Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([O:29][CH3:30])[C:20]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:16]2[CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[O:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38]Cl.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([O:29][CH3:30])[C:20]([N:21]([CH2:38][CH:34]3[CH2:35][CH2:36][CH2:37][O:33]3)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(C)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Reactant: ClCC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(-c2cccc3c(N(CC4CCCO4)C(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
After dissolving tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate (50 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) was added while cooling on ice, and then 2-tetrahydrofuranylmethyl chloride (16 μL) was added and the mixture was stirred for 3 hours at 60° C. under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylcarbamate. The crude product was dissolved in ethyl acetate (2 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer washed with water and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure to obtain N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine as a crude product. This was dissolved in tetrahydrofuran (2 mL) without purification, and after adding cyclopropanecarboxyaldehyde (27 μL) and 3 M aqueous sulfuric acid (0.121 mL), sodium borohydride (9 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, the solvent was concentrated, the residue was purified by silica gel column chromatography, and the title compound (31 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=2)[C@H:12]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C)C1C=CC=CC=1.[Cl:32]C(OC(Cl)=O)C>ClCCl>[ClH:32].[CH3:1][NH:8][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=2)[C@H:12]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN(Cc1ccccc1)C[C@H]1CCc2cc(-c3cccs3)ccc2[C@H]1c1ccccc1
Solvent: ClCCl
Product: CNC[C@H]1CCc2cc(-c3cccs3)ccc2[C@H]1c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cis-2-(N-benzyl-N-methylamino)methyl-1-phenyl-1,2,3,4-tetrahydro-6-(2-thienyl)naphthalene (727 mg) in dichloromethane (75 cm3) which was being maintained at 0° C. under nitrogen was added 1-chloroethylchloroformate (0.208 cm3) dropwise. The mixture was then allowed to warm to room temperature, before being heated to reflux. After approximately 2 h analysis of the reaction mixture indicated complete consumption of the starting material. The dichloromethane was evaporated and the residue was then taken up into methyl alcohol and heated to reflux for 1 h. The solvent was evaporated to afford the title compound which was used in the next reaction without further purification; positive ion ESI (M+H)+ 334.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:19]([O:18][P:17]([CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc(OCc2ccccc2)c1)OCC
Temperature: 150 °C

Procedure:
1-Benzyloxy-3-bromomethyl-benzene (4.95 g, 17.9 mmol) was treated with triethyl phosphite (3.2 mL, 18.7 mmol) and heated to 150° C. After 3 hours the reaction was cooled to room temperature and concentrated to give the title compound which was used without further purification (5.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:11]([CH3:10])(=[O:13])=[O:12])[S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N(c1cc(Br)cnc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyridin-3-amine (3.04 g, 14.7 mmol) of pyridine (20 mL) in 150-mL round-bottom flask, methanesulfonyl chloride (2.83 ml, 36.6 mmol) was added dropwise at 0° C. The ice bath was removed and the light brown solution was stirred at RT for overnight. Water (100 mL) was added and the precipitate was formed. The mixture was stirred at RT to break up lumps. The cream color solid was collected via filtration and washed with water several times then air dried to afford N-(5-bromo-2-chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (5.16 g, 96.9% yield) as a cream colored powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.65 (s, 6H), 8.69 (d, J=2.3 Hz, 1H), 8.75 (d, J=2.3 Hz, 1H). m/z (ESI, positive ion): 362.8 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([C:19](OCC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([CH2:19][OH:20])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (17.94 g, 51.85 mmol, e.g. which can optionally be as prepared in Intermediate 4) in dichloromethane (150 ml) was cooled to 0° C. under an atmosphere of nitrogen, and was treated with di-iso-butylaluminum hydride (100 ml of a 1.5 M solution in toluene, 150 mmol) added dropwise over 30 minutes, keeping the temperature steady at 0° C. The reaction was stirred at 0° C. for a further 30 minutes after completion of the addition. The reaction was quenched by the dropwise addition of saturated aqueous potassium sodium tartrate solution (120 ml), keeping the temperature below 5° C. The resulting mixture was diluted with ethyl acetate (300 ml) and the whole filtered through a pad of Celite, to form two layers. During this filtration the sinter funnel imploded. Material spilt on the fumehood floor was soaked up and recovered as much as possible. The organic layer was separated and dried (MgSO4), the drying agent was filtered off, and the filtrate evaporated to give a first batch of product. The aqueous layer and the celite were extracted with a larger amount of ethyl acetate to give a second batch of product after evaporation. The two batches of product were combined to give the title compound (14 g) as an off-white waxy solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2.C([Sn](CCCC)(CCCC)[C:26]1[N:27]=[CH:28][N:29](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=1)CCC>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:9]1[CH:10]=[C:2]([C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2c(Cl)cc(-c3c[nH]cn3)cc2CN1Cc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A mixture of 5-Bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (127 mg, 0.343 mmol), 4-Tributylstannanyl-1-trityl-1H-imidazole (300 mg, 0.514 mmol), and Pd(PPh3)4 (79 mg, 0.0514 mmol) in toluene (15 mL) stirred overnight at 110° C. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue (7-Chloro-2-(4-chloro-benzyl)-5-(1-trityl-1H-imidazol-4-yl)-2,3-dihydro-isoindol-1-one) was dissolved in formic acid (5 mL) and stirred at room temperature for 18 hrs. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed with 3N HCl (2×30 ml) and the aqueous washes were combined, neutralized with 1N NaOH, and extracted with ethyl acetate. The organics were washed with brine, and dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (100% Ethyl acetate—5% 2M NH3 in MeOH/CH2Cl2) provided the title compound (22 mg, 18%). 1H NMR (300 MHz, CDCl3): δ 7.80 (s, 2H), 7.7.75 (s, 1H), 7.46 (s, 1H), 7.35-7.30 (m, 4H), 4.77 (s, 2H), 4.27 (s, 2H).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([CH3:17])([NH:15][CH3:16])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([N:15]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=2)[CH3:16])([CH3:17])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: CNC(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 2,2-diphenyl-5-methyl-5-methylaminohexanamide (0.31 g--see Preparation 13), 4-fluorophenethyl bromide (0.2 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.1 g.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:23])#[N:2].C(N(CC)CC)C.[CH3:31][NH:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:35]2[CH2:36][CH2:37][C@H:33]([NH:32][CH3:31])[CH2:34]2)=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:23])#[N:2]
Reactant: CN[C@H]1CCNC1
Reactant: Cc1c(-c2cccs2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@H]1CCN(c2c(-c3cccs3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59.3 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-(thiophen-2-yl)-1,3-benzoxazole-2-carboxamide (I-308) (160 mg, 0.49 mmol) was dissolved in dimethyl sulfoxide (8.7 ml), and at room temperature, triethylamine (81 μl, 0.58 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (62 μl, 0.58 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. After stirred at the same temperature for 50 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and saturated brine. The aqueous layer was further fractionated twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was roughly purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and the roughly-purified product was again purified by preparative TLC (eluent, chloroform:methanol=9:1, v/v) to obtain the entitled compound (119 mg, 60%) as a yellow amorphous substance.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[C:24]2=[O:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)N(c3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 13.3 %

Procedure:
The procedure of Example 1 is repeated using 10 grams of 2,6-di-tert-butyl-4-mercaptophenol, 7.26 grams of N-phenyl maleimide, and 0.73 grams of triethylamine. The residue is recrystallized from isopropanol to give 2.3 grams (48% yield) of white solid, m.p. 134°-137° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:10]=[N:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH2:22][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:3]([C@H:10]([NH:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:22][C:21]2[CH:20]=[C:19]([F:18])[CH:27]=[C:26]([F:28])[CH:25]=2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[Br:1][C:2]1[C:3]([C@@H:10]([NH:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:22][C:21]2[CH:20]=[C:19]([F:18])[CH:27]=[C:26]([F:28])[CH:25]=2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(C=N[S@@](=O)C(C)(C)C)n1
Reactant: Fc1cc(F)cc(C[Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)N[S@@](=O)C(C)(C)C)n1
Product: CSc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)N[S@@](=O)C(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)—N-((5-bromo-2-(methylthio)pyrimidin-4-yl)methylene)-2-methylpropane-2-sulfinamide (11C, 2.97 g. 8.8 mmol) in THF (18 mL) cooled to −78° C. was drop wise added 3,5-difluorobenzylmagnesium bromide (53 mL, 0.25 M in Ether, 13.3 mmol). After stirring at −78° C. for 10 min, NH4Cl (sat. aq.) (10 ml) was added to the reaction and warmed up to ambient temperature. Extracted with EtOAc and the organic layer was dried with Na2SO4(s). The solvent was removed and the residue was purified by flash column to yield the title compound (11E) and (S)—N—((S)-1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (11D). MS (m/z) 465.87 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][C:21]3[O:24][CH:25]=[CH:26][C:20]=3[CH2:19]2)=[O:17])=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].[CH2:32]=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][C:21]3[O:24][C:25]([CH2:29][N:30]([CH3:32])[CH3:31])=[CH:26][C:20]=3[CH2:19]2)=[O:17])=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc(CC(=O)N2CCc3occc3C2)ccc1OCc1ccccc1
Reactant: CNC
Solvent: CC(=O)O
Product: COc1cc(CC(=O)N2CCc3oc(CN(C)C)cc3C2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.260 g (0.689 mmol) of 2-(4-benzyloxy-3-methoxyphenyl)-1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)ethan-1-one in 20 ml of acetic acid, 0.093 ml (1.03 mmol) of 50% aqueous dimethylamine and 0.084 ml (1.03 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1 to 25/1) to yield the desired product.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([Br:20])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=1>>[Br:5][C:6]1[CH:7]=[C:8]([CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([Br:20])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH:1]([CH3:3])[CH3:2])[N:14]=1
Reactant: CC(C)I
Reactant: CC(=O)OCCc1cc(Br)c(Oc2ccc(=O)[nH]n2)c(Br)c1
Product: CC(=O)OCCc1cc(Br)c(Oc2ccc(=O)n(C(C)C)n2)c(Br)c1
Temperature: 50 °C
Yield: 79 %

Procedure:
This compound was prepared by a similar method to that described in Example 10, Step 2 except that isopropyl iodide was used in place of methyl iodide and acetic acid 2-[3,5-dibromo-4-(6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (39) was used in place of acetic acid 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (34). The method was similar except that the reaction was heated to 50° C. for 24 h. The product was purified by column chromatography using silica gel eluted with 10% ethyl acetate in hexanes to 100% ethyl acetate to afford 2-[3,5-dibromo-4-(1-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (40) (79%) as a white solid; LRMS for C17H18Br2N2O4 (M+CH3CN+H) m/z=516, Molecular Weight=474.1520; Exact Mass=471.9633
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=CC=1.[CH3:68][O:69][C:70](=[O:80])[C:71]1[CH:76]=[C:75]([F:77])[C:74]([NH2:78])=[C:73]([F:79])[CH:72]=1>N1C=CC=CC=1>[CH3:68][O:69][C:70](=[O:80])[C:71]1[CH:72]=[C:73]([F:79])[C:74]([NH:78][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:75]([F:77])[CH:76]=1
Reactant: COC(=O)c1cc(F)c(N)c(F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: COC(=O)c1cc(F)c(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
This compound was prepared in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid, 4-amino-3,5-difluoro-benzoic acid methyl ester and using pyridine as a base.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[O:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27]Br>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([CH2:27][CH:23]2[CH2:24][CH2:25][CH2:26][O:22]2)[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CCCO1
Reactant: Oc1cccc(C23CCCC2CNCC3)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cccc(C23CCCC2CN(CC2CCCO2)CC3)c1
Temperature: 25 °C

Procedure:
A solution of 1.5 g. of 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 15 ml. of N,N-dimethylformamide containing 1.0 g. of sodium bicarbonate and 0.95 g. of 2-tetrahydrofurylmethyl bromide was heated at reflux for four hours. After cooling the reaction mixture to about 25° C., the mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 4a-(3-hydroxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil so formed was dissolved in diethyl ether and added to a solution of hydrogen bromide gas in diethyl ether. The product crystallized out of solution and was collected by filtration to provide 1.0 g. of 4a-(3-hydroxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium bromide. M.P. 190°-192° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([CH2:23]O)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:56]I>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:12]=[C:13]([CH2:23][I:56])[N:14]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:16]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(CI)nc(NC3CCCC3)n2)cc1
Yield: 59.6 %

Procedure:
[6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)-4-pyrimidinyl]methanol (215 mg, 0.49 mmol) was dissolved in a mixture of benzene (4 mL) and ether (8 mL). Imidazole (134 mg, 2.0 mmol) and triphenylphosphine (191 mg, 0.73 mmol) were added sequentially. A solution of iodine (179 mg, 0.71 mmol) in ether (5 mL) was added dropwise to the reaction mixture over 10 minutes. The resultant solution was stirred for an additional 20 minutes then diluted with 10 mL of ether. The mixture was filtered to remove solids. Concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-(iodomethyl)-2-pyrimidinamine (160 mg, 60%) as a solid. Rf 0.47 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.38 (d, 1H), 7.67 (m, 2H), 7.28 (m, 1H), 7.18 (t, 2H), 7.03 (d, 1H), 6.38 (s, 1H), 5.19 (d, 1H), 4.35 (m, 1H), 4.02 (s, 2H), 2.10 (m, 2H), 2.67 (m, 6H).