Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:26])[C:18]4[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2.O[N:29]1[C:33]2C=C[CH:36]=[CH:37][C:32]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(N)CCC>C1COCC1.CN(C=O)C.C(OCC)(=O)C.O>[CH2:33]([NH:29][C:23]([C:20]1[CH:21]=[CH:22][C:17]2[O:16][CH2:15][C:14]([CH3:26])([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:1])([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[C:18]=2[CH:19]=1)=[O:24])[CH2:32][CH2:37][CH3:36]
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCN
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)c1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2

Procedure:
A solution of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2H-1-benzofuran-5-carboxylic acid (100 mg, 0.275 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1,3-dicyclohexylcarbodiimide (112 mg, 0.55 mmol) and butylamine (19 mg, 0.255 mmol) in 5 ml of THF and 2 ml of DMF is stirred at room temperature for 6 hours. 30 ml of water and 30 ml of ethyl acetate are added. After stirring and separation of the phases by settling, the aqueous phase is extracted with 2×30 ml of ethyl acetate. The organic phases are then combined and washed twice with 30 ml of water, then dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is then purified by flash chromatography on a column of silica (50% heptane/50% ethyl acetate).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH:16]2[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:20][CH2:21]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(OC(c2ccccc2)c2ccc(F)cc2)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccc(F)cc2)CC1
Yield: 86.6 %

Procedure:
A quantity of 92.9 g of ethyl chlorocarbonate was added dropwise to a solution of 50.2 g of (±)-4-[(4-fluorophenyl)phenylmethoxy]-1-methylpiperidine in 200 ml of toluene, and the resulting solution was refluxed for 8 hours. After cooling, the reaction solution was washed with hydrochloric acid and water, dried and concentrated to give 51.9 g of yellowish brown liquid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:21])[NH:12][NH:13][C:14]=2C2C=CC=CC=2)=[CH:5][CH:4]=1.CC([O:25][CH2:26][C@H:27]1[O:32][C@H:31](Br)[C@H:30]([O:34]C(C)=O)[C@@H:29]([O:38]C(C)=O)[C@@H:28]1[O:42]C(C)=O)=O.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[C@@H:31]1([O:21][C:11]2[C:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:14][NH:13][N:12]=2)[O:32][C@H:27]([CH2:26][OH:25])[C@@H:28]([OH:42])[C@H:29]([OH:38])[C@H:30]1[OH:34]
Reactant: CSc1ccc(Cc2c(-c3ccccc3)[nH][nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc(Cc2c[nH]nc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a suspension of 4-[(4-methylthiophenyl)methyl]-5-phenyl-1,2-dihydro-3H-pyrazole-3-one (0.087 g), acetobromo-α-D-glucose (0.62 g) and benzyltri(n-butyl)ammonium bromide (0.054 g) in dichloromethane (3 mL) was added a sodium hydroxide aqueous solution (5 mol/L, 0.9 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetraacethyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (5 mL), and sodium methoxide (28% methanol solution, 0.28 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. Acetic acid (0.090 g) was added to the reaction mixture, and the solvent was removed. Water (5 mL) was added to the residue, and the mixture was purified by solid phase extraction on ODS (washing solvent: water/methanol=5/1, eluent: methanol). Column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-7/1) was used for further purification to give the title compound (0.033 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH:26]([OH:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH:26]([OH:28])[CH3:27])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 43 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using (rac)-1-amino-2-propanol instead of ethanolamine, to the title compound (100 mg, 43%) which was obtained as a colourless gum. MS: m/e=388.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].C(N(CC)CC)C.[CH3:22][C:23]1([CH3:37])[C:27]([CH3:29])([CH3:28])[O:26][B:25]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[O:24]1.CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:34][C:33]1[CH:32]=[CH:31][C:30]([B:25]2[O:26][C:27]([CH3:29])([CH3:28])[C:23]([CH3:37])([CH3:22])[O:24]2)=[CH:36][CH:35]=1)=[O:14]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
936 mg of 2-fluoro-5-trifluoromethylphenylisocyanate and then 0.64 ml of triethylamine are added to a solution of 1 g of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)aniline in 15 ml of tetrahydrofuran, at ambient temperature. The reaction medium is stirred at ambient temperature for 18 h, and then treated with methanol and then, finally, evaporated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on silica using, as eluent, a (99.5/0.5 then 90/10) methylene chloride/methanol mixture. The fractions containing the expected product are concentrated to dryness so as to give 1.45 g of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea in the form of a white solid. MS (ES) MH+ m/z=425.
Reaction SMILES: [CH2:1]([C@H:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@@H:9]([OH:37])[CH2:10][C@@H:11]([NH:26]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:26][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[CH2:10][C@H:9]([OH:37])[C@@H:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(C[C@@H](C[C@H](O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)nc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2ccc(C[C@H](N)C[C@H](O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution containing the product from Example 92G (0.198 g, 0.325 mmol) in a mixture of methanol (1.6 mL) and ethyl acetate (1.6 mL) was treated with Pd(OH)2 on carbon (0.060 g, 20% Pd by wt.) and HCl solution (0.080 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 18 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: CO.C[O-].[Na+].[C:6](I)([C:9]([C:12]([C:15]([C:18]([C:21]([C:24]([C:27]([F:30])([F:29])[F:28])([F:26])[F:25])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]>O>[CH:6]([C:9]([C:12]([C:15]([C:18]([C:21]([C:24]([C:27]([F:28])([F:29])[F:30])([F:25])[F:26])([F:22])[F:23])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Into a 500 cc four-necked equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, 200 cc of methanol and 32.4 g (0.6 mol) of sodium methoxide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 273 g of (0.5 mol) of C8F17I was dropwise added thereto over a period of one hour. After completion of the dropwise addition, heating and refluxing were continued for 10 hours. The conversion at that time was 99.8%. The reactor was cooled to room temperature. Then, 300 g of water was added to dissolve precipitated potassium iodide. The crude reaction solution was separated into two layers, and the fluorocarbon layer (lower layer) was further washed with 300 g of water to obtain 201 g of C8F17H having a purity of 99.4%. In the reactor, no formation of tar was observed.
Reaction SMILES: C(OC1CC(C)(C)N(O)C(C)(C)C1)(=O)[C:2]1[C:3](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([OH:15])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5].[C:35]([O:43][CH:44]1CC(C)(C)N(O)C(C)(C)C1)(=[O:42])[C:36]1C=CC=C[CH:37]=1>>[C:4]([O:6][CH:7]1[CH2:8][C:9]([CH3:16])([CH3:17])[N:10]([O:15][CH2:37][CH2:36][C:35]([O:43][CH3:44])=[O:42])[C:11]([CH3:13])([CH3:14])[CH2:12]1)(=[O:5])[C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:2]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: COC(=O)CCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
When following the general procedure of Example 3 the bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) phthalate is replaced by an equivalent amount of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, the title compound is obtained as a white solid melting at 64°-69° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C2CCC(=O)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into a solution of 4-(4-hydroxy-phenyl)cyclohexanone (as prepared in Example 40, Step E, 2.4 g, 12.6 mmol), N,N-dimethylethanolamine (Aldrich, 3.37 g, 37.8 mmol) and triphenylphosphine (Aldrich, 9.91 g, 37.8 mmol) in THF (100 mL) at 0° C. was added dropwise a solution of diisopropyl azodicarboxylate (7.44 mL, 37.8 mmol) in THF (15 mL) under Ar. The resulting solution was stirred at 0° C. for 1 h and at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuo to give a colorless oil, which was purified on a silica gel column by a CombiFlash® system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH:20]1([NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Reactant: O=C1CCCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cnc2[nH]cc(Cc3ccc(NC4CCCCC4)nc3F)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (49, 100 mg, 0.39 mmol) and cyclohexanone (67, 0.0465 mL, 0.449 mmol) in 3.00 mL of acetonitrile, triethylsilane (0.400 mL, 2.50 mmol) and trifluoroacetic acid (0.300 mL, 3.89 mmol) were added. The reaction was stirred at 80° C. overnight, then extracting with ethyl acetate and 1N aqueous sodium bicarbonate. The organic layer was washed with brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-60% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-3008, 115 mg). MS (ESI) [M+H+]+=339.0.
Reaction SMILES: [C:1]([N:4]([CH3:27])[NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:17](=[O:26])[C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:28]C(C)([O-])C.[K+].CI>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([N:4]([CH3:27])[N:5]([C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:17](=[O:26])[C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1)[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)N(C)Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN1CCCC1=O
Product: CC(=O)N(C)N(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 4-(2-acetyl-2-methylhydrazino)-8-(2,6-dichlorobenzoylamino)quinoline (140 mg) in N-methylpyrrolidone (1.5 ml) was added potassium tert-butoxide (40.9 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. Methyl iodide (59.1 mg) was added thereto under ice-cooling, and the mixture was stirred for 12 hours at ambient temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) and recrystallized from ethanol to give 4-(2-acetyl-1,2-dimethylhydrazino)-8-(2,6-dichlorobenzoylamino)quinoline (62 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:15]2[C:20]3[S:21][C:22]([CH:24]([CH3:26])[CH3:25])=[N:23][C:19]=3[CH2:18][CH2:17][N:16]=2)[CH:3]=1.[BH4-].[Na+].CCN(C(C)C)C(C)C.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>CCO.C(Cl)Cl>[CH2:42]([O:41][C:39]([N:16]1[CH2:17][CH2:18][C:19]2[N:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[S:21][C:20]=2[CH:15]1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:40])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1=NCCc2nc(C(C)C)sc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(C(C)C)nc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of ethyl 2-(4-chloro-2-(2-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-4-yl)phenoxy)acetate (33 mg, 84 μmol, 1.0 eq.) in EtOH (5 mL), NaBH4 (3.5 mg, 92 μmol, 1.1 eq.) was added. The cooling bath was removed and the yellow solution was stirred at r.t. for 2 hours. The reaction mixture was poured in water (15 mL). The mixture was extracted with DCM (2×20 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. To an-ice cooled solution of the residue and DIPEA (43 μL, 252 μmol, 3.0 eq.) in DCM (5 mL), benzyl chloroformate (14 μL, 92 μmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 1 hour. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×5 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[N:8](C(C)(C)C)[CH:7]=[C:6]([C:21]([O:23]CC)=[O:22])[C:5]2=[O:26].Cl.C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[NH:8][CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:26]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Br)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1c[nH]c2nc(N3CCCC3)c(Br)cc2c1=O

Procedure:
A solution of Example 79A (128 mg) in 1:1 6M HCl/ethanol (15 mL) was refluxed for 24 hours then cooled, diluted with water, and filtered. NMR (300 MHz, DMSO) δ 15.22 (s, 1H), 13.11 (br s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 3.84-3.80 (m, 4H), 1.95-1.91 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)(=[O:5])=[O:4].C(N(CC)C(C)C)(C)C.C([O:29][C:30]([C:32]1[N:37]2[C:38]([C:41](=[O:46])C(Cl)(Cl)Cl)=[CH:39][N:40]=[C:36]2[CH:35]=[CH:34][CH:33]=1)=O)C>C(#N)C>[F:17][C:2]([F:16])([F:1])[S:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[C:30](=[O:29])[C:32]3[N:37]4[C:38](=[CH:39][N:40]=[C:36]4[CH:35]=[CH:34][CH:33]=3)[C:41]2=[O:46])=[CH:11][CH:10]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Reactant: Nc1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=c1c2cccc3ncc(c(=O)n1-c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1)n32
Yield: 6.7 %

Procedure:
To a solution of 1.18 g (4.4 mmol) of 4-[2-(trifluoromethanesulfonamido)ethan-1-yl]aniline and 0.68 g (5.3 mmol) of N,N-diisopropylethylamine in 20 ml of acetonitrile was added a solution of 1.53 g (4.4 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine. The mixture was heated for 38 hours under reflux. After cooling, and the solvent was distilled off. To the residue was added chloroform. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 130 mg of the desired compound (6.8%, brown solid).
Reaction SMILES: [Cl-].[C:2]([OH:8])(=O)[CH2:3][CH2:4][C:5]#[CH:6].[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([N:16]([CH3:17])[C:2](=[O:8])[CH2:3][CH2:4][C:5]#[CH:6])[CH:13]=[CH:14][CH:15]=1
Reactant: C#CCCC(=O)O
Reactant: CNc1cccc(Cl)c1
Agent: [Cl-]
Solvent: ClCCl
Product: C#CCCC(=O)N(C)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Oxayl chloride (89 μL, 1.02 mmol) was added to a solution of pent-4-ynoic acid (50 mg, 0.51 mmol) in DCM (3 mL). The reaction mixture was stirred at 50° C. for 1 hour, was cooled to 0° C. and was added dropwise to a solution of (3-chloro-phenyl)-methyl-amine (62 μL, 0.51 mmol). The reaction mixture was stirred for 2 hours at room temperature. After evaporation of the solvent, the crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 100 mg (0.45 mmol, 88%) of pent-4-ynoic acid (3-chloro-phenyl)-methyl-amide.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:20]([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[CH:31][CH:32]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(C(=O)OCc4ccccc4)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 8.4 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-[(benzyloxy)carbonyl]phenylboronic acid (0.051 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0038 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Temperature: 60 °C
Yield: 37.7 %

Procedure:
To a solution of 2-[(2-Cyclopropylethyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (300 mg) in dry DMF (5 mL) was added anhydrous potassium carbonate (457 mg) and the mixture was heated at 60° C. for 1.5 h. The reaction was cooled to room temperature and tetrahydro-3-furanylmethyl methanesulfonate (164 mg) was added. The reaction was heated at 90° C. for 3.5 h and was then quenched into water (50 mL) and extracted with EtOAc (3×50 mL). The organics were separated, dried by passing through a hydrophobic frit and evaporated under reduced pressure to give a glassy solid. The material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to give the title compound (103.8 mg).