Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Agent: CC(C)C[AlH]CC(C)C
Product: Ic1cnc2c(c1)NCCN2
Yield: 31 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (200 mg) was reduced as in General Procedure 3 using 4 eq DIBAL-H to give the title compound as a white solid (31% yield). M.p. 126-128° C., LCMS: m/z=262.30 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.13-3.17 (m, 2H), 3.27-3.29 (m, 2H), 5.78 (s, 1H), 6.37 (s, 1H), 6.78 (d, J=2.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([CH3:14])[S:11][C:12]=2[NH2:13])[CH:7]=1.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]2=[C:19]([C:26](Cl)=[O:27])[CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([CH3:14])[S:11][C:12]=2[NH:13][C:26]([C:19]2[CH:18]=[N:17][N:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=23)=[O:27])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nc(C)sc1N
Reactant: O=C(Cl)c1cnn2cccnc12
Product: COc1ccc(Cl)cc1-c1nc(C)sc1NC(=O)c1cnn2cccnc12

Procedure:
Using 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-amine and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride the title compound was synthesized following the synthetic procedures described for N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with further purification by flash chromatography on silica gel (0 to 100% ethyl aceate in DCM) to give N-(4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as an orange solid. LCMS (ESI) m+H=400.0; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, br, 1H); 9.38 (dd, 1H); 8.75-8.73 (m, 1H); 8.72 (s, 1H); 7.52 (dd, 1H); 7.47 (d, 1H); 7.34-7.32 (m, 2H); 3.79 (s, 3H); 2.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:6]([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: O=[N+]([O-])c1ccc(N(c2ccc(Cl)cc2)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Bis(p-nitrophenyl)-p-chlorophenylamine (3.70 grams, 0.010 mol) obtained by the Ullmann condensation of p-chloroaniline and p-nitroiodobenzene was mixed with 125 ml of N,N-dimethylformamide and 2,50 grams (0.045 mol) of iron powder, and dilute hydrochloric acid prepared using 1.5 ml of concentrated hydrochloric acid and 4 ml of water was added to the mixture which was then reacted for 1 hour at 100° C. The mixture was then neutralized by the addition of a saturated aqueous solution of sodium carbonate and the resulting mixture was filtered while hot. The filtrate was poured into 1.5 liters of ice water and 2.33 grams (yield 69%) of p-aminophenyl-p-nitrophenyl-p-chlorophenylamine was obtained on recovering the material which precipitated out by filtration.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1O)([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:28][N:27]=[N:26][N:20]=3)=[CH:15][CH:14]=2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cc(SCc2ccc(C#N)cc2)cc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(SCc2ccc(-c3nnn[nH]3)cc2)cc(C(C)(C)C)c1
Temperature: 115 °C
Yield: 22 %

Procedure:
A mixture of 2.0g (0.011 mole) of 2,6-di-t-butyl-4-[(4-cyanophenyl)methylthio]phenol, 1.1 g (0.034 mole) of sodium azide, 0.6 g (0.034 mole) of ammonium chloride, 0.24 g (0.011 mole) of lithium chloride and 20 ml of N,N-dimethylformamide was heated at 115° C. in a stoppered flask for 120 hours. The N,N-dimethylformamide was evaporated and the residual material partitioned between water and chloroform. The chloroform layer was dried with magnesium sulfate, and was then evaporated to give the crude product as a brown oil. This oil was purified by silica gel chromatography eluting with a mixture of chloroform/methanol/acetic acid in a ratio of 98/2/0.25 followed by two recrystallizations from a mixture of chloroform and hexane to give 0.92 g of 5-{4-[(3,5-di-t-butylphenylthio)methyl]phenyl}tetrazole as a cream-colored solid, m.p. 187°-189° C. Analysis: Calculated for C22H28N4OS: %C, 66.6; %H, 7.1; %N, 14.1; Found: %C, 66.6; %H, 7.3; %N, 14.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH2:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(Cl)cc1)C2=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(Cl)c2c(c1)CN(Cc1ccc(Cl)cc1)C2=O
Yield: 62.5 %

Procedure:
A mixture of 7-chloro-5-ethenyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.032 g, 0.1 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-chloro-5-ethyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.020 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.23 (t, 3H), 2.68 (q, 2H), 4.18 (s, 2H), 4.72 (s, 2H), 7.09 (s, 1H), 7.22-7.32 (m, 5H). GC-MS: m/z 319 (M−1)+, 284 (M−35)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)nc5ccccc45)cc3CC[C@@H]12
Yield: 63.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 4-chloro-2-phenylquinazoline (111 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80-100% ethyl acetate/hexanes eluent gradient) to give 112 mg (63%) of the title compound as an off white solid. mp 185°-193°. FDMS: m/e=465. α[D]589 =+49.59 (c=0.57, chloroform).
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][S:12][CH2:13]2)[CH2:9]1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[CH:10]12[CH2:16][CH:14]([CH2:15][NH:8][CH2:9]1)[CH2:13][S:12][CH2:11]2
Reactant: c1ccc(CN2CC3CSCC(C3)C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: C1NCC2CSCC1C2
Yield: 57.9 %

Procedure:
A 50-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a heating mantle, a standard condenser with a N2 inlet and two glass stoppers. In one portion, anhydrous HCO2NH4 (1.11 g, 17.1 mmol) was added under N2 to a mixture of the amine (27, 0.90 g, 3.86 mmol) and 10% Pd/C (0.90 g) in anhydrous CH3OH (25 mL). With stirring, the mixture was brought to reflux for 30 min, filtered through a Celite pad on a fritted funnel (which was washed thoroughly with CH2Cl2), and then concentrated to give a gummy oil with suspended solid. This material was again dissolved in CH2Cl2 (~15 mL), and the suspension was filtered to remove any unreacted ammonium formate. The filtrate was then concentrated to near saturation and placed in a diffusion chamber of ether overnight. Crude amine (28) became an oil; however, the mother liquor, containing predominantly starting material, could be decanted. Chromatography of the oil employed a gradient elution of CH3OH/CH2Cl2 (300 mL of 10% CH3OH/CH2Cl2, 50 mL of 20% CH3OH/CH2Cl2, 100 mL of 50% CH3OH/CH2Cl2, and 100 mL of CH3OH) on silica gel (35 g, 1.5 cm×62 cm) and afforded 0.32 g (56.9%) of amine (28) (Rf =0.11, 10% CH3OH/CH2Cl2) as a light, gummy solid which was used without further purification. 1H NMR (DCCl3) δ1.84, 2.04 [two bd, 2H, H(9)], 2.31 [bs, 2H(1,5)], 2.80 [bd, 2H, H(2,4)ax, J=12.3 Hz], 3.20 [bd, 2H, H(2,4)eq, J=13.7 Hz], 3.45 [m, 2H, H(6,8)ax ], 3.73 [bd, 2H, H(6,8)eq, J=13.2 Hz], 7.59 (bs, 1H, N--H); 13C NMR (DCCl3) ppm 24.88 [d, C(1,5)], 29.79 [t, C(9)], 32.17 [t, C(2,4)], 47.8 [t, C(6,8)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][NH2:33])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][NH:33][C:41](=[O:43])[CH3:42])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-c2nnc3n2CCCC3(CN)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nnc3n2CCCC3(CNC(C)=O)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-{8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanamine (76.7 mg) and triethylamine (26.2 μL) in THF (1 mL) was added acetic anhydride under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (59.6 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][CH:6]=1)[C:2]#[CH:3].[OH:15][S:16]([OH:19])(=[O:18])=[O:17]>>[S:16]([OH:19])([OH:18])(=[O:17])=[O:15].[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[C:2]#[CH:3]
Reactant: C#CCOc1ccc(NC(C)=O)cc1
Agent: O=S(=O)(O)O
Product: C#CCOc1ccc(N)cc1
Yield: 68 %

Procedure:
A solution of N-(4-(propargyloxy)phenyl)acetamide 5 (650 mg, 3.44 mmol) in 4 M H2SO4 (10 mL) was stirred under reflux for 3 h. The generated white crystals were filtrated and washed with diethyl ether to give 6 (577 mg, 68%). 1H NMR (300 MHz, DMSO-d6): δ 8.18 (br, 2H), 6.97-6.90 (m, 4H), 4.73 (d, J=3.0 Hz, 2H), 3.55 (t, J=3.0 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 153.92, 134.71, 120.94, 117.17, 80.61, 79.20, 57.06. HRMS: calcd for C9H10NO (MH+) 148.0757. found 148.0754.
Reaction SMILES: [O-:1][W:2]([O-])(=[O:4])=[O:3].[Na+].[Na+].[P:8](=[O:12])([OH:11])([OH:10])[OH:9].S(=O)(=O)(O)O.OO>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH2:1].[OH:10][P:8]([OH:12])([OH:11])=[O:9].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3].[O:1]=[W:2](=[O:4])=[O:3]
Reactant: O=[W](=O)([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[W](=O)=O
Temperature: 25 °C

Procedure:
For example, by dissolving sodium tungstate (VI) in distilled water, adding an aqueous solution of phosphoric acid to the obtained solution, and then adding concentrated sulfuric acid to adjust the pH to an acidic range, followed by addition of hydrogen peroxide, stirring at room temperature, and then, adding a halogenated quaternary ammonium such as tetra-(n-butyl)ammonium chloride, it is possible to obtain the tungstophosphoric acid salt represented by the formula (3) such as tri[tetra-(n-butyl)ammonium]tetra(diperoxotungsto)phosphoric acid salt.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[CH2:31][CH2:30]1)[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:35][C:36]([CH3:38])=[O:37].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:36]([OH:37])([CH3:38])[CH3:35])[CH2:30]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
15.81 ml (25.3 mmoles) of a 1.6M hexane solution of butyllithium were added, at -78° C. and under an atmosphere of nitrogen, to a solution of 3.55 ml (25.3 mmoles) of diisopropylamine in 30 ml of anhydrous tetrahydrofuran. The mixture was then stirred for 30 minutes, after which a solution of 3.58 g (11.5 mmoles) of (5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-one (prepared as described in Preparation 5) in 10 ml of anhydrous tetrahydrofuran was added to the mixture. It was then stirred at -78° C. for 1 hour, after which 1.86 ml (25.3 mmoles) of distilled acetone was added, and the mixture was stirred for a further 2 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a 10% w/v aqueous solution of citric acid, with water, and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (using a 1:1 by volume mixture of hexane and diethyl ether as eluent), to give 3.65 g (yield 86%) of the title compound as the product of lesser polarity, in the form of white crystals, melting at 123°-125° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[F:10][C:11]([F:22])([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:12](=[O:13])[C:11]([F:21])([F:22])[F:10])=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cn1
Reactant: O=C(N=c1cccc[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(F)nc1)C(F)(F)F

Procedure:
57 mg (0.30 mmol) of the 5-bromomethyl-2-fluoropyridine obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 57 mg (0.30 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetoamide synthesized by the method described in (1) of Synthetic Example P1 and 69 mg (0.50 mmol) of potassium carbonate were added thereto in sequence, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature to filter insoluble materials, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→3:1) to obtain the subject material. Amount obtained 21 mg (yield 23%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:19])[CH3:18]>>[C:17]([O:20][N:21]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:19])[CH3:18]
Reactant: CC(=O)ONC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (42) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino acetate according to Scheme 2. (0.5 g, 16%), 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26-8.34 (1H, m), 8.17-8.25 (1H, m), 8.03-8.11 (2H, m), 3.46 (3H, s), 2.32 (3H, s), 1.28 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH:12](SC)[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CSC1CC(c2cc(Cl)c(C)c(Cl)c2)=NNC1=O
Agent: Cl
Solvent: O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 90 %

Procedure:
A mixture of 6.06 g (0.02 mole) of 6-(3,5-dichloro-4-methylphenyl)-4-methylthio-4,5-dihydro-3(2H)pyridazinone, prepared as described in Example 1(d), 20 ml of water and 5.2 ml of concentrated hydrochloric acid was heated under reflux for 2 hours. The mixture was then cooled and the resulting crystals were collected by filtration, air-dried, washed with a small amount of ethyl acetate and again air-dried, to give 4.59 g (yield 90%) of the desired 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone, melting at 254°-258° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:8]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: COc1cccc(C(CC2CCCC2)C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(CC2CCCC2)C(=O)Nc2nccs2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid (500 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.1 mL, 2.20 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min then at 25° C. for 30 min. The reaction mixture was then treated with 2-aminothiazole (444 mg, 4.42 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.83 mmol) in tetrahydrofuran (10.1 mL). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide (549 mg, 82.6%) as a white solid: mp 44–45° C.; EI-HRMS m/e calcd for C18H22N2O2S (M+) 330.1402 found 330.1398.
Reaction SMILES: [F:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[C:3]([O:5]C)=[O:4].N1C2C(=CC(C(C)C(O)=O)=CC=2)C=CC=1>>[F:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(F)c1ccc2ncccc2c1
Agent: CC(C(=O)O)c1ccc2ncccc2c1
Product: CC(F)(C(=O)O)c1ccc2ncccc2c1

Procedure:
To a solution of methyl 2-(quinolin-6-yl)propanoate (0.868 g, 4.03 mmol) in THF (1.1M, 3.7 mL) at −78° C. was added LiHMDS (1M in THF) (5.24 ml, 5.24 mmol). The reaction was stirred at −78° C. for ˜15 minutes, then to it was added a solution of N-fluorobenzenesulfonimide (1.40 g, 4.44 mmol) in THF (1.0M, 4.5 mL). The reaction was allowed to warm to −10° C. over 2 h. The reaction was filtered through a plug of Celite, washed with EtOAc and the filtrate was then concentrated in vacuo. The concentrated material was rediluted with EtOAc and washed with saturated NH4Cl solution. The aqueous layer was then extracted with EtOAc, and the organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with isocratic 40% EtOAc:Hexanes to yield methyl 2-fluoro-2-(quinolin-6-yl)propanoate (0.709 g, 75.4% yield) as a yellow oil. To synthesize the corresponding acid, methyl 2-fluoro-2-(quinolin-6-yl)propanoate was saponified in a method similar to that of 2-(quinolin-6-yl)propanoic acid.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:16][CH:15]=1.[OH-].[Na+].O>[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][C:19]([CH3:22])([CH3:23])[CH2:20][O:21][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: FCCOc1ccc(CCl)cc1
Reactant: CC(C)(CO)Oc1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(COCc1ccc(OCCF)cc1)Oc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture consisting of 1.0 g of 4-(2-fluoroethoxy)benzyl chloride, 1.0 g of 2-(4-chlorophenoxy)-2-methylpropyl alcohol, 0.3 g of triethylbenzylammonium bromide and 20 g of a 50% aqueous solution of sodium hydroxide was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and poured into water. Toluene was added, and the mixture was fully stirred. The toluene layer was separated, washed with water, and dried over anhydrous sodium sulfate. Toluene and low-volatile components were evaporated under reduced pressure to give 1.6 g of the desired 4-(2-fluoroethoxy)benzyl 2-(4-chlorophenoxy)-2-methylpropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[CH3:22])[N:8]=1)=[O:5]>[Pd].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])=[N:8]2)=[C:14]([CH3:22])[CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 1.5 h

Procedure:
To 10% palladium on activated carbon (wet, degussa type E101 NE/W) (350 mg, 3.29 mmol, Aldrich) was added a solution of 2,6-difluoro-N-{1-[(2-methyl-4-nitrophenyl)methyl]-1H-pyrazol-3-yl}benzamide (for a preparation see Intermediate 32)(1.6 g, 4.30 mmol) in ethanol (80 ml). The solution was hydrogenated for 1.5 h at ambient temperature. The suspension was filtered through a celite cartridge (10 g) and the catalyst residue washed with methanol (50 ml). The solvent was removed in vacuo to give the title compound as a white foam (1.43 g). LCMS: (System 4) MH+=343, tRET=1.50 min.