Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=[C:7]2[NH:23][CH2:24][CH3:25])(=[O:3])[CH3:2].[C:26](OCC)(=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].CCOCC.[H-].[Na+]>CN(C)C=O.Cl.O>[CH2:24]([NH:23][C:7]1[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]3[O:14][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:2][C:1](=[O:3])[C:4]=3[CH:5]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)[CH3:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCc1c(O)c(C(C)=O)cc2c(NCC)cc(C(=O)OCC)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c2nc(C(=O)OCC)cc(NCC)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 72 h
Yield: 55 %

Procedure:
A mixture of the product of step (b) (2.2 g; 6.3953 mmoles) and diethyl oxalate (8.5 g; 58.2191 mole) in dry dimethylformamide (50 ml) was added slowly to a stirred suspension of ether washed sodium hydride (0.38 g, 15.83 mmole) under nitrogen. After the addition, the mixture was allowed to stir under nitrogen for 72 hours. The mixture was poured onto ice, followed by acidification with dilute hydrochloric acid. The pH of the mixture was adjusted to about 7 before extraction into ethyl acetate. The extract was washed with water, dried and evaporated to give a light yellow solid. The solid was dissolved in ethanolic hydrochloric acid and heated to reflux on a steambath for 3 hours. The mixture was cooled, and treated with water. This was then concentrated and the pH of the mixture was adjusted to about 7, followed by extraction with ethyl acetate. The extract was washed, dried and evaporated to give a brown solid (2 g; 74%). The solid was recrystallised from ethanol to give a light brown solid (1.5 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:26](=[O:27])[C:22]3([CH2:25][CH2:24][CH2:23]3)[N:21]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([NH2:39])=O)=[CH:30][CH:29]=3)[C:20]2=[S:40])=[CH:15][C:14]=1[C:41]([F:44])([F:43])[F:42])#[N:12].C(N(CC)CC)C>ClCCl>[C:37]([CH2:36][CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([N:21]2[C:20](=[S:40])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([C:41]([F:44])([F:42])[F:43])[CH:15]=3)[C:26](=[O:27])[C:22]32[CH2:23][CH2:24][CH2:25]3)=[CH:33][CH:32]=1)#[N:39]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMSO (0.01 mL, 0.12 mmol) in dry dichloromethane (1 mL) was added to a stirred solution of oxalyl chloride (0.01 mL, 0.09 mmol) in dry dichloromethane (2 mL) at −78° C. After 15 min, a dichloromethane solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, RD130 (Formula 52) (35 mg, 0.07 mmol) was added to the reaction mixture. Stirring was continued for 20 min at −78° C., and then triethylamine (0.03 mL, 0.22 mmol) was added. After 30 min at −78° C., the reaction mixture was warmed to room temperature and then reaction was quenched with saturated aq. NH4Cl solution. The reaction mixture was diluted with dichloromethane, and extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4-(5-(4-(3-Cyanopropyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile, RD170 (Formula 53) (29 mg, 87%) as a viscous oil. 1H NMR δ 7.98 (d, 1H, J=1.8 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.86 (dd, 1H, J=8.3, 1.8 Hz), 7.43 (d, 2H, J=8.4 Hz), 7.27 (d, 2H, J=8.4 Hz), 2.90 (t, 2H, J=7.3 Hz), 2.63-2.73 (m, 2H), 2.52-2.62 (m, 2H), 2.42 (t, 2H, J=7.3 Hz), 2.18-2.30 (m, 1H), 2.07 (p, 2H, J=7.3 Hz), 1.63-1.73 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20](/N=C/N(C)C)=[O:21])=NC=1.NN>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:20][O:21]3)[N:9]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(-c2nc[nH]n2)nc1
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cn1
Agent: NN
Product: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Yield: 83 %

Procedure:
5-Bromo-2-(1H-1,2,4-triazol-3-yl)pyridine. A solution of (E) -5-bromo-N-((dimethylamino)methylene)picolinamide (0.604 mg, 2.36 mmol) and hydrazine (2.12 g, 66.1 mmol) was stirred at 25° C. for 3 h. The reaction was concentrated and diluted with water. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.442 g, 83% yield). MS (ESI) m/z 226.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[N+:15](=[CH2:17])=[N-:16].[CH2:18](OCC)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH:17]=[N+:15]=[N-:16])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH:12][CH3:18]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCOCC
Reactant: C=[N+]=[N-]
Product: CNS(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl

Procedure:
14 g of 4-chloro-3-sulfamoylbenzoylchloride were reacted as prescribed in Example 66(b) with diazomethane in diethyl ether and the crystallized precipitate was filtered. Fair yellow crystals, melting point: 174° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:9]=1)=[O:4].F[C:18](F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH2:1]([O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)=[O:4])[CH3:18]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(C(=O)C2CCCC2)c[nH]1
Agent: CC[SiH](CC)CC
Product: CCOC(=O)c1cc(CC2CCCC2)c[nH]1
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
To a mixture of 4-cyclopentanecarbonyl-1H-pyrrole-2-carboxylic acid methyl ester (A1-I) and trifluoroacetic acid was added triethylsilylhydride drop wise under stirring at 0-5° C. Stirring was further continued for 20 hours at 0-25° C. Trifluoroacetic acid was removed under reduced pressure and the residue was diluted with diethyl ether, ether layer was separated and washed with 1N NaOH followed by brine, organic layer was dried over anhydrous sodium sulfate and was evaporated to yield 4-cyclopentylmethyl-1-H-pyrrole-2-carboxylic acid ethyl ester (A1-II).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](SC)[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:32]([O-:37])(O[O-])(=O)=[O:33].[K+].[K+].[CH3:40]OC(C)(C)C>C(#N)C.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([S:32]([CH3:40])(=[O:37])=[O:33])[N:21]=3)[C@H:14]2[CH3:29])[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:30])[CH:8]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: COC(C)(C)C
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Reaction time: 14 h
Yield: 96 %

Procedure:
To a suspension of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 8, 10 g, 18.86 mmol) in acetonitrile (25 mL) and water (25 mL) was added potassium peroxymonosulfate (27.8 g, 45.3 mmol). After it was stirred at room for 14 hours, LCMS showed complete conversion of the starting material. It was distributed between water (200 mL) and t-butyl methyl ether (300 mL). The organic layer was washed with water (200 mL) and brine, dried over sodium sulfate, filtered and the filtrate concentrated to get the title compound (10.2 g, 96% yield) as a brightly white solid. LCMS (M+H)+: 564.05. 1H NMR (CDCl3, 500 MHz): δ 8.99 (s, 1H), 7.93 (s, 1H), 7.84 (s, 2H), 6.02 (d, 8.5 Hz, 1H), 5.14 (d, 18.5 Hz, 1H), 4.56 (m, 1H), 4.42 (d, 18.0 Hz, 1H), 3.37 (S, 3H), 0.86 (d, 6.5 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+].O>OS(O)(=O)=O>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)Cc1cccc2cnccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1cccc2cnccc12
Temperature: 100 °C

Procedure:
Ethyl 5-isoquinolinylacetate (1.15 g, 5.34 mmol) was dissolved in concentrated H2SO4 (12 mL) and heated at 100° C. for 2 hours. The reaction mixture was poured into ice (20 g) and the pH was adjusted to 6 with 50% NaOH/H2O. The mixture was allowed to set of several hours, filtered, and the filter cake was rinsed with water to provide the title compound. MS (ESI+) m/z 188 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 4.07 (s, 2H), 7.67 (m, 2H), 7.83 (d, J 5.7, 1H), 8.05 (d, J 8.1, 1H), 8.53 (d, J 6.1, 1H), 9.32 (s, 1H), 12.50 (s, 1H); 13C NMR (DMSO, 75 MHz) δ 37.6 (CH2CO), 117.1 (CH, C4), 126.8, 127.0 (CH, C7 & C8), 128.4 (C), 131.1 (C), 132.0 (CH, C6), 134.4 (C), 143.0 (CH, C3), 152.7 (CH, C1), 172.3(CO); Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.42; H, 4.93; N, 7.34.
Reaction SMILES: C([O:9][C@H:10]([CH3:31])[C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[C@H:13]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@@H:12]1[OH:30])(=O)C1C=CC=CC=1.N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C.CCOC(C)=O.N>[CH3:29][O:28][CH2:27][CH2:26][O:25][C@@H:13]1[C@H:12]([O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@@H:11]([C@@H:10]([CH3:31])[OH:9])[O:15][C@H:14]1[N:16]1[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCCO[C@@H]1[C@H](O)[C@@H]([C@@H](C)OC(=O)c2ccccc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: N
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCO[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@@H](C)O)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of Compound 10 (1.33 g, 3.06 mmol) and imidazole (2.09, 30.70 mmol) was dissolved in anhydrous DMF (11.4 mL). To this solution tert-butyldimethylsilyl chloride (2.31 g, 15.33 mmol) was added with stirring at room temperature for 16 h under an atmosphere of argon. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated aqueous NaHCO3 (2×60 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was dissolved in methanolic ammonia (20 mL, 7 M) and stirred for 24 h at 55° C. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography and eluted with 50% EtOAc in hexanes to yield Compound 11 (1.21 g, 89%). ES MS m/z 455.2 [M+H]+.
Reaction SMILES: C(N[C:9](=[O:36])[C:10]1[C:15]([O:16][CH2:17][C:18]23[CH2:23][CH:22]2[CH2:21][N:20]([C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([F:35])([F:34])[F:33])[CH2:28][CH2:27]2)=[O:25])[CH2:19]3)=[CH:14][CH:13]=[CH:12][N:11]=1)C1C=CC=CC=1.F[C:38](F)(F)[C@H:39]1CC[C@H](C(O)=O)CC1.N1C2C(=CC=CC=2)C=C1C(O)=[O:60]>>[F:34][C:32]([F:35])([F:33])[C@H:29]1[CH2:28][CH2:27][C@H:26]([C:24]([N:20]2[CH2:21][CH:22]3[C:18]([CH2:17][O:16][C:15]4[C:10]([C:9]([O:36][CH2:38][CH3:39])=[O:60])=[N:11][CH:12]=[CH:13][CH:14]=4)([CH2:23]3)[CH2:19]2)=[O:25])[CH2:31][CH2:30]1
Reactant: O=C(NCc1ccccc1)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: CCOC(=O)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using ethyl 3-((3-azabicyclo[3.1.0]hexan-1-ylmethoxy)picolinate dihydrochloride (EXAMPLE 88, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=4)=[N:15][N:14](COC(=O)C(C)(C)C)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:35](=[O:39])[N:36]([CH3:38])[CH3:37].[OH-].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([N:24]([CH3:25])[CH3:26])=[CH:22][CH:23]=4)=[N:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:35]([N:36]([CH3:37])[CH3:38])=[O:39]
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2ccc(N(C)C)cc2)nn3COC(=O)C(C)(C)C)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]nc(Cc4ccc(N(C)C)cc4)c3c2)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(4-dimethylamino-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester was dissolved in tetrahydrofuran. 1 M sodium hydroxide in methanol was added to the mixture, and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, filtered, and concentrated. The crude material was purified by mass-triggered reverse-phase HPLC to give 2-amino-5-[3-(4-dimethylamino-benzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.43 (dd, J=8.5, 2.3 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.5 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 5.34 (s, 2H), 4.17 (s, 2H), 2.96 (s, 6H), 2.81 (s, 6H). MS: m/z 415.5 (M+H+).
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=C(Cl)[C:34]([F:38])=[CH:33][N:32]=1>CO>[Cl:30][C:31]1[N:36]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@@:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)[C:34]([F:38])=[CH:33][N:32]=1
Reactant: COC(=O)C1(C)CCCC(NC(=O)OC(C)(C)C)C1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate, 52g, (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes. The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added iPr2NEt (10.84 mL, 62.25 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The reaction was stirred at reflux overnight, concentrated in vacuo and resulting residue was purified by silica gel chromatography (1:1 Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil. 300 mg of the racemic methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate was submitted for SFC chiral separation, yielding 100 mg of the desired product, 52h, as a yellow oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[C@H:5]1[CH2:4][CH2:3]2.NCCC1C=CC=[CH:27][N:26]=1.[OH-:31].[Na+]>C(O)=O>[CH:27]([NH:26][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:12]([CH2:4][CH2:3][C@:2]12[CH3:1])[C:13]1[CH:14]=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=1[CH2:15][CH2:5]3)=[O:31]
Reactant: NCCc1ccccn1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NC=O)CC[C@@H]12

Procedure:
A mixture of estrone methyl ether (14.2 g) and 2-(2-aminoethyl)pyridine (24 ml, 24.4 g) is stirred and cooled in an ice bath. To this mixture, formic acid (97-98%, 11.5 ml) is added in portions. The mixture is then heated in an oil bath (180°-190° C. bath temp.) for 24 hours. The mixture is poured onto ice, treated with NaOH, and extracted with methylene chloride (3X). The extracts are dried (Na2SO4), filtered, and concentrated to give a solid. The solid is crystallized from methylene chloride-hexane to give crystals. Recrystallization from methylene chloride-acetone gives the title compound, mp 252°-253° C. preceded by yellowing. (PLA2-, diabetes)
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.C[NH:11][CH:12](C(O)=O)[CH2:13][CH2:14][CH3:15]>C(#N)C>[C:7]([C:3]1[NH:1][C:12]([CH2:13][CH2:14][CH3:15])=[N:11][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCCC(NC)C(=O)O
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CCCc1nc(C)c(C(C)=O)[nH]1
Yield: 51.6 %

Procedure:
To 40 g (0.31 moles) of 3-oximino-2,4-pentanedione dissolved in 297 ml of acetonitrile was added 40.64 g (0.31 moles) of methyl d,l-norvaline. The reaction mixture was refluxed 21.2 h under nitrogen, cooled, then concentrated in vacuo. The resulting oil was dissolved in 50 ml of ethanol and 140 ml of 10% aqueous sodium hydroxide. After 4 h of reflux, the cooled mixture was extracted with ethyl acetate (900 ml total) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded 0.16 moles (51% yield) of 5-acetyl-4-methyl-2-propylimidazole.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([O:28]CC)=O)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1.[CH3:35][S:36][CH2:37][CH2:38][NH2:39]>>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:39][CH2:38][CH2:37][S:36][CH3:35])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CSCCN
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Product: CSCCNC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F

Procedure:
Ethyl 2-{[5-fluoro-2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}benzoate (200 mg, 0.51 mmoles) and 2-(methylthio)ethylamine (2 mL) were heated at 120° C. for 48 h. The reaction mixture was concentrated to dryness under vacuum and the title compound was purified by flash chromatography on silica gel (ethyl acetate containing 0.1% triethylamine). MS: M(C26H31FN6O2S)=510.2, (M+H)+=511.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[N:13]1.[Cl:24][CH2:23][CH2:22][CH2:21][N:13]1[CH:12]=[C:11]2[C:15]([CH:16]=[CH:17][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10]2)=[N:14]1
Reactant: c1ccc(COc2ccc3[nH]ncc3c2)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCn1cc2cc(OCc3ccccc3)ccc2n1
Product: ClCCCn1ncc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-benzyloxyindazole (30 g) in dimethylformamide (150 ml), 50% sodium hydride (6.7 g) was added and the mixture was stirred at room temperature for 10 minutes. The solution was then added dropwise to 150 ml of dimethylformamide containing 1-bromo-3-chloropropane (30 g) while cooling with ice, and, after stirring at room temperature for 30 minutes, the mixture was extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate, and distilled to remove the solvent used. The residue was chromatographed with a column filled with silica gel to give 16 g of 1-(3'-chloropropyl)-5-benzyloxyindazole (m. p. 65°-66° C.) and 4.5 g of 2-(3'-chloropropyl)-5-benzyloxyindazole (m.p. 97°-98° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[CH3:17][NH2:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:18][CH3:17])[CH2:8][CH2:7]1
Reactant: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 72 h

Procedure:
To a solution of 1-(3,4-Dichloro-benzyl)-piperidin-4-one (3.1 g) in dichloromethane (50 ml) and acetic acid (0.69 ml) was added methylamine (6 ml of a 1M solution in tetrahydrofuran). The mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3 g) and the resulting mixture stirred for 72 hours. Sodium bicarbonate solution (100 ml) added and the mixture stirred vigorously for 5 minutes before extraction of the product with dichloromethane (2×200 ml). The organics were separated, bulked and dried, (MgSO4). Purification by Biotage® 40S eluting 10%MeOH/0.5% 800 ammonia/dichloromethane gave the sub-title compound (1.8 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C1(C)C(C)=CC=CC=1.Cl>C(OCC)C>[ClH:1].[F:29][C:15]([F:14])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: O=c1cnn(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)[nH]1
Yield: 26.3 %

Procedure:
The compound 1b (6.67 g; 0.033 mol) and 4-(3-trifluoromethylphenyl)piperazine (15.3 g; 0.066 mol) are heated to dryness for 7 hours at 120-130° C. Xylene (40 ml) is added and heated for one additional hour under reflux. After cooling and concentrating to dryness under vacuum, the residue is taken up in water (30 ml) and in ethyl ether (2×100 ml). The organic phases are dried (Na2SO4) and concentrated to dryness under vacuum. The oil obtained is taken up in ethyl ether (50 ml) and then supplemented, dropwise, with hydrochloric acid in ethyl ether (20 ml). A solid is drained which is crystallized from ethanol (50 ml). After filtration, washing with ethyl ether and drying under vacuum at 80° C., the compound 1 (3.77 g) is obtained.