Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:27]1([O:26][C:20]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([NH:17][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][C:11]([F:15])=[C:10]([F:16])[CH:9]=3)[CH2:14]2)=[O:31])[CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2cc(F)c(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3cc(F)c(F)cc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
The mixture 2-(2-cyclobutoxy-3-methyl-benzoylamino)-5,6-difluoro-indan-2-carboxylic acid ethyl ester (104) (367 mg, 0.85 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the solid is purified by HPLC to give a pure product (105) as white solid (300 mg, 88%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.Br[CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]>C(#N)C.ClCCl>[N:7]1([CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: O=C1c2ccccc2CCC1Br
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1c2ccccc2CCC1n1cncn1

Procedure:
To a mixture of 30 g. potassium carbonate, 15 g. 1,2,4-triazole and 250 ml acetonitrile at 40° C. was added a solution of 45 g. 3,4-dihydro-2-bromo-1(2H)-naphthalenone in 150 ml acetonitrile. The mixture was allowed to react for 5 hours at 40° C. and then at reflux temperature for 2 hours. The solid was removed by filtration and the filtrate concentrated to dryness leaving a solid residue. This was dissolved in dichloromethane and washed twice with water. The organic extract was dried over sodium sulfate and evaporated to give 42 grams of product having a melting point of 96°-98° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O-:19])(=O)=[O:17])=[CH:12][CH:11]=1>O>[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([Cl:2])(=[O:19])=[O:17])=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
About 320 g of phosphorus pentachloride was taken in a three-neck round-bottomed flask. One neck was fitted with a mechanical stirrer, and a second neck was fitted with a plastic tube to collect hydrochloric acid produced by the reaction. About 190 g of p-styrenesulfonate sodium salt was added in small portions to the phosphorus pentachloride through the third neck while cooling the flask to 0° C. After the addition, the contents were allowed to stir at ambient temperature for 2 hours. Deionized ice water was then added dropwise to the flask, cooling the contents again to 0° C. The mixture was transferred to a separating funnel using additional water. An oily organic layer was collected and the remaining aqueous solution was extracted with dichloromethane. The organic layer was then combined and dried with anhydrous sodium sulfate. This solution was filtered through a small silica gel (100 g) column. The filtrate was collected and dichloromethane was removed under vacuum to obtain 125 g of p-styrenesulfonyl chloride blocked acid monomer.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2NC1C=CC(C)=C(O)C=1)=[O:5])[CH3:2].[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:31][C:30]1[CH:32]=[CH:33][C:27]([Br:26])=[CH:28][C:29]=1[F:34])=[O:5])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc(C)c(O)c3)c2c1OC
Product: CCOC(=O)c1cn2ncnc(Nc3ccc(Br)cc3F)c2c1OC

Procedure:
The title compound was prepared from Compound G of Example 96 (0.2 mmol) and 4-bromo-2-fluoro-aniline (76 mg, 0.3 mmol) by the procedure analogous with the preparation of Compound H of Example 96. Thus, when the reaction was complete it was concentrated and washed with 1 N aqueous HCl to provide a solid which was triturated with aqueous NaHCO3 and water and then dried to provide 58 mg (70.9%) white solid. MS: [M+H]+=409, 411 (1:1); 1H NMR (d-DMSO): δ 8.83 (s, 1H), 7.97-7.93 (m, 2H), 7.90 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.24 (q, J=7.5 Hz, 2H), 3.97 (s, 3H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.[CH3:14]O>>[CH3:14][O:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([NH2:4])[CH:6]=1
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CO
Product: COC(=O)c1ccnc(N)c1

Procedure:
2-Acetylamino-isonicotinic acid (3.10 g, 17.2 mmol) was stirred in 35 mL MeOH at 0° C. HCl (g) was bubbled through the solution for 10 minutes and then the reaction was heated to reflux. After 16 hours the reaction was concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 7 with Na2CO3 (s). A white precipitate formed which was filtered to afford a portion of pure desired product. The aqueous phase was extracted three times with 95:5 dichloromethane (DCM)/nBuOH. The organic phases were dried over Na2SO4, filtered and concentrated to afford more of the pure product as a white solid. 1H NMR (CDCl3) δ 8.19 (d, 1H, J=5.3 Hz), 7.17 (dd, 1H, J=1.4, 5.3 Hz), 7.07 (d, 1H, J=1.3 Hz), 4.64 (bs, 2H), 3.92 (s, 3H). MS [M+H]+=153.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCCCC2)cc1
Temperature: 100 °C
Yield: 78.6 %

Procedure:
4-bromophenol (5.2 g, 30 mmol), K2CO3 (10.4 g, 75 mmol) and anhydrous DMF (50 ml) were mixed together under Ar and heated at 100° C. 1-(2-chloroethyl)-piperidine hydrochloride (5.5 g, 30 mmol) was added in portions over 10 min and the reaction maintained at 100° C. for 1.5 h. After cooling the reaction, the solid was filtered off and the solvent removed under vacuum. The crude product was chromatographed on silica gel with methanol/ethyl acetate (3:1) to yield 6.7 g (78%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.44 (2H, m, NCH2CH2CH2), 1.59, (4H, m, NCH2CH2), 2.48 (4H, m, NCH2CH2), 2.73 (2H, t, NCH2CH2O), 4.03 (2H, t, NCH2CH2O), 6.76 (2H, d, ArH), 7.33 (2H, d, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Yield: 69.6 %

Procedure:
A mixture of 2-(4-bromophenyl)acetic acid (50 g, 0.23 mol), benzyl alcohol (26 mL. 0.25 mol) and p-toluenesulfonic acid (0.3 g) in 200 ml toluene were heated at reflux with the azeotropic removal of water (15 h). The yellow solution was washed with water (250 mL), saturated aqueous sodium bicarbonate (250 mL) and then dried (MgSO4). Concentration provided a light yellow solid that was recrystallized from cold hexanes to give benzyl 2-(4-bromophenyl)acetate (48.5 g, 0.16 mol) in 69% yield, mp. 47.5°-48° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1.O1CCOC[CH2:34]1.C[Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23]([OH:25])([CH3:34])[CH3:24])[CH:20]=[C:19]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[CH:10]1
Reactant: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)=O)n3)cc2OC)cn1
Reactant: C1COCCO1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)(C)O)n3)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(2-(3-Methoxy-4-(4-methoxy-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-4-yl)ethanone (145 mg, 0.32 mmol) was coevaporated with dioxane and dissolved in THF (10 mL). The mixture was added slowly to a well stirred solution of methylmagnesium bromide (0.857 mL, 3 M solution, 2.57 mmol) in THF (5 mL). The mixture was stirred at rt for 5 min. The mixture was cooled on ice bath and ammonium chloride (aq, 5 mL) was added. The mixture was extracted with ethyl acetate (2×10 mL), the organic phase was filtered and concentrated in vacuum. The residue was separated purified by preparative HPLC to give the title compound as a dry film, 68 mg (46%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[C:16]([F:27])=[CH:17][N:18]=[C:19]2[C:24]=1[N:23]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20]2.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[N:23]=2)[N:18]=[CH:17][C:16]=1[F:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
Diethyl malonate (12.4 mL, 81.7 mmol) was added to a suspension of NaH (3.0 g, 47.9 mmol, 60% in mineral oil) in dioxane (35 mL). The mixture was stirred at rt for 5 min and then heated at 80° C. for 1 h. After cooling to rt, CuBr (1.4 g, 9.6 mmol) and 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (7.0 g, 27.2 mmol, prepared according to WO 2007/122258) were added. The mixture was stirred at 100° C. for 6 h. After cooling to rt, 10% NaHSO4 (100 mL) was added. The mixture was stirred for 30 min at rt. The two layers were decanted and the aq. layer was extracted three times with EA (3×150 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 3:1 then 1:1) to afford the title intermediate as a yellow oil (8.22 g, 90% yield).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:37])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[S:39].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:9]2[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]3[NH:37][C:38](=[S:39])[O:1][N:2]=3)=[CH:11][CH:10]=2)/[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:26]=[CH:25]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC/C(=C(/c1ccc(/C=C/C(N)=N/O)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC/C(=C(/c1ccc(/C=C/c2noc(=S)[nH]2)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a solution of (1Z,2E)-N′-hydroxy-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylimidamide (90 mg, 0.18 mmol; Compound 435, Step 2) and thiocarbonyldiimidazole (50 mg, 0.28 mmol) in anhydrous acetonitrile (1.5 mL) was added DBU (0.11 mL, 0.72 mmol). The solution was stirred at room temperature for 4 h then directly concentrated onto silica gel. Purification by column chromatography (0 to 80% EtOAc/hexanes) afforded 69 mg of the title compound as an orange oil. LCMS: 451 [(M-THP+H)+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH2:9][CH3:10])[CH3:8])[N:6]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[C:21]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH2:9][CH3:10])[CH3:8])[N:6]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCC(C)c1csc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1nc(C(C)CC)cs1)C(=O)OCC
Yield: 99.9 %

Procedure:
2-Amino-4-(2-butyl)thiazole (8.44 g., 54 mmoles) and diethyl ethoxymethylenemalonate (11.7 g., 54 mmoles) were combined and heated on a steam bath for 1 hour and cooled to yield 2-(2,2-dicarbethoxyethenylamino)-4-(2-butyl)thiazole (17.6 g., Rf 0.75 on silica gel thin layer chromatography with chloroform/1% ethanol as eluant).
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4](OC)=[O:5].[CH3:21][NH2:22]>CO>[CH3:21][NH:22][C:4](=[O:5])[CH2:3][C@@H:2]([OH:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCC[C@H](O)CC(=O)OC
Reactant: CN
Solvent: CO
Product: CCCCCCCCCCCCC[C@H](O)CC(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-Methyl 3-hydroxyhexadecanoate (1.0 g) was dissolved in a solution of 40% methylamine in methanol (15 ml). This mixture was stirred at room temperature for 2 hours. The resulting crystalline solid was collected by filtration to give (S)-N-methyl-3-hydroxyhexadecanamide (0.71 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH:10]2[CH2:23][O:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (896 mg) were added triethylamine (0.50 mL) and methanesulfonyl chloride (0.26 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid, distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.07 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])(=O)C.[Se](=O)=[O:34]>C(OCC)(=O)C.CCCCCC>[OH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCO)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (120 mg, 0.27 mmol) was added selenium dioxide (120 mg, 1.08 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-hydroxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (40 mg, 37% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C@H:13]3[O:20][C:21]2[CH:26]=[CH:25][C:24]([C@H:27]3[CH2:29][C@@H:28]3[C:30]([OH:32])=[O:31])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O-:36].[Na+]>CO>[C:18]([C:17]1[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([O:36][CH3:35])=[CH:3][CH:4]=2)=[C:10]2[C:14](=[CH:15][CH:16]=1)[C@H:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]3[CH2:29][C@@H:28]3[C:30]([OH:32])=[O:31])=[CH:25][CH:26]=1)[CH2:12][CH2:11]2)#[N:19]
Reactant: C[O-]
Reactant: N#Cc1ccc2c(c1Cc1ccc(Cl)nc1)CC[C@H]2Oc1ccc([C@H]2C[C@@H]2C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2c(C#N)ccc3c2CC[C@H]3Oc2ccc([C@H]3C[C@@H]3C(=O)O)cc2)cn1
Temperature: 90 °C
Reaction time: 24 h
Yield: 13.4 %

Procedure:
(1S,2S)-2-{4-[(R)-4-(6-Chloro-pyridin-3-ylmethyl)-5-cyano-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid (Example 40, 100 mg, 0.22 mmol) is suspended in methanol (10 mL) and sodium hydride (60% in mineral oil, 27 mg, 0.67 mmol) is added. After 6 hours at 90° C. sodium methoxide (130 mg, 2.25 mmol) is added and the mixture stirred for 24 hours at 90° C. The solvent is removed under vacuum and the residue is purified by flash chromatography (0-10% MeOH in CH2Cl2) to give the title compound (Yield: 13 mg). LC (METHOD 3): tR=4.04 min; Mass spectrum (ES+): m/z=441 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:38]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=5)=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:37][S:34]([C:31]1[CH:30]=[CH:29][C:28]([C:24]2[C:23]3[N:22]([N:21]=[C:20]([NH:19][C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:18]=4)[N:38]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:33][CH:32]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cnn(C5CCNCC5)c4)nc23)cc1
Reaction time: 1 h

Procedure:
To a well stirred solution of 4-{4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-pyrazol-1-yl}-piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.186 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.65 mL, 8.77 mmol) dropwise at room temperature. After 1 h, the reaction mixture was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The crude product was crystallized from a mixture of dichloromethane, methanol, ether and hexane. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-piperidin-4-yl-1H-pyrazol-4-yl)-amine was isolated as a greenish-yellow solid (58 mg, 71%). MP=Softened at 154-159° C. then melted at 211-213° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.79 (d, J=6.48 Hz, 1H), 8.42 (d, J=7.96 Hz, 2H), 8.06 (d, J=7.97 Hz, 2H), 7.94 (d, J=7.45 Hz, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.12 (t, J=7.04 Hz, 1H), 4.14 (t, J=11.29 Hz, 1H), 3.29 (s, 3H), 3.035 (d, J=12.28 Hz, 2H), 2.58 (t, J=12.16 Hz, 2H), 1.935 (d, J=11.41 Hz), 1.68-182 (m, 2H). MS=438 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([I:28])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[CH2:14]([O:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([CH3:1])=[C:3]([I:28])[N:4]=[C:5]2[CH2:10]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cnc2n1CCN(C(=O)OCc1ccccc1)C2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1c(I)nc2n1CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a solution of benzyl 3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (1.085 g, 4.00 mmol) in 1,2-dichloroethane (60 ml) was added NIS (4.50 g, 20.00 mmol) and the reaction was heated at reflux for one hour. The reaction was cooled to room temperature and poured into 100 ml of saturated 5% sodium thiosulfate solution. The layers were separated and the aqueous layer was re-extracted with 1,2-dichloroethane (40 ml). The combined organic layers were washed with water (100 ml), dried over sodium sulfate, filtered and concentrated. Product was extracted from the residue by trituration with 3×50 ml portions of ether. The extract was filtered and concentrated to yield 2-Iodo-3-methyl-5,6-dihydro-8H-imidazo[1,2-a] pyrazine-7-carboxylic acid benzyl ester (1.42 g, 89%) as a pale yellow oil. LCMS (Table 1, Method a) Rt=3.32 min, m/z 398.59 (M+H)+; 1H NMR (400 MHz, CHCl3)δ 7.35 (m, 5H), 5.13 (s, 2H), 4.56 (s,broad, 2H), 4.38 (t, 2H), 3.82 (s, broad, 2H), 2.09 (s, 3H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([C:37](=[O:49])[CH2:38][O:39][CH2:40][C:41]2[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[CH:42]=2)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20](C(OCC4C=CC=CC=4)=O)[CH2:19]3)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[Cl:9].CCOCC>C(O)(=O)C>[Cl:48][C:43]1[CH:42]=[C:41]([CH2:40][O:39][CH2:38][C:37](=[O:49])[CH:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][C:16]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19]3)[CH2:17][CH2:18]2)[CH:46]=[C:45]([Cl:47])[CH:44]=1
Reactant: O=C(COCc1cc(Cl)cc(Cl)c1)C(CCN1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccccc12)c1ccc(Cl)c(Cl)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(COCc1cc(Cl)cc(Cl)c1)C(CCN1CCC2(CC1)CNc1ccccc12)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add a solution of HBr (gas) in acetic acid (3.0 ml) to phenylmethyl 1'-[3-(3,4-dichlorophenyl)-5-[(3,5-dichlorophenyl)methoxy]-4-oxopentyl]-1,2-dihydro-spiro[3H-indole-3,4'-piperidine]-1-carboxylate [0.250 g, 0.34 mmoles) dissolved in glacial acetic acid (2.0 ml). Stir the solution at room temperature for 4 h, then add Et2O (30 ml). Decant the liquid and wash the resultant solid with Et2O. Suspend the solid in water (10 ml) and add 1.0M aqueous KOH (5.0 ml). Extract the mixture with Et2O (3×30 ml), combine the extracts, wash with water and dry (Na2SO4). Remove the solvent and purify the reaction mixture by preparative thin layer chromatography (SiO2), eluting the plates twice with ETOAc:hexanes:CH3OH(NH3) (15:85:3). Extract the desired product with 5% CH3OH(NH3)/EtOAc. Yield: 57 mg.