Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:20][CH:19]=1)[CH2:12][OH:14])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2ccc(CO)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of methyl 4-(4-ehtylbenzyl)-3-hydroxybenzoate (1.3 g) in N,N-dimethylformamide (15 mL) were added potassium carbonate (0.79 g) and benzyl bromide (0.62 mL), and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (10 mL). The resulting solution was added to a suspension of lithium aluminium hydride (0.57 g) in diethyl ether (50 mL) at 0° C., and the mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to 0° C., water (0.60 mL), 15% aqueous sodium hydroxide solution (0.60 mL) and water (1.8 mL) were successively added to the reaction mixture, and the mixture was stirred for 5 minutes. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give 3-benzyloxy-4-(4-ethylbenzyl)benzyl alcohol (1.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:5]([F:20])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([Cl:24])=[O:12])=[C:5]([F:20])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(OCc2ccccc2C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(OCc2ccccc2C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-(4-cyano-2-fluoro-phenoxymethyl)-benzoic acid (1.0 g, 3.68 mmol) in dichloromethane (15 ml) was added oxalyl chloride (0.45 ml, 4.79 mmol), followed by a drop of N,N-dimethylformamide, and stirred for 12 h at 25° C. The resulting clear solution was evaporated in vacuo and the crude product was used in the next step without any further purification (99%). MS (Turbo Spray): m/z=290.1 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]=[C:6]=[S:7].[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[S:7])[NH:15][NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCN=C=S
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Product: COCCNC(=S)NNc1ccccc1

Procedure:
In benzene was dissolved 11.7 g of 2-methoxyethyl isothiocyanate with stirring and after adding thereto 11.9 g of phenylhydrazine at room temperature, the mixture was heat-refluxed. After performing the reaction for 6 hours, the reaction mixture was cooled and crystals thus formed were collected by filtration. The yield for the product was 66.7%. The product, 4-(2-methoxyethyl)-1-phenylthiosemicarbazide thus obtained could be used for the subsequent reaction without being purified.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1.CCCCCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:22][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH:24]=2)[OH:27])=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 4-bromothioanisole (10.0 g, 49.0 mmol) in 60 mL of anhydrous tetrahydrofuran was cooled to -78° C. under nitrogen and 32 mL (49 mmol) of 1.55M n-butyllithium in hexane was was added dropwise at a rate to maintain temperature below -60° C. The reaction was stirred an additional 15 minutes after addition was complete, and a solution of crude 3-(tert-butyldimethylsilyloxy)benzaldehyde (11.6 g, 49 mmol) in 50 mL of dry tetrahydrofuran was added dropwise over 20 minutes. The reaction was stirred another 30 minutes and quenched at -78° C. with saturated aqueous ammonium chloride. After warming to room temperature, the reaction was diluted with 200 mL of diethyl ether and washed with 50 mL of water and 50 mL of saturated aqueous sodium chloride. After drying over sodium sulfate, the solvent was removed to give 17.5 g (99%) of crude (4-methylthiophenyl) (3-tert-butyldimethylsilyloxyphenyl)methanol as an orange oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>ClCCl.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:5][CH2:6]1)=[O:11]
Reactant: NCCN1CCN(C=O)CC1
Reactant: C=C(C)C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCN1CCN(C=O)CC1
Yield: 43.7 %

Procedure:
117.9 g (0.75 mol) of N-2-aminoethyl-N'-formylpiperazine, 85.8 g (0.85 mol) of triethylamine and 100 mg of 2,6-di-tert.-butyl-4-methylphenol were reacted in 230 ml of dichloromethane with 78.4 g (0.75 mol) of methacryloyl chloride as described in Example 1 and the mixture was worked up. 73.9 g (44% of theory) of N-formyl-N'-(methacryloylaminoethyl)piperazine were obtained in this manner as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(C(C)C)CC)(C)C>ClC(Cl)C>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([NH:10][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(Cl)ncc2Br)C1

Procedure:
A solution 5-bromo-2,4-dichloro-pyrimidine 4 g, 17.6 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (3.6 g, 17.6 mmol) and diisopropylethylamine (3.1 ml, 18 mmol) in dichloroethane (200 ml) was warmed to 40-50° C. for 16 hours. The reaction was cooled and washed with water, dried (MgSO4), and filtered. The oil was purified by silica gel chromatography (10-25% ethyl acetate/hexane) to give (S)-3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as an oil that was taken to the next step. The oil was diluted with dichloromethane (100 ml) cooled to 5° C. and treated with trifluoroacetic acid (40 ml). After stirring at room temperature for 5 hours, all solvent was evaporated. The residue was dissolved in chloroform (150 ml) and washed with cold dilute aqueous sodium carbonate. The organics were dried (MgSO4) and evaporated to give an oil that solidified on standing in ether/hexane to give 3.5 g (68%) of (5-bromo-2-chloro-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine as a solid. 1H NMR (300 MHz), dmso-d) δ ppm, 8.23 (s, 1H), 7.17 (s, 1H), 3.99 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[O:20]>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[N:7]([C:19]([Cl:21])=[O:20])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 3-t-butyl-5-(methylthio)pyrazole (10 g), and triethylamine (6.0 g) were added dropwise at -20° to a stirred solution of phosgene (7.5 ml) in tetrahydrofuran (75 ml). The solution was allowed to come to room temperature, and was then stirred for 2 hours. Excess phosgene was removed by drawing dry air through the mixture for 1/2 hour. The reaction mixture was filtered, and evaporated to give a yellow oil which quickly crystallised. Recrystallisation from petrol gave 3-tert-butyl-1-chlorocarbonyl-5-(methylthio)pyrazole, 5.0 g (64% yield), melting point 64°-6°.
Reaction SMILES: FC(F)(F)C(O)=O.IC[C:10]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:39])[C@H:24]([CH:36]([CH3:38])[CH3:37])[NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>ClCCl>[CH2:29]([O:28][C:26]([NH:25][C@H:24]([C:23]([O:22][CH2:21][CH2:20][O:19][C:17]1[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=1)=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOc1ccc(C(=O)O)c(CI)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxybenzyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate (10.2 g, 19.04 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and the mixture was stirred 3 hours at room temperature. The solution was evaporated under reduced pressure and co-evaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 6.9 g=87%. The product may be activated and esterified direct to a drug or converted to iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid as described above, that is by treatment with a base, chloroiodomethane, separation and then treatment with NaI.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(OCC)C>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9][CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: CN1CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C)CC1
Reaction time: 72 h
Yield: 61.6 %

Procedure:
A solution of acryloyl chloride (9 g, 0.10 mole) in ethyl ether (20 ml) was added dropwise to a stirring, cold solution of N-methylpiperazine (10 g, 0.10 mole) and triethylamine (30.6 ml, 0.22 mole) in ethyl ether (150 ml) over a thirty minute period. An additional 75 ml of ethyl ether was added and the reaction stirred for 72 hours. The resulting white solid was filtered and washed well with ethyl ether. The ethyl ether was collected, combined with the filtrate and the solvent evaporated on a rotary evaporator to yield 9.5 g of product as an orange oil. NMR confirmed the structure of the product.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C(OCC)C.C(=O)([O-])O.[Na+]>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Brc1ccoc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccoc1
Temperature: -76 °C
Reaction time: 0.25 h

Procedure:
3-Bromofuran (1.23 ml) was dissolved in diethyl ether (15 ml) and cooled to -76° C. Butyllithium (8.5 ml, 1.6M in hexane) was added dropwise ensuring the temperature remained below -60° C. After stirring for 15 minutes, tributyltin chloride (3.69 ml) was added. The reaction was stirred at -76° C. for 1 hour. The reaction was diluted with aqueous sodium hydrogencarbonate (20 ml) and the product extracted with diethyl ether (3×20 ml). The combined organic fractions were dried (brine, MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with hexane to yield the title compound as a colourless oil. 1H NMR (CDCl3, 360 MHz), δ 0.91 (9H, t, J 8.9 Hz), 1.03 (6H, t, J 10.4 Hz), 1.34 (6H, sx, J 7.3 Hz), 1.58 (6H, m), 6.35 (1H, d, J 1.5 Hz), 7.23 (1H, s), 7.56 (1H, t, J 1.4 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C)=O.[SH2]=N.[C:13]1([NH:19][C:20](C2C=CC=CC=2C(O)=O)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([NH:19][C:20]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)N1CCOCC1
Yield: 32.8 %

Procedure:
A solution of 0.9 g morpholine with 5 ml aceton was added dropwise during 5 minutes to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml acetone, under stirring. The reaction mixture was stirred for a further 30 minutes at ambient temperature, then diluted with 150 ml water. Acetone was distilled off, the mixture was cooled, and 0.35 g phenylcarbamoyl-morpholine was isolated by filtration. The white crystalline material melted at 160°-162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:12]3[CH2:13][N:14]([C:34]([NH:33][C:27]4[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=4[F:25])=[O:35])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cc1ccc(C2(c3ccc(C)cc3)OC(=O)N3CCNCC32)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2(c3ccc(C)cc3)OC(=O)N3CCN(C(=O)Nc4ccc(F)cc4F)CC32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of 1,1-bis(4-methylphenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.62 mmol) in tetrahydrofuran (6 mL) was added 2,4-difluorophenyl isocyanate (0.090 mL, 0.76 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=98:2 to hexane:ethyl acetate=1:1), and then recrystallized from diisopropyl ether to obtain the title compound (0.20 g, yield 68%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (16.0 g, 0.0864 mol) in dry DMF (100 mL) was added with stirring potassium carbonate (59.0 g, 0.43 mol) followed by methyl iodide (24.5 g, 0.173 mol) and the mixture was stirred for 3 h at ambient temperature. The reaction mixture was diluted with ice water (500 mL), extracted with EtOAc (3×100 mL) and the combined organic phases were washed with water (3×100 mL) and saturated brine solution (100 mL). The organic phase was dried (Na2SO4) and the solvent evaporated affording 17.0 g (99%) of 4-fluoro-3-nitro-benzoic acid methyl ester.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:10])[CH3:9].[OH-].[Na+]>>[CH2:8]([NH:10][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH3:9]
Reactant: BrCC1OCCO1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1OCCO1
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (15 grams; 0.09 mole) and ethylamine (74 ml; 1.65 mole) were charged into a Parr Shaker. The shaker was sealed and was heated with an infra-red lamp to a pressure of about 50 p.s.i. Heating was stopped and the reaction mixture was shaken for a period of about 1/2 hour. After this time aqueous sodium hydroxide (12 ml; 50% concentration) was added to the reaction mixture with stirring. The organic phase was then separated from the aqueous phase, was dried over anhydrous magnesium sulfate and distilled under reduced pressure to yield the desired product N-ethyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:26]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:26])[C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(=O)[nH]c3cc(Cl)cnc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)n([C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(6-chloro-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (110 mg, 0.33 mmol) in dry THF (5 mL) was added 60% NaH in oil (20 mg, 0.5 mmol). The mixture was stirred at rt for 5 min and MeI (0.02 mL, 0.33 mmol) was added. The mixture was stirred overnight, diluted with EtOAc (100 mL), washed with brine (2×10 mL) and dried over Na2SO4. Removal of the solvent left an oil (118 mg) which was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford 5 fractions. Fractions 2 & 3 were pooled and concentrated to give (R)-tert-butyl 3-(6-chloro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (109 mg, 95%) as a red oil. LC-MS Method 1 tR=1.82 min, m/z=353, 279.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[OH-].[Na+].C(O)(=[O:18])C>O1CCCC1>[Cl:1][C:2]1[NH:11][C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2nc(Cl)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 2,4-dichloro-6-methylquinazoline (2.13 g, 10 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (2 N, 20 mL). After being stirred at room temperature for 4 hours, the reaction mixture was chilled and acidified to pH 5 with acetic acid. The formed solid was collected by filtration, washed with water, and dried in vacuo to afford 1.7 g of the desired product as a white solid (yield was 87.6%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:25]=1[CH3:26].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: Cc1c(I)cnn1-c1ccccn1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccn4)c3C)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.12 mmol), 2-(4-iodo-5-methyl-1H-pyrazol-1-yl)pyridine (51.0 mg, 0.18 mmol), copper (I) iodide (6.8 mg, 0.036 mmol), and tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.012 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.033 ml, 0.24 mmol). The mixture was sparged with argon for 3 minutes and heated to 60° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-[(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)ethynyl]pyrazolo[1,5-a]pyridine.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.[OH-].[Na+].CCO>C1(C)C=CC=CC=1.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>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(Br)cc1
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(CO)cc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2.80 g (9.36 mmol) of 2-(N-t-butylsulfamoyl)-5-n-propylphenylboronic acid (from Step B) and 4-bromobenzyl alcohol (5.25 g, 3 equiv) in toluene (125 mL) was added 1.25N NaOH (32 mL), EtOH (86 mL) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 3 mol %). The mixture was stirred at 100° C. under N2 for 3 hours. The reaction was concentrated and the residue was extracted with ethyl acetate. The organic solution was washed with 1N NaOH, H2O and brine. Next, the organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to provide the titled compound; Rf =0.42 (1:1 EtOAc-hexane).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9](/[CH:40]=[CH:41]/[C:42]2C=C[C:45](OC)=[CH:44][CH:43]=2)=[N:8]1.O1[CH2:55][CH2:54][O:53][CH2:52]C1>Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3/[CH:40]=[CH:41]/[C:42]2[CH:55]=[C:54]([O:53][CH3:52])[CH:45]=[CH:44][CH:43]=2)=[N:17]1
Reactant: C1COCCO1
Reactant: COc1ccc(/C=C/c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Agent: Cl
Product: COc1cccc(/C=C/c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 17.4 %

Procedure:
Hydrolysis was performed by stirring 1-((1E)-2-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}vinyl-4-methoxybenzene in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl at room temperature for 6.5 hours. A mixture of 2 isomers was isolated after purification by preparative HPLC (3% of the minor isomer) (0.014 g, 17.4% yield) 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 8.55 (s, 1H), 8.15 (d, 1H), 7.7 (t, 3H), 7.5 (d. 2H), 7.0 (d, 2H), 3.8 (s, 3H); ES-MS (m/z) 318 [M+1]+.