Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[CH:14]=2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[N:9]1([CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[CH:14]=2)[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C1CN(CCc2ccc3c(c2)COC3=O)CCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCc2cc(CCN3CCNCC3)ccc21
Temperature: 25 °C

Procedure:
To 1,1-dimethylethyl-4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (120 g, 347 mmol) in dioxane (800 mL) was added 4 N HCl in dioxane (87.0 mL, 347 mmol) and the resulting mixture was stirred at room temperature over night. The reaction mixture was concentrated and stored under vacuum overnight to afford 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride. This can be used as is or converted to the free base by partitioning between an organic solvent and saturated NaHCO3 solution. MS: m/z 247 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH3:1][C:2]1[C:3]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(F)cc2)c(C)c1
Reactant: CC(C)CBr
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c(C)c1
Yield: 53.2 %

Procedure:
The title compound (53.7 mg) was prepared from N-(3,5-dimethylpyridin-2-yl)-4-fluorobenzenesulfonamide (84 mg, 0.300 mmol) and 1-bromo-2-methylpropane (0.065 mL, 0.599 mmol), following procedure described for Example 22. LCMS (2 min, formic) Rt 0.96 min, m/z (ES+) 337 (M+H).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][CH2:33][NH2:34])[C:29]([OH:31])=[O:30])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:19]1[C:20]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][CH2:33][NH:34][C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])[C:29]([OH:31])=[O:30])=[O:26])[C:22]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Cl)C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)C1CCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclobutanecarbonyl chloride (69.7 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (92.6 mg, 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)([Cl:14])=O>>[Cl:14][C:5]1[N:4]=[CH:3][CH:2]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)cnc1O
Reactant: O=S(Cl)Cl
Product: O=C(O)c1cccnc1Cl

Procedure:
Substituted pyridines 12 can be prepared by the procedure described in Scheme 4. A solution of sodium hypobromite is freshly prepared and added to a 2-hydroxynicotinic acid 7 and heated, such as at a temperature of about 50° C. Additional sodium hypobromide may be added to form the bromo compound 8 as needed. The 5-bromo-2-hydroxynicotinic acid 8 is reacted with thionyl chloride, at suitable temperature, such as at a temperature >RT, and preferably at about 80° C., to form the 2-chloro-nicotinic acid analog 9. The acid is coupled with an amine, preferably in the presence of a suitable coupling agent(s), such as EDC, HOBT, and DIEA, to form the corresponding substituted amide 10. Suzuki coupling with the bromo nicotinamide 10 and suitable boronic acids, provides the substituted nicotinamide 11. 2-Amino-nicotinamides 12 are prepared from the corresponding chloro compounds 11 such as by reacting with substituted amines at a suitable temperature, such as about 80° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1.CS(C)=O>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nc(N)nc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 2.0 g (7.7 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 2.0 g (10.0 mmol) piperidin-3-yl-carbamic acid tert-butyl ester using 1.29 mL (9.2 mmol) triethylamine in 5 mL NMP and 5 mL DMSO. 200 mL ethyl acetate and 100 mL half concentrated aqueous Na2CO3 solution are added and the phases are separated. The aqueous phase is extracted 2 times with ethyl acetate (100 mL each). The combined organic layers are dried over sodium sulfate and the solvent is removed under reduced pressure. The crude product is used without further purification in the next step.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.[CH:12]1[C:15]2[CH:16]=[CH:17][C:18]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][C:27]([N+]([O-])=O)=[CH:28][CH:29]=[C:22]4[C:21]3=[O:33])=[CH:19][C:14]=2[CH:13]=1>O>[CH:12]1[C:15]2[CH:16]=[CH:17][C:18]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][C:27]([O:7][C:1]5[CH:6]=[CH:5][CH:4]=[C:3]([C:12]#[C:13][C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[CH:2]=5)=[CH:28][CH:29]=[C:22]4[C:21]3=[O:33])=[CH:19][C:14]=2[CH:13]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc2c(c1)C=C2
Reactant: [O-]c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccc(Oc3cccc(C#Cc4ccccc4)c3)cc2C(=O)N1c1ccc2c(c1)C=C2
Temperature: 35 °C
Reaction time: 2 h

Procedure:
The dark phenolate/DMSO solution was allowed to cool to about 35° C. in an oil bath. N-4-benzocyclobutenyl 4-nitrophthalimide (1.00g, 3.40 mmol) was added next. The resultant reaction mixture was stirred under N2 at 30°-35° C. for another 21/2 hours. Then, the reaction mixture was poured into a separatory funnel containing about 300 ml of H2O and extracted with ethyl acetate (100 ml, 3×50 ml). The organic extract was then washed with saturated NaCl solution (2×150 ml) and dried over MgSO4. The volume of the dried extract was concentrated on a rotary evaporator to about 10 ml and passed through a chromatographic column containing about 100 g of silica gel saturated with petroleum ether. Elution was carried out with 100 ml petroleum ether, followed by 1:2 CH2Cl2 / petroleum ether. 4 bands were developed in the column. The desired product which was contained in the first band, was isolated as light yellow microcrystals. Yield: 0.45 g (30%). Calc. for C30H19NO3 : 81.62% C; 4.34% H; 3.17% N. Found: 81.05% C; 4.31% H; 3.09% N. Mass Spectroscopy: 441 (M+, 100%). Proton NMR (CDCl3): 3.20 (singlet, alicyclic protons); 7.00-7.93, (complex, aromatic protons). IR(KBr): 2700 m (alicyclic C--H stretches); 1706 m, 1778 vs (symmetric and asymmetric stretches of imide group): 1238 ms (Ar--O--Ar stretch).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[N:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[F:13][C:12]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][CH:9]=[CH:10][N:11]=1
Reactant: Fc1nccnc1C1=CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1nccnc1C1CCOCC1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoropyrazine (1.1754 g, 6.52 mmol) and palladium hydroxide on carbon (0.458 g, 0.652 mmol) in EtOAc (21.75 mL). The round bottomed flask was flushed with argon and then placed under vacuum three times. A hydrogen balloon was then attached to the reaction. After stirring overnight, the reaction was filtered through celite to provide 2-fluoro-3-(Tetrahydro-2H-pyran-4-yl)pyrazine. [M+H]=183.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH3:10].C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:12])[C:4](=[N+:22]=[N-:23])[C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C/C=C\CCC(=O)CC(=O)OC
Solvent: CCN(CC)CC
Product: C/C=C\CCC(=O)C(=[N+]=[N-])C(=O)OC
Yield: 87 %

Procedure:
In accordance with the process of Example 2, (Z)-3-oxo-6-octenoic acid methyl ester (0.77 g; 4.52 m mol), triethylamine (0.46 g; 4.52 m mol), p-toluenesulfonylazide (0.89 g; 4.52 m mol) were used as starting materials to obtain 0.77 g of (Z)-2-diazo-3-oxo-6-octenoic acid methyl ester as yellow oily product.
Reaction SMILES: [CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([CH:9]2[O:13][CH:12]([CH2:14][O:15][P:16]([O:19][P:20]([O:23][P:24]([O-:27])([OH:26])=[O:25])([O-:22])=[O:21])([O-:18])=[O:17])[CH:11]([OH:28])[CH:10]2[OH:29])[CH:2]=1.[Na+].[Na+].[Na+].[CH2:33]([N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>O>[CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][O:15][P:16]([O:19][P:20]([O:23][P:24]([OH:26])([OH:27])=[O:25])([OH:22])=[O:21])([OH:18])=[O:17])[C@@H:11]([OH:28])[C@H:10]2[OH:29])[CH:2]=1.[CH2:42]([N:37]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44][CH3:45]
Reactant: O=c1ccn(C2OC(COP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O)C(O)C2O)c(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
UTP trisodium salt (1.00 g, 1.82 mmol) was dissolved in deionized water (13 mL), and the solution was caused to pass through a strong cation-exchange column (PK 216, proton-type, 10 cc). The eluate was mixed with a column wash solution, and the mixture was neutralized with tributylamine (1.75 mL, 7.35 mmol). The resultant solution was concentrated under reduced pressure, and the residue was co-boiled four times with dioxane (10 mL). The residue was dissolved in dimethylformamide (10 mL), to thereby yield a 0.133 M dimethylformamide solution of UTP tributylamine salt.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>[Rh].C(OC(C)C)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: [Rh]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (400 μl). 5% Rhodium on carbon (2 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). Spectroscopic data as in Example 40, Method 1.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[O:7][C:8]([CH3:27])([CH3:26])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][C:12]3=[O:25])[C:5]=2[CH:4]=1)#[N:2].[O:30]([C:37](Cl)=[S:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[O:7][C:8]([CH3:26])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([O:24][C:37]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[S:38])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][C:12]3=[O:25])[C:5]=2[CH:4]=1)#[N:2]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CC(O)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC(OC(=S)Oc1ccccc1)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1

Procedure:
In 10 ml of acetonitrile, is dissolved 314 mg of 6-cyano-2,2-dimethyl-4-{2-oxo-4-(1-hydroxy-2-ethoxycarbonylethyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 31. Then, 195 mg of 4-dimethylaminopyridine and 0.17 ml of phenoxythiocarbonyl chloride are added at room temperature and reacted at that temperature for 19.5 hours. After stopping the reaction by adding 0.1M aqueous solution of sodium hydrogen carbonate, the reaction mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 2/3 mixture of ethyl acetate/n-hexane. Thus, there are obtained 77 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-2-ethoxycarbonylethyl)-1-pyridinyl}-2H-benzo[b]pyran and, as a by-product, 20 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(2-ethoxycarbonylethenyl)-1-pyridinyl}-2H-benzo[b]pyran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]4[CH2:29][O:28]C(C)(C)[O:26]4)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]([OH:26])[CH2:29][OH:28])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(OC[C@@H]4COC(C)(C)O4)cc3)n2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OC[C@@H](O)CO)cc3)n2)cc1Cl
Temperature: 70 °C
Yield: 95.3 %

Procedure:
To a solution of (R)-3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.339 g, 0.762 mmol) in THF (15.24 ml) was added a solution of 1N HCl (1.524 ml, 1.524 mmol). After 48 h additional 1N HCl (2.286 ml, 2.286 mmol) was added and the reaction mixture was heated to 70° C. for about 2 h. After cooling to ambient temperature a solution of 1N NaOH (3.81 ml, 3.81 mmol) was added and the reaction mixture was concentrated in vacuo. The resulting solid was washed with copious amounts of water and dried in vacuo to provide (S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)propane-1,2-diol (0.294 g, 94%) as a colorless solid. LCMS (Table 1, Method c) Rt=2.73 min, m/z 405 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[CH2:35][C:36]1[O:40][N:39]=[CH:38][CH:37]=1>>[O:40]1[C:36]([CH2:35][N:15]2[CH2:16][CH2:17][CH:12]([CH2:11][C:10]3[N:2]([CH3:1])[C:3]4[C:8]([N:9]=3)=[C:7]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:6]=[C:5]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[N:4]=4)[CH2:13][CH2:14]2)=[CH:37][CH:38]=[N:39]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: BrCc1ccno1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(Cc4ccno4)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and 5-(bromomethyl)isoxazole were reacted to give 570. LCMS m/z: 264.7 (2M+H+)
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[CH3:13][NH:14][NH2:15].Cl.O>CCCCO>[CH3:13][N:14]1[C:2]2=[C:3]3[CH:12]=[CH:11][NH:10][C:4]3=[N:5][CH:6]=[C:7]2[CH:8]=[N:15]1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: CNN
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Cn1ncc2cnc3[nH]ccc3c21
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.37 g, 7.59 mmol, Adesis) and methylhydrazine (0.599 mL, 11.4 mmol) in n-BuOH (7 mL) were heated to about 95° C. After about 15 min, concentrated HCl (0.500 mL, 16.4 mmol) was added and the reaction mixture was heated to about 120° C. After about 4 h, water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was basified with saturated aqueous NaHCO3 to about pH 8 and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g column) eluting with a gradient of 5-60% EtOAc in heptane to give 1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.960 g, 74%): LC/MS (Table 2, Method d) Rt=1.40 min; MS m/z: 173 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][C@:42]([CH3:48])([CH:45]([CH3:47])[CH3:46])[CH2:43][OH:44].CCN(C(C)C)C(C)C>C(#N)C>[OH:44][CH2:43][C@@:42]([NH:41][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:48])[CH:45]([CH3:47])[CH3:46]
Reactant: O=C(O)c1cc(OCC2CCC2)c(Cl)cn1
Reactant: CC(C)[C@@](C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)[C@](C)(CO)NC(=O)c1cc(OCC2CCC2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-cyclobutylmethoxy-pyridine-2-carboxylic acid (60 mg, 249 μmol) in acetonitrile (2 mL) was added HATU (123 mg, 324 μmol), (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1, 32.1 mg, 274 μmol) and DIEA (217 μL, 1.25 mmol). The brownish reaction mixture was stirred for 18 h at room temperature. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) and finally chiral chromatography (ChiralPak AD, heptane/ethanol 9:1) to deliver the desired compound (27.3 mg, 43%) as colorless oil. MS (ESI, m/z): 341.1 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:29]2[CH:28]=[N:27][CH:26]=[N:31][CH:30]=2)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cncnc2)c1
Yield: 77.8 %

Procedure:
To the solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromopyridine (580 mg, 1.69 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (58 mg, 1%) and tributyl(pyrimidinyl)tin (0.75 g, 2.03 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:3) to afford an oil (450 mg, 78%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.30-2.44 (m, 2H), 3.88-3.96 (m, 2H), 4.22 (m, 1H), 4.44 (m, 1H), 4.58 (m, 1H), 7.44 (m, 1H), 8.44 (m, 2H), 8.98 (s, 2H); MS (CI/NH3) m/z 343 (M+H)+.
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.CC1ON=C(C2C=CC=CC=2)C=1COC1C=CC(C(O)=O)=CN=1.[CH2:47]([CH2:49][NH2:50])[OH:48]>>[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:50][CH2:49][CH2:47][OH:48])=[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: NCCO
Agent: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: O=C(NCCO)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 70 %

Procedure:
As described for example 191, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.3 mmol) was converted, instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, using ethanolamine instead of (1R,2R)-2-amino-cyclohexanol hydrochloride (1:1), to the title compound (79 mg, 70%) which was obtained as a white solid. MS: m/e=374.0 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C:13]1[N:17]=[C:16]([CH3:18])[O:15][N:14]=1)[CH3:12])C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[CH3:18][C:16]1[O:15][N:14]=[C:13]([C@H:11]([NH2:10])[CH3:12])[N:17]=1
Reactant: Cc1nc([C@@H](C)NC(=O)OCc2ccccc2)no1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1nc([C@@H](C)N)no1
Temperature: 25 °C

Procedure:
To a solution of benzyl[(1R)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]carbamate (1.10 g, 4.21 mmol) in dichloromethane (40 mL) was added 1 M boron trichloride solution in dichloromethane (21.1 mL, 21.1 mmol) at 0° C. The reaction mixture was allowed to warm from 0° C. to 20° C. over 4 h. The solution was quenched by 5 ml of methanol at 0° C. After warming to ambient temperature, the mixture was concentrated and the residue was washed with 100 mL of diethyl ether (2×) to give the hydrochloride salt of (1R)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethanamine was obtained as solid (0.84 g). 1H NMR (500 MHz, CD3OD): δ 4.70-4.61 (m, 1H); 2.63 (s, 3H); 1.67 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12])[CH2:8][Br:13]
Reactant: Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(CBr)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A mixture of 2-chloro-4-methyl-1-trifluoromethylbenzene 26 (0.20 g, 1 mmol), N-bromosuccinimide (0.17 g, 1 mmol) and benzoyl peroxide (7.4 mg, 0.03 mmol) in carbon tetrachloride (2 mL) was heated to reflux for 2 hours. Another portion of benzoyl peroxide (20 mg, 0.08 mmol) was added. The mixture was heated to reflux for another 0.5 hours. The reaction mixture was further stirred at room temperature for 16 hours. The solid was removed by filtration. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica, using petroleum ether as eluent, to give 0.22 g (80%) of Compound 27.