Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: COCCN(C)C(=O)CCl
Product: COCCN(C)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 35.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.3 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[Br:23][CH:24](Br)[CH3:25]>[OH-].[Na+]>[Br:23][CH2:24][CH2:25][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(Br)Br
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(SCCBr)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 10.4 ml of 2 N sodium hydroxide solution. 2.3 g of dibromoethane are added and the mixture is stirred at room temperature for 4 hours. The organic layer is then removed, the aqueous phase is subsequently shaken with 10 ml of toluene, and the combined organic phases are washed twice with 5 ml of 2 N sodium hydroxide solution each time, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. 2-(2-Bromoethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole, Rf =0.65 (silica gel, toluene/ethyl acetate 10:1) is obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](OCC)=[O:12])(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][OH:12])(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCCCN1S(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.5 %

Procedure:
Ethyl 1-(methylsulfonyl)piperidine-2-carboxylate (6.9 g, 29.3 mmol) in anhydrous tetrahydrofuran (40 mL) was added slowly to a stirring suspension of lithium aluminum hydride (1.5 g, 40 mmol) in anhydrous tetrahydrofuran (80 mL) kept at 0° C. with an external ice bath. After fifteen minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature and stirred for an additional 4.5 hours. The mixture was cooled to 0° C., and water (1.5 mL) was added dropwise, followed by aqueous sodium hydroxide (1.5 mL), and water (4.5 mL). The mixture was stirred for 15 mins at room temperature, followed by the addition of magnesium sulfate and additional stirring. The mixture was filtered through Celite, washed three times with ether, and the combined organic fractions concentrated under reduced pressure. The crude residue was passed through a pad of silica gel, washing with ethyl acetate, to give the desired product as a clear liquid (4.9 g, 87%). 1H NMR (CDCl3, 300 MHz) δ 4.06-4.03 (m, 1H), 3.96-3.92 (dd, 1H, J=11.1, 9.3 Hz), 3.73-3.68 (br d, 1H, J=14.1 Hz), 3.61-3.56 (dd, 1H, J=11.1, 4.8 Hz), 3.12-3.03 (br t, 1H, J=12.1 Hz), 2.96 (s, 3H), 2.17 (br s, 1H), 1.74-1.47 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[NH:19])[C:10]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:13]=[N:12][CH:11]=2)[CH:3]=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:19]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[CH:15]=3)[N:8]=[C:4]2[CH:3]=1
Reactant: N=C(Nc1cc(Cl)ccn1)c1cncc(C2CC2)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccn2nc(-c3cncc(C4CC4)c3)nc2c1
Temperature: 150 °C

Procedure:
Lead tetra acetate (0.684 g, 0.0015 mol) was added to a solution of N-(4-chloropyridin-2-yl)-5-cyclopropylnicotinimidamide (42-1; 0.280 g, 0.001 mol) in toluene (30 mL) in a 40 mL microwave vial at RT. The reaction mixture was heated to 150° C. for 2 h under microwave irradiation. It was cooled to RT then diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compound. 1H NMR (400 MHz, DMSO) δ 9.08-9.02 (t, J=7.2 Hz, 2H), 8.52 (s, 1H), 8.10-8.05 (d, J=18.4 Hz, 2H), 7.32-7.31 (d, J=6.8 Hz, 1H), 2.08 (s, 1H), 1.07-1.05 (d, J=10.4 Hz, 2H), 0.82-0.81 (d, J=4.4 Hz, 2H). MS (M+1): 271.7.
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3](=O)[CH3:4].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:14][C:2]([CH3:6])=[C:3]([CH3:4])[N:15]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: CC(=O)C(C)Cl
Product: COc1ccc(-c2nc(C)c(C)o2)cc1
Temperature: 115 °C
Yield: 83.6 %

Procedure:
A mixture of 3-Chloro-2-butanone (2.1 g, 10.0 mmol) and 4-methoxybenzamide (0.30 g, 1.0 mmol) was heated at 115° C. for 15 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 20% EtOAc-Hexane) to get the desired product (0.17 g, 42%) as a white solid. The corresponding chloro derivative was also prepared by the same general method.
Reaction SMILES: [C:1]([C:5]1([C:13]2[S:17][C:16]([S:18]([CH2:21][N+:22]([O-:24])=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=2)OCC(C)(C)C[O:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>C(O)C>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]([C:13]1[S:17][C:16]([S:18]([CH2:21][N+:22]([O-:24])=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1)=[O:6]
Reactant: CC1(C)COC(c2ccc(S(=O)(=O)C[N+](=O)[O-])s2)(C(C)(C)C)OC1
Solvent: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1ccc(S(=O)(=O)C[N+](=O)[O-])s1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 53.3 %

Procedure:
A mixture of 2-t-butyl-5,5-dimethyl-2-[2-(nitromethylsulphonyl)thien-5-yl]-1,3-dioxane (A) (1.47 g), trifluoroacetic acid (15 ml), and water (1.5 ml) was stirred for 45 minutes at 60° C. The reaction mixture was poured into water (50 ml), and extracted with ether (2×50 ml). The combined ether extracts were washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water (3×20 ml), and then dried (MgSO4). The solvent was removed by evaporation to give 2-(2,2-dimethylpropionyl)-5-(nitromethylsulphonyl)thiophene as a white solid (0.605 g, 54% yield), m.p. 98°-99° C. (after recrystallisation from aqueous ethanol); MMR (250 MHz): 1.42(s, 9H), 5.72(s, 2H), 7.78(d, 1H), 7.82(d, 1H); m/e (electron impact) 292 (M+H)+ ; microanalysis, found: C,41.3, H.4.5, N,4.7%; C10H13NO5S2 requires: C,41.2, H,4.5, N,4.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.P(Cl)(Cl)([Cl:22])=O.CN(C)C1C=CC=CC=1.Cl>>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Temperature: 25 °C

Procedure:
A suspension of 2-(2-methoxyphenyl)quinazolin-4(3H)-one (567 g, 2.1 mol) in phosphoryl chloride (2 L, 21 mol) and a catalytic amount of N,N-dimethyl aniline was brought to reflux. The reaction started immediately with the evolution of gas (HCl) upon the addition of N,N-dimethyl aniline. After the production of gas had ceased the mixture was cooled to room temperature. The excess POCl3 was evaporated. The resulting dark solution was cooled to room temperature and slowly poured on ice and water, while maintaining the temperature below 5° C. The cold suspension was extracted with dichloromethane. The extract was dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude material was purified by column chromatography (silica gel, CH2Cl2). Yield: 189 g (33%) of 4 chloro-2-(2-methoxyphenyl) quinazoline. 1H-NMR (300 MHz, Me2SO-d6): δ 3.85 (s, 3H), 7.15 (t, 1H), 7.25 (d, 1H), 7.60 (t, 2H), 7.70 (d, 1H), 7.8 (d, 1H), 7.9 (t, 1H), 8.2 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:17]([OH:20])=[CH:16][N:15]=[CH:14][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:21]CN(C(C)C)C(C)C.[Si](C=[N+]=[N-])(C)(C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:17]([O:20][CH3:21])=[CH:16][N:15]=[CH:14][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Oc1cncc2cc(-c3cnc4ccc(Cl)nn34)sc12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COc1cncc2cc(-c3cnc4ccc(Cl)nn34)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of 2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thieno[3,2-c]pyridin-7-ol (38 mg, 0.126 mmol, 1.0 equiv) in DCM (3.0 mL) and MeOH (1.0 mL) was added DIPEA (0.188 mmol, 1.5 equiv) then TMSCHN2 (94 microliter, 0.188 mmol, 1.5 equiv). The reaction mixture was stirred at rt for 3 h, then quenched with water and extracted with ethyl acetate. Purification by column chromatography using 20% ethyl acetate in hexanes elution gave 20 mg of the yellow solid, 50%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH2:15])=[N:3]1.[C:16]([OH:20])(=[O:19])[CH:17]=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:17][C:16]([OH:20])=[O:19])=[N:3]1
Reactant: O=CC(=O)O
Reactant: Cn1nc(N)c2cc(C(F)(F)F)ccc21
Product: Cn1nc(NCC(=O)O)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as white solid from reductive amination of 1-methyl-5-trifluoromethyl-1H-indazol-3-ylamine (as prepared in the previous step) and glyoxylic acid using the procedure described in Step B of Example 1.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[OH-].[K+].Cl>C(O)C.O>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cccc(O)c1C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (2.24 g) and 4-bromobenzaldehyde (2.78 g) in ethanol (30 mL) were added water (10 mL) and potassium hydroxide (6.73 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (70 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-bromo-2′-(carboxymethoxy)-6′-hydroxychalcone (3.77 g). To a suspension of the obtained 4-bromo-2′-(carboxymethoxy)-6′-hydroxychalcone (3.7 g) in benzene (150 mL) were added tris(triphenylphosphine)rhodium(I) chloride (1.82 g) and triethylsilane (6.2 mL), and the mixture was stirred at 70° C. overnight. To the reaction mixture were added 2 mol/L aqueous sodium hydroxide solution and diethyl ether, and the aqueous layer was separated. The aqueous layer was washed with diethyl ether and acidified by addition of concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane-ethyl acetate. The precipitated crystals were collected by filtration. The crystals were washed with n-hexane and dried under reduced pressure to give 4-bromo-2′-(carboxymethoxy)-6′-hydroxydihydrochalcone (1.1 g). This material was dissolved in acetic acid (4.15 mL). To the solution were added sodium acetate (1.5 g) and acetic anhydride (1.5 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added sodium methoxide (28% methanol solution, 1.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (0.85 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1([Mg]Br)C=CC=CC=1.[CH:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]([OH:24])[CH:21]([CH3:23])[CH3:22])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])c1cc(I)ccc1I
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
To a solution of 1,4-diiodo-2-nitrobenzene (2.24 g, 6.0 mmol) in anhydrous THF (20 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.2 mL, 6.4 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for 5 minutes, followed by addition of isobutyraldehyde (0.726 mL, 8.0 mmol). The mixture was gradually warmed up to room temperature, quenched with saturated NH4Cl (8 mL), then poured into water (100 mL). The mixture was extracted three times with ethyl acetate (150 mL), and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield racemic (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol (1.54 g, 80%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.18 (d, 1 H, J=1.7 Hz, Ph-H), 7.93 (dd, 1 H, J=1.7 and 8.3 Hz, Ph-H), 7.50 (d, 1 H, J=8.3 Hz, Ph-H), 5.04 (m, 1 H, Ph-CH), 2.17 (d, 1 H, J=4.4 Hz, OH), 1.98 (m, 1 H, CH), 0.93 (d, 3 H, J=4.4 Hz, CH3), 0.92 (d, 3 H, J=4.4 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 148.62 (C), 141.81 (CH), 138.57 (C), 132.72 (CH), 130.49 (CH), 91.51 (C), 73.48 (CH), 34.22 (CH), 19.62 (CH3), 16.71 (CH3).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:23]=3)[C:18]([CH3:33])=[C:17]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)=[CH:11][CH:10]=1)(=O)=O.Cl.[F:49][CH2:50][C@@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([O:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:53]3[CH2:54][CH2:55][C@@H:51]([CH2:50][F:49])[CH2:52]3)=[CH:10][CH:11]=1)[C:17]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:38][CH:39]=1)=[C:18]2[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: FC[C@@H]1CCNC1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCOS(C)(=O)=O)cc2)c2ccc(OCc3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCN3CC[C@@H](CF)C3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C

Procedure:
A mixture of 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethyl methanesulfonate, (R)-3-(fluoromethyl)pyrrolidine (Intermediate 8) and potassium carbonate in acetonitrile was degassed with three vacuum/N2 cycles. The reaction was heated at 80° C. for 10 hrs, allowed to cool to room temperature and then diluted with water (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL) and the combined ethyl acetate extracts were then washed with water (40 mL), washed with brine (40 mL), dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (0%-5% MeOH in DCM) to give 274 mg of (R)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indole. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, 4H), 7.44-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.30 (d, 2H), 7.21 (d, 1H), 7.15-7.10 (m, 3H), 6.81 (dd, 1H), 6.74 (s, 4H), 5.17-5.10 (m, 6H), 4.33-4.30 (m, 1H), 4.22-4.18 (m, 1H), 3.94 (t, 2H), 2.70 (t, 2H), 2.56-2.40 (m, 3H), 2.60 (t, 1H), 2.36-2.31 (m, 1H), 2.16 (s, 3H), 1.86-1.76 (m, 1H), 1.40-1.30 (m, 1H). LCMS: 655.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](S)[S:8][C:4]=2[CH:3]=1.S(Cl)([Cl:15])(=O)=O>>[Cl:15][C:7]1[S:8][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Fc1ccc2nc(S)sc2c1
Reactant: O=S(=O)(Cl)Cl
Product: Fc1ccc2nc(Cl)sc2c1

Procedure:
6-Fluoro-benzothiazole-2-thiol was treated with sulfuryl chloride by the procedure described in PCT/US04/14036 to give the desired product, which was used in the next step without further purification. EI-MS m/z 187 (M+); 1H NMR (DMSO-d6) δ 8.00 (m, 2H), 7.40 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:12][CH:13]([CH3:24])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])=O)=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[N:9][N:8]2[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([CH3:24])[O:12][C:7]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OC(C)C(=O)c2ccc(C)cc2C)n[nH]c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nn2c(-c3ccc(C)cc3C)c(C)oc12
Yield: 88 %

Procedure:
A mixture of 3-[2-(2,4-dimethyl-phenyl)-1-methyl-2-oxo-ethoxy]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (273 mg, 0.83 mmol), para-toluenesulfonic acid mono-hydrate (160 mg, 0.83 mmol) in toluene (15 ml) and AcOH (5 ml) is refluxed for 3 days. The reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc (40 ml). The organic solution is washed successively with Na2CO3 2M in water (2×20 ml) and brine (20 ml), dried over Na2SO4, filtered and concentrated to dryness. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, iso-hexane/TBME 98:2→7:3) to yield the title compound (227 mg, 0.73 mmol, 88%) as a colorless oil. TLC: RF=0.81 (iso-hexane/TBME 1:1); HPLC: AtRet=2.85; MS: m/z 313.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J 7.1, 3H), 2.20 (s, 3H), 2.34 (s, 3H), 2.36 (s, 3H), 2.41 (s, 3H), 4.26 (q, J 7.1, 2H), 7.17 (m, 1H), 7.24 (br. s., 1H), 7.31 (m, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](O)([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19]>CCOCC>[CH2:17]([CH:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)[CH2:20][CH2:21][CH3:22])[CH2:18][CH3:19]
Reactant: CCCC(O)(CCC)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCCC(CCC)c1cccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under nitrogen, a suspension of LiAlH4 (3.6 g, 94.9 mmol) in dry Et2O (500 mL) was cooled to 0° C. by an ice/water bath. AlCl3 (24.9 g, 186.7 mmol) was then added in small portions. After addition, the mixture was stirred at 0° C. for 1 hour. A solution of 4-thiophen-2-yl-heptan-4-ol (10.2 g, 51.3 mmol) was then added dropwise. The mixture was stirred at 0° C. for 2 hours, and allowed to warm to room temperature and stirred at room temperature overnight. After cooling to 0° C., the reaction was quenched by adding water. The reaction mixture was washed with water and brine, dried over Na2SO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as the eluent, leading to a colorless oil as the product (9.1 g, 97.2%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)CCc1ccc(I)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccc2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (100 mg, 0.34 mmol) and phenylacetylene (0.04 mL, 0.36 mmol) according to the general procedure IA to give 66 mg (72%) of a brown oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:10). Rf: 0.31 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.53-7.50 (m, 2H), 7.47-7.44 (m, 2H), 7.34-7.32 (m, 3H), 7.19-7.16 (m, 2H), 3.66 (s, 3H), 2.98-2.93 (t, 2H, J=7.5 Hz), 2.66-2.61 (t, 2H, J=7.5 Hz); 13CNMR (CDCl3) δ 173.1, 140.8, 131.7, 131.5, 128.3, 128.3, 128.1, 123.3, 121.2, 89.3, 89.1, 51.6, 35.4, 30.8; ESI-MS m/z 287.1 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22]N=CC=4NN=3)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[H-].[Na+].Br[CH:30]([F:36])[C:31]([O:33]CC)=[O:32]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:11]=[N:10][N:9]4[CH:8]=[CH:6][CH:22]=[N:23][C:24]=34)=[O:15])=[CH:11][N:10]([CH:30]([F:36])[C:31]([OH:33])=[O:32])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(F)Br
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1n[nH]c2cncnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(F)C(=O)O)cc1NC(=O)c1cnn2cccnc12
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo pyrimidine-3-carboxamide (37.1 mg, 0.10 mmol) in 1.5 DMF was added sodium hydride (10 mg, 0.40 mmol) and the mixture stirred for 5 min at which time ethyl bromofluoroacetate (37 mg, 0.20 mmol) was added. The mixture was stirred overnight, then purified by reverse phase HPLC and lyophilized to afford 13.3 mg (30%) of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)-2-fluoroacetic acid as a colorless solid. LCMS (ESI) m+H=445.1. 1H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 9.33 (d, J=7.0 Hz, 1H), 8.76-8.71 (m, 1H), 8.66 (d, J=8.3 Hz, 1H), 8.38 (s, 1H), 7.58-7.20 (m, 5H), 5.98 (d, J=56.5 Hz, 1H), 3.84 (s, 3H).