]([N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:9]2[CH:8]=[C:7]3[C:6](=[CH:11][CH:10]=2)[NH:5][C:4](=[O:31])[C:3]3=[CH:2][NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:37][CH:38]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1)[CH3:30]
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(CC(=O)O)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 1, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added 4-aminophenylacetic acid (16.4 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of ice cold THF yielding 42% (16.7 mg, 0.030 mmol) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:25]2[S:29][C:28]([C:30]([CH:35]3[CH2:37][CH2:36]3)([CH:32]3[CH2:34][CH2:33]3)[OH:31])=[N:27][CH:26]=2)[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH:35]1([C:30]([CH:32]2[CH2:33][CH2:34]2)([C:28]2[S:29][C:25]([C:15]3[CH:14]=[C:13]([NH:12][C:2]4[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=4)[CH:18]=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=3)=[CH:26][N:27]=2)[OH:31])[CH2:37][CH2:36]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(-c2cnc(C(O)(C3CC3)C3CC3)s2)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: OC(c1ncc(-c2cc(Nc3nccc(C(F)(F)F)n3)cc(N3CCOCC3)c2)s1)(C1CC1)C1CC1
Temperature: 125 °C
Yield: 53.6 %

Procedure:
To a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (0.079 mL, 0.654 mmol) and the product of Step 5 (221 mg, 0.595 mmol) in dioxane (4.0 mL) was added cesium carbonate (388 mg, 1.190 mmol), Pd(OAc)2 (6.68 mg, 0.030 mmol) and XantPhos (51.6 mg, 0.089 mmol) and the mixture was heated to 125° C. for 2 hours. After cooling to room temperature, 1.5 mL of water was added and the reaction mixture was filtered through a celite column with dichloromethane. The filtrate was concentrated and the residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes). The yellow residue was triturated in diethyl ether (with trace dichloromethane) to give dicyclopropyl{5-[3-(morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}methanol (165 mg, 0.319 mmol, 54% yield) as an off-white solid. MS APCI: [M+H]+ m/z 518.1. 1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H); 8.84 (d, J=4.9 Hz, 1H); 7.98 (s, 1H); 7.57 (s, 1H); 7.40 (s, 1H); 7.28 (d, J=4.9 Hz, 1H); 6.89 (s, 1H); 5.38 (s, 1H); 3.77 (t, J=4.3 Hz, 4H); 3.17 (t, J=4.4 Hz, 4H); 1.41-1.33 (m, 2H); 0.54-0.38 (m, 6H); 0.32-0.24 (m, 2H). rhSYK activity=+++
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][C:22]#[N:23])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Sn]([N:39]=[N+:40]=[N-:41])(CCCC)(CCCC)CCCC.[OH-].[K+].CO>C1(C)C=CC=C(C)C=1>[CH:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]#[CH:19])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][C:22]2[NH:41][N:40]=[N:39][N:23]=2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: C#CCOc1ccc(NCC#N)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1cccc(C)c1
Solvent: CO
Product: C#CCOc1ccc(NCc2nnn[nH]2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of 0.82 g (2.47 mmol) [2-(4-isopropyl-benzoyl)-4-prop-2-ynyloxy-phenyl-amino]-acetonitrile and 0.8 ml (3.31 mmol) Bu3SnN3 in 20 ml m-xylene is stirred at reflux temperature for 5 h. Then the reaction mixture is cooled to room temperature and 15 ml 2N KOH and 2 ml MeOH are added. This mixture is stirred vigorously for 15 min. After that the phases are separated and to the water layer 4 N HCl is added until a pH ˜1 is reached. The aqueous layer is extracted with dichloromethane/isopropanol=3:1. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is suspended in diethyl ether, stirred for 0.5 h, filtered and dried to afford 0.89 g of the title compound as yellow crystals.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].[OH-].[Na+].O>C(O)C>[C:10]1([CH:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 68.9 %

Procedure:
To a solution of 140 g (0.71 mol) of deoxybenzoin and 170 g (1.7 mol) of ethyl acrylate in 2 L of absolute ethanol at ambient temperature was added in portions 20 mL of 50% aqueous sodium hydroxide. An additional 170 g (1.7 mol) of ethyl acrylate was then added over a 15 min. period. The mixture was stirred vigorously for 2.5 h, poured into 1 L of water and extracted with 3×1 L of ether. The organic layers were combined, washed with water and brine, and dried over sodium sulfate. The filtrate was concentrated to near dryness, triturated with 1.5 L of pentane, filtered and the filtrate allowed to stand at -20° C. giving 145 g (69%) of ethyl 4,5-diphenyl-5-oxopentanoate as a white solid (top 45°-57° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])=[CH:15][CH:14]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CC(C)C(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(Cc1ccc(C(=O)C(C)C)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 3a using 3-oxopentanoic acid ethyl ester and 1-(4-bromomethylphenyl)-2-methylpropan-1-one.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:27]([C:31]([OH:33])=[O:32])([F:30])([F:29])[F:28]>C1(C)C=CC=CC=1>[F:28][C:27]([F:30])([F:29])[C:31]([OH:33])=[O:32].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH2:7][C:6]([OH:26])=[O:5])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCC(=O)O)cc12

Procedure:
A solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine t-butyl ester (24 mg, 0.06 mmol) in CF3CO2H (0.5 ml) was stirred at 0° C. for 1.5 h. The reaction mixture was diluted with PhMe, evaporated in vacuo, azeotroping with PhMe, and the residue triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine trifluoroacetate (21 mg, 0.05 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7](=[S:31])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccccc1NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1NC(=S)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 145.1 %

Procedure:
A mixture of 102.4 g of 4-trifluoromethyl-2'-methoxybenzanilide prepared by the same manner as described in (1), 77.2 g of Lawesson's reagent, and 400 ml of toluene was refluxed for 1 hour. The reaction mixture was cooled to about 100° C. and then 300 ml of water was added. The resulting mixture was refluxed for 1 hour. The organic layer was separated, dried over magnesium sulfate, and concentrated to about 200 ml of volume. The precipitate was collected by filtration, washed with toluene, and dried to give 86.2 g of 4-trifluoromethyl-2'-methoxybenzothioanilide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)=[S:24])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2ccccn2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccccn3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenylthio)pyridine (6.0 mmoles, 1.2 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (6.0 mmoles, 1.4 g) were reacted according to procedure C to yield the title compound, 1.9 g, 72%. Mass spec (FD) 439. Calculated for C19H13ClF3N3 S2 : C, 51.88; H, 2.98, N, 9.55 Found: C, 51.99; H, 3.15; N, 9.63.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[N:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)=[O:7])C>O1CCCC1.O>[Cl:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[N:15]=2)[N:10]=[CH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ncc(C(=O)O)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.1 %

Procedure:
Sodium hydroxide (5.86 g, 140.6 mmol, 2.5 eq) is added protionwise at room temperature to a stirred solution of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (15.0 g, 56.25 mmol, 1.0 eq) in tetrahydrofuran (150 mL) and water (80 mL). After 15 hours stirring at room temperature, tetrahydrofuran is removed, the aqueous layer is cooled down to 0° C. and the pH is adjusted to 3 by the addition of a 2N hydrochloric acid aqueous solution. The resulting precipitate is collected by filtration, washed with water and dried under high vacuum to afford 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid as a light red solid (12.9 g, 96% yield).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C)C=O>[Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[N:4]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: O=Cc1c(Br)n[nH]c1Br
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(Br)c(C=O)c2Br)cc1
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
3,5-Dibromo-1H-pyrazole-4-carbaldehyde (987.9 mg, 3.89 mmol) and potassium carbonate (1.613 g, 11.67 mmol) were dissolved in N,N-dimethylformamide (39 mL) at 25° C. under Ar. 4-methoxybenzyl bromide (617 μl, 4.28 mmol) was added dropwise. The reaction mixture was allowed to stir for 2 h 10 min. The reaction was stopped, quenched by addition of saturated aqueous ammonium chloride (30 mL), and the mixture extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×20 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-55%). The title compound (L3342 g, 3.57 mmol, 92% yield) was recovered as a colorless, very viscous oil. LC-MS [M+1]=373.1.
Reaction SMILES: [C:1]([Si:3]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5])#[CH:2].Br[C:14]1[CH:15]=[CH:16][C:17]([F:21])=[C:18]([OH:20])[CH:19]=1.C(N(CC)CC)C>CN(C=O)C.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[F:21][C:17]1[CH:16]=[CH:15][C:14]([C:2]#[C:1][Si:3]([CH:7]([CH3:9])[CH3:8])([CH:4]([CH3:6])[CH3:5])[CH:10]([CH3:12])[CH3:11])=[CH:19][C:18]=1[OH:20]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Oc1cc(Br)ccc1F
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1ccc(F)c(O)c1)(C(C)C)C(C)C

Procedure:
A solution of Ethynyl-triisopropyl-silane (1.13 g, 6.20 mmol), 5-bromo-2-fluorophenol (0.955 g, 4.98 mmol), bis(triphenylphosphino)palladium(II) chloride (0.105 g, 0.15 mmol), copper iodide (0.039 g, 0.205 mmol) and triethylamine (2.9 g, 28.7 mmol) in DMF (4.0 mL) is irradiated in the CEM explorer at 80° C. for 30 min. The solvent is removed and the product purified by Flash Chromatography to yield 2-fluoro-5-((triisopropylsilyl)ethynyl)phenol.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7](/[C:11](/[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:12]\[CH2:13][CH2:14][CH2:15][N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl>[NH2:4][C:5]1[CH:6]=[C:7](/[C:11](/[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:12]\[CH2:13][CH2:14][CH2:15][N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(/C(=C\CCCn2cnnn2)c2cccnc2)c1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Product: Nc1cccc(/C(=C\CCCn2cnnn2)c2cccnc2)c1

Procedure:
5.7 g of 4E-1-(5-(3-acetylaminophenyl)-5-(3-pyridyl)-pent-4-enyl)tetrazole are heated in 60 ml of 4N hydrochloric acid for 5 hours at 60° C. The reaction solution is neutralised by the addition of sodium bicarbonate and then adjusted to a pH value of 4-5 by the addition of citric acid. The aqueous phase is extracted with dichloromethane/methanol=4:1. The organic phase is washed with saturated sodium chloride solution, dried and concentrated by evaporation.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:29][C:30]1[C:35]([Pb+3])=[C:34]([CH3:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:29][C:30]1[C:35]([CH:4]2[C:3](=[O:12])[CH:2]3[CH:6]([CH:7]4[O:10][CH:1]3[CH2:9][CH2:8]4)[C:5]2=[O:11])=[C:34]([CH3:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 25 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (166 mg, 1 mmol) and 4-dimethylaminopyridine (610 mg, 5 mmol) under an atmosphere of nitrogen is added dry chloroform (5.6 ml), and the mixture is stirred at room temperature until all the solids are dissolved. To this solution is then added dry toluene (2 ml), and 3,5-dimethylbiphen-4-yllead triacetate (0.5 M solution in dry chloroform, 2.4 ml, 1.2 mmol). The reaction mixture is heated at reflux for 1 hour, then cooled to room temperature, acidified to pH1 with 2N aqueous hydrochloric acid, filtered and extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(3,5-dimethylbiphen-4-yl)-10-oxa-tricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20]([N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])=[C:4]([O:31]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20]([N:23]([CH3:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:21])=[O:22])=[C:4]([OH:31])[CH:3]=1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N(C)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(c1ccccc1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1O
Temperature: -78 °C

Procedure:
4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-N-phenyl-benzenesulfonamide (88 mg, 0.18 mmol) was dissolved in DCM (5 mL) and cooled to −78° C. A solution of BBr3 (125 mg, 0.5 mmol, 47 μL) in DCM (1 mL) was added at −78° C. and then warmed to −20° C. for 2 h. The reaction was quenched by addition of water (2 mL) and the mixture was warmed to r.t. followed by addition of EtOAc. The organic layer was separated, washed with NaHCO3 (aq) and dried (MgSO4). Purification by prep TLC eluting with 20% acetone/hexane gave 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-hydroxy-N-methyl-N-phenyl-benzenesulfonamide contaminated with 30% of the starting material (69 mg). 35 mg of this material was dissolved in DMF (0.3 mL) and K2CO3 (14 mg, 0.1 mmol) was added followed by t-butyl-bromoacetate (20 mg, 0.1 mmol) and the mixture was stirred at r.t. for 3 days. The solvent was removed in vacuo and purification by prep TLC eluting with 20% acetone/hexane gave [5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid tert-butyl ester (27 mg, 0.046 mmol). MS [M+H-tBu+H]+: 526.0; tR=3.18 min. (method 1)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[CH2:2]1.Cl[C:18]1[N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=1.C(N(CC)CC)C>O1CCCC1>[CH3:31][N:19]1[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=[C:18]1[N:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[CH2:2]1
Reactant: CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Yield: 58 %

Procedure:
A solution of N-(4-((2S)-morpholin-2-yl)phenyl)acetamide (2.63 g, 11.9 mmol), 2-chloro-1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine (2.60 g, 11.9 mmol), and triethylamine (3.60 g, 35.7 mmol) in tetrahydrofuran (100 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to afford N-(4-((2S)-4-(1-Methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidin-2-yl)morpholin-2-yl)phenyl)acetamide (2.8 g, 58%) as pale yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=O.[C:24]([NH2:27])(=[S:26])[CH3:25].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:23][N:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]1[N:27]=[C:24]([CH3:25])[S:26][CH:2]=1)=[CH:13]2)[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: CN(c1cccc2cc(C(=O)CCl)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)cs1
Yield: 10.6 %

Procedure:
A mixed solution of N-[2-(2-chloroacetyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (570 mg), thioacetamide (0.20 g) and N,N-dimethylacetamide (15 ml) was stirred at 80° C. for 2 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-4:6), the obtained crude product was purified by preparative HPLC, and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (64 mg, yield 11%) as colorless needle crystals. melting point 161-162° C. MS:390 (MH+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:8]=1[CH3:23]>C1COCC1.CO>[CH3:23][C:8]1[N:9]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]=1[CH2:6][C:5]([OH:24])=[O:4]
Reactant: COC(=O)Cc1c(C)n(Cc2cccnc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1cccnc1
Reaction time: 2 h

Procedure:
1M Aqueous NaOH (0.5 mL) is added to a stirring solution of (2-methyl-1-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (35 mg, 0.12 mmol) in 1:1 THF/MeOH (2 mL). After 2 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 3-4, and the resulting precipitate collected by filtration to furnish (2-methyl-1-pyridin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid; MH+=282.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6](N2CCCC2)=[C:5]([C:19]#[N:20])[C:4]1=[O:21])[CH3:2].[OH-:22].[Na+].Cl>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6]([OH:22])=[C:5]([C:19]#[N:20])[C:4]1=[O:21])[CH3:2]
Reactant: [OH-]
Reactant: CCn1c(=O)c(C#N)c(N2CCCC2)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1c(=O)c(C#N)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 0.5 g. of 1-ethyl-1,2-dihydro-7-methyl-2-oxo-4-(1-pyrrolidinyl)-1,8-naphthyridine-3-carbonitrile in 15 ml. of 20% aqueous sodium hydroxide containing 15 ml. of ethanol was heated under reflux for 3 hours. The solution was cooled and was acidified with concentrated hydrochloric acid. The precipitate which formed was collected, air dried and was recrystallized from ethanol to afford 0.2 g. of the title compound, m.p. 274°-6° C.