Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[S-:12][C:13]#[N:14].[K+].Cl.[OH2:17]>C(O)C>[OH:17][C:13]1[S:12][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[N:14]=1
Reactant: N#C[S-]
Reactant: O
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Oc1nc(-c2ccncc2)cs1
Reaction time: 5 h

Procedure:
A mixture of α-bromo-4-acetylpyridine hydrobromide (140.0 g, 0.50 mol) and potassium thiocyanate (53.4 g, 0.55 mol) in absolute ethanol (1500 mL) was heated to reflux for two hours. To the resulting mixture was added concentrated hydrochloric acid (250 mL) and water (500 mL) and reflux continued for five hours. After cooling, the crystallized solid was collected by filtration and washed with ethanol. The resulting material was suspended in water and neutralized with aqueous sodium bicarbonate to obtain, after filtration and drying, 2-hydroxy-4-(4-pyridyl)thiazole 39.0 g, 44%). mp. 250° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[N:13]2[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Temperature: 45 °C
Yield: 102.1 %

Procedure:
To a stirred solution of ethyl 4-benzyloxy-1-methyl-1H-indole-2-carboxylate (3.09 g) in THF (200 mL) was added LiOH.H2O (1.26 g) in water (200 mL) and the resulting two phase solution was heated at 45° C. under nitrogen overnight. The cooled reaction mixture was evaporated to remove THF and the remaining aqueous solution was acidified with NaHSO4 to precipitate the title compound, which was collected, washed with water, and dried to give 2.87 g of the title compound. Mp 216.6-216.8° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][C:15]=3[CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:26](=O)([O-])[O:27]C1C=CC([N+]([O-])=O)=CC=1C1CCC1.C(N(C(C)C)C(C)C)C.[O:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1>>[CH:56]1([O:52][C:26]([N:22]2[CH2:23][CH2:24][CH:19]([CH:17]3[CH2:16][C:15]4[CH:25]=[C:11]([C:8]5[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=5)[CH:12]=[CH:13][C:14]=4[O:18]3)[CH2:20][CH2:21]2)=[O:27])[CH2:55][CH2:54][CH2:53]1
Reactant: C1CCOC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Reactant: O=C([O-])Oc1ccc([N+](=O)[O-])cc1C1CCC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC4CCC4)CC2)O3)cc1

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine (100 mg), cyclobutyl-4-nitrophenyl carbonate (67 mg), and ethyldiisopropylamine (46 μL) in tetrahydrofuran (2 mL) is stirred under reflux over night. The solvent is evaporated and the residue is solved in ethyl acetate. The solution is washed with aqueous NaOH solution (1 M) and brine, dried (Na2SO4) and the solvent is evaporated to give the title compound. Yield: 92 mg (72% of theory); LC (method 2): tR=1.45 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][O:6][C:7]1[C:12]([NH2:13])=[C:11]([O:14][CH3:15])[N:10]=[C:9]([CH3:16])[N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:12]1[C:7]([O:6][CH3:5])=[N:8][C:9]([CH3:16])=[N:10][C:11]=1[O:14][CH3:15])=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: COc1nc(C)nc(OC)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(OC)c1N=C=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Thiophosgene (7.7 mL, 101 mmol) was added dropwise to a stirred mixture of 4,6-dimethoxy-2-methylpyrimidin-5-amine (14.2 g, 84.3 mmol) in tetrahydrofuran (110 mL) and saturated aqueous sodium hydrogen carbonate (110 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a brown powder (12.5 g, 59.0 mmol, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1([CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH2:25][O:24]1.O>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]([OH:24])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH2:25][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][NH:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CNN2CC(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 47 %

Procedure:
5-Nitroindazole (3.44 g, 21.08 mmol) was suspended in N,N-dimethylformamide (100 ml) and sodium hydride (0.93 g, 23.19 mmol) was slowly added to the suspension at 0° C., followed by stirring for 30 min and then for an additional 30 min at room temperature. The addition of 1-((2-(2,4-difluorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole (5 g, 21.08 mmol) was performed before stirring at 60° C. for 2 hours. The addition of water (1 ml) at 0° C. led to termination of the reaction. After being diluted with ethyl acetate (200 ml), the reaction mixture was washed with saturated ammonium chloride solution (200 ml) and then with brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate and vacuum evaporated to concentrate it. The product was purified by chromatography on silica gel to give the title compound (Yield 47%). This compound was found to have a melting point from 63 to 64° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:54])[C:28]([CH3:53])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:54])[C:28]=3[CH3:53])[CH:37]=[CH:38][C:39]=2[O:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 9.6 %

Procedure:
3-Aminopyridine (0.141 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.2115 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.024 g, 0.0480 mmol, 10%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](P(O)(O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].N12CCCN=C1CCCCC2.[CH:32]12[CH:38]([CH:39]=O)[CH:35]([CH2:36][CH2:37]1)[CH2:34][CH2:33]2>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]([NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[CH:39][CH:38]1[CH:35]2[CH2:36][CH2:37][CH:32]1[CH2:33][CH2:34]2
Reactant: O=CC1C2CCC1CC2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=CC1C2CCC1CC2)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
In a round bottom flask was placed N-(benzyloxycarbonyl)-α-phosphonoglycine methyl ester (680 mg, 2.05 mmol) in dichloromethane (5 mL) and cooled to 0° C. in an ice bath. To this mixture was added slowly 1,8-diazabicyclo[5.4.0]undec-7-ene (266 μL, 1.78 mmol) and stirred at 0° C. for 20 min. The mixture was treated with a solution of bicyclo[2.2.1]heptane-7-carbaldehyde (170 mg, 1.36 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was allowed to warm to 25° C. and stirred overnight. The mixture was concentrated in vacuo and the residue taken up in ethyl acetate (50 mL) and washed with a saturated aqueous ammonium chloride solution (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (4 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-7-yl-acrylic acid methyl ester (150 mg, 33%) as a clear colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CNc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N(C)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Fluoro-N-methylaniline (0.33 g, 2.67 mmol) was added to a solution of ethyl 2-bromo-2-phenylacetate (0.36 ml, 2.06 mmol) in acetonitrile (6.86 ml) and DIPEA (0.47 ml, 2.67 mmol). The dark solution was stirred at 100° C. under microwave irradiation for 1 hour. Then solvent was evaporated and the crude was purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain intermediate I5 (0.59 g, 100% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: Oc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc(Br)c(OC2CCNCC2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (50.6 g, 251 mmol) and di-tert-butyl azodicarboxylate (71.0 g, 308 mmol) in THF (350 mL) was added 2-bromo-5-fluorophenol (36 mL, 324 mmol). The mixture was cooled to −78° C. and a solution of triphenylphosphine (81.5 g, 311 mmol) in CH2Cl2 (130 mL) was added via a cannula. The reaction was then warmed to room temperature and stirred overnight. The solvents were removed under vacuum and the crude oil was dissolved in EtOH (200 mL). The solution was cooled to −78° C. and treated with 4 M HCl in 1,4-dioxane (450 mL). The reaction was warmed to room temperature and stirred 24 h. After this time, the solvents were removed under vacuum. The salts were neutralized with 1 N NaOH (750 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined and concentrated to dryness. The crude material was treated with heptane (1 L) and a white precipitate was filtered and discarded. The heptane layer was diluted with Et2O and treated with 4 M HCl in 1,4-dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with Et2O:hexanes (1:1). The salts were again neutralized with 1 N NaOH (500 mL) and extracted with a mixture of Et2O:hexanes (1:1) several times. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated. The crude material was dissolved in heptane (2 L), washed four times with 1 N NaOH (250 mL), brine and dried (MgSO4). The organic layer was filtered and concentrated to dryness to afford the title product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=S)=[CH:6][N:5]=[C:4](C)[N:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[NH2:14].C1(C)C=C[C:23]([S:26](O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C(C)=CC=CC=1.O>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[NH:14][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([S:26][CH3:23])=[N:5][CH:6]=1
Reactant: Cc1ncc(C=S)c(N)n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(N)n1
Reaction time: 1 h
Yield: 143.7 %

Procedure:
A mixture of 10 g (59.2 mmol) of 4-amino-2-methylthiopyrimidine-5-carboxaldehyde, 9.7 g (59.9 mmol) of 2,6-dichloroaniline and 1 g (5.3 mmol) of 4-toluenesulfonic acid in 200 ml of xylene was heated at reflux with the azeotropic removal of water for 24 hours. The mixture was cooled and evaporated. 50 ml of acetic acid and 20 ml of toluene were added to the residue. The mixture was cooled in ice and treated portionwise over 30 minutes with 5 g (147 mmol) of sodium borohydride. After 1 hour the mixture was evaporated and the residue was stirred in a mixture of 100 ml of ethyl acetate and 100 ml of 2M aqueous sodium hydroxide for 1 hour. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated. Crystallisation of the residue from aqueous ethanol gave 2.4 g (13%) of 5-(2,6-dichlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine as a white solid. The mother liquors were evaporated and flash chromatography of the residue on silica gel using diethyl ether/hexane (1:1) for the elution gave a further 2.1 g (11%) of 5-(2,6-dichlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine as a white solid.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 92.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (23 mg) was obtained.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=3[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCCN3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.2 %

Procedure:
tert-Butyl 2-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I41) (0.087 g, 0.15 mmol) was dissolved in dry DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.351 mL, 4.58 mmol) was added to the solution and the reaction was stirred at room temperature for 22 hours. Volatiles were removed in vacuo, EtOAc (20 mL) and sat. aq. NaHCO3 (15 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice to give the title compound (8) (0.064 g, 89% yield) as a pale yellow solid;
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[CH:19]=3)[O:12]2)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=1.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.CS(C)=[O:39]>>[CH:18]([OH:22])=[O:39].[CH:31]1([NH:36][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@H:11]3[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]4[O:22][N:21]=[C:20]([CH2:23][CH3:24])[CH:19]=4)[O:12]3)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)on1
Reactant: CS(C)=O
Reactant: NC1CCCC1
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NC5CCCC5)nc43)[C@H](O)[C@@H]2O)on1
Product: O=CO
Temperature: 90 °C

Procedure:
Intermediate 14 (0.206 g, 0.471 mmol) was dissolved in dry DMSO (2.2 ml). An a aliquot of this solution (0.1 ml, 0.021 mmol) was added to cyclopentylamine (0.011 g, 0.126 mmol) in a 1 ml sealed vial (e.g. Reacti-vial™). Mixture was heated at 90° C. for 114.75 h. The resultant crude product was purified by autoprep. HPLC to afford the title compound after freeze-drying as a white solid (0.001 g). LC/MS SYSTEM B Rt=3.07 mins, m/z=486 MH+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CC[C@@H](O)C3)n2n1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol) and (R)-pyrrolidin-3-ol (53 mg, 0.603 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-25% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (21.1 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H), 1.91-2.12 (m, 2 H), 2.34 (s, 3 H), 3.82-4.13 (m, 5 H), 4.44 (br. s., 1 H), 6.16 (s, 1 H), 6.71 (s, 1 H), 7.63 (d, J=8.59 Hz, 2 H), 7.98 (d, J=8.34 Hz, 2 H), 10.95 (s, 1 H); ESI-MS: m/z 396.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>[OH-].[Na+].CC(C)=O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of the methacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm−1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.Cl.[CH2:13]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=2)=[CH:26][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A suspension of 2-chloro-4-methyl-3-nitropyridine (8.63 g), 4-benzyloxyaniline hydrochloride (13.0 g) and triethylamine (20.9 ml) in DMSO (150 ml) was stirred at 120° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (10.7 g).