Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[CH:6][N:7]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(C)=O)cn2)cc1

Procedure:
Procedure U′: To a stirring solution of 1-(6-chloro-pyridin-3-yl)-ethanone (1.0 mmol, CAS # 55676-22-7) and 4-methoxycarbonylphenyl boronic acid (1.2 mmol) in dioxane (0.15M), add tetrakis-(triphenylphosphine) palladium (0.044 mmol) and 2M aqueous sodium carbonate (5.0 mmol). Heat the reaction to 90° C. for three hours. After this time, remove the heat and concentrate in vacuo. Purify the title compound via radial chromatography eluting with methanol and dichloromethane. MS (m/e): 256.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[N:21]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>ClCCl>[CH3:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:20]([CH3:19])[N:21]1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[CH:32][CH:33]=1
Reactant: CC1CCCC(C)N1Cc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: CC1CCCC(C)N1Cc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-(2,6-dimethylpiperidin-1-ylmethyl)phenylamine. Yield: 100 mg (22% of theory); melting point: 158° C.-163° C.; C29H29ClN2O (M=457.01); calc.: molecular ion peak (M+H)+: 458/460 (Cl); found: molecular ion peak (M+H)+: 458/460 (Cl); Rf value: 0.50 (silica gel, dichloromethane/methanolic ammonia (90:10:0.1)).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[NH:6][C:7]2=[O:12].C(=O)(O)[O-].[Na+].Br[CH2:25][CH2:26][OH:27]>C(#N)C>[OH:27][CH2:26][CH2:25][N:16]1[CH2:17][CH2:18][CH:13]([C:5]2[NH:6][C:7](=[O:12])[C:8]3[C:3]([CH:4]=2)=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH2:14][CH2:15]1
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCO)CC3)cc12
Yield: 33.8 %

Procedure:
5-Methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one (1.0 g), sodium bicarbonate (0.52 g) and 2-bromoethanol (0.67 g) were dissolved in acetonitrile (20 mL) and the solution was heated under reflux. After the completion of the reaction, the reaction mixture was concentrated and water was added to the obtained residue. The mixture was extracted with chloroform, and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give 3-[1-(2-hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-1-one (0.4 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: CC(C)CCN
Product: CC(C)CCNCc1ccc(O)c2ccccc12

Procedure:
Using the procedure outlined in Preparation 83, 4-hydroxynaphthaldehyde and 3-methylbutylamine were converted to the title compound: RT=2.38 min; m/z (ES+)=144.1 [M+H]+.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1C1=COCCN1C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and o-tolylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (57% yield); 1H-NMR (d6-DMSO) 0.97 (9H, s), 2.15 (3H, s), 3.69 (2H, t), 4.14 (2H, t), 6.06 (1H, s), 7.10-7.15 (4H, m); MS ES(+) 220.0 (M+-tBu). IR λmax=1694, 1365, 1165 cm−1.
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])[CH:36]=[CH:37][CH:38]=[C:39]([CH:41]=O)[CH3:40])[CH3:31]>C1OCCC1.CO.O>[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])/[CH:36]=[CH:37]/[CH:38]=[C:39]([CH3:41])[CH:40]=[CH:10][C:4]1[S:5][C:6]([CH3:9])=[C:7]([CH3:8])[C:3]=1[CH3:2])[CH3:31]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Br-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1sc(C)c(C)c1C

Procedure:
3.2 G. of (3,4,5-trimethyl-2-thenyl)triphenyl phosphonium bromide were suspended in 80 ml of butylene oxide and 1.5 g. of 3-methyl-7-formyl-octa-2,4,6-trienoic acid ethyl ester were added. The resulting mixture was refluxed under argon for one hour after which the solvent was evaporated. The residue which formed was diluted with a mixture of methanol/water (6:4) and extracted four times with hexane. The combined hexane solutions were washed once with methanol/water (6:4) and twice with pure water, dried with sodium sulfate, filtered and evaporated. The resulting crude product was purified by column chromatography on silica gel and elution with hexane/5% ether. Recrystallization of the all trans-3,7-dimethyl-9-(3,4,5-trimethyl-2-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester so obtained from hexane/1% ethyl acetate gave yellow crystals, m.p. 96°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5](F)=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[CH:33]=[N:32]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]([NH:40][C:35]2[C:34]3[CH:33]=[N:32][N:31]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[C:39]=3[CH:38]=[CH:37][CH:36]=2)=[N:6][CH:7]=1
Reactant: Cc1nc(-c2cc(Br)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Br)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-(5-bromo-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.250 g, 0.637 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (0.138 g, 0.637 mmol) in THF (10 mL) was stirred at 0° C. and treated dropwise with lithium bis(trimethylsilyl)amide, 1.0 M solution in THF (1.912 mL, 1.912 mmol) (Aldrich catalog number 225770) and stirred at 0° C. for 30 minutes. The mixture was quenched with water (10 mL), diluted with water (50 mL) and extracted with dichloromethane. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3/MeOH in dichloromethane to give N-(5-bromo-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine as yellow crystals. This was treated with dichloromethane (5 mL) and trifluoroacetic acid (5 mL) (Aldrich, St. Louis, Mo.) to give N-(5-bromo-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine, m/z (ESI, +ve) 421/423 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s., 1H); 13.25 (br. s., 1H); 12.85 (br. s., 1H); 8.69 (br. s., 1H); 8.48 (br. s., 1H); 7.99 (br. s., 1H); 7.32 (br. s., 1H); 7.23 (br. s., 1H); 2.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=1)=[O:8].[OH-].[Na+].[NH2:23][CH2:24][CH2:25][CH2:26][P:27](=[O:30])([OH:29])[OH:28].C([BH3-])#N.[Na+]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7](=[O:8])[NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:23][CH2:24][CH2:25][CH2:26][P:27](=[O:28])([OH:30])[OH:29])[N:14]=1
Reactant: O=Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reactant: NCCCP(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH3-]C#N
Agent: [Br-]
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CNCCCP(=O)(O)O)cs1
Reaction time: 8 h

Procedure:
300 mg of 1-(3,4-dichlorobenzyl)-3-(4-formylthiazol-2-yl) urea was dissolved in 5 ml MeOH. 1.0 eq. of tetrabutylammonium bromide and 1.0 eq. of sodium hydroxide were added followed by addition of 1.0 eq. of 3-aminopropylphosphonic acid. To the mixture, 3.0 eq. of sodium cyanoborohydride was added and the reaction was stirred at room temp. overnight. The reaction mixture was loaded to reverse phase column and purified by HPLC to give 3-((2-(3-(3,4-dichlorobenzyl)ureido)thiazol-4-yl)methylamino)propylphosphonic acid.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:22]([NH2:39])=[N:23][CH:24]=[C:25]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[CH:31]=2)[CH:26]=1>C(Cl)Cl>[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:22]([NH2:39])=[N:23][CH:24]=[C:25]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:33][CH2:34][N+:35]([CH3:38])([O-:9])[CH2:36][CH2:37]3)[CH:31]=2)[CH:26]=1
Reactant: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[N+]1([O-])CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Reaction time: 0.08 h

Procedure:
3-Chlorobenzenecarboperoxoic acid (0.046 g) was added to 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.100 g) in DCM (10 ml). The resulting solution was stirred for 5 minutes. The resultant precipitate was collected by filtration, washed with DCM (2 ml) and dried under vacuum. The residue was purified by SCX ion exchange chromatography (elution with 7M methanolic ammonia) and there was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-1-oxido-piperidin-1-ium-4-yl)pyrazol-4-yl]pyridin-2-amine (0.026 g); Mass Spectrum: M+H+ 391.29; RT 1.18 min; NMR Spectrum: (DMSOd6) 8.49 (d, 1H), 8.41 (d, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.78 (dd, 1H), 7.73 (dd, 1H), 7.57 (br s, 2H), 7.38 (m, 2H), 4.26 (tt, 1H), 3.46 (m, 2H), 3.11 (s, 3H), 3.06 (m, 2H), 2.68 (m, 2H), 1.90 (br m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6](Br)[CH:5]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH:5]=1)[CH:21]=[O:22]
Reactant: COC(OC)c1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(F)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A total of 2.49 g of 3-bromo-4-fluorobenzaldehyde dimethylacetal produced in Production Example I-4-a was dissolved in 20 ml of dry tetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogen gas, 8.5 ml of a 1.56 M solution of n-butyllithium in hexane was added. After stirring for 30 minutes, 1.0 ml of N,N-dimethylformamide was added and the mixture was heated to room temperature. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:12.5), to give 1.35 g of the title compound as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(NC1NC2C(N=C(OC)N=2)=C(N)N=1)CCC.C(=O)([O-])[O-].[K+].[K+].BrCCCCCCl.[NH:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(N(CC)CC)C.[CH2:52]([NH:56][C:57]1[N:65]=[C:64]2[C:60]([N:61]=[C:62]([O:78]C)[N:63]2[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]N2CCCCCC2)=[C:59]([NH2:80])[N:58]=1)[CH2:53][CH2:54][CH3:55]>CN(C=O)C>[NH2:80][C:59]1[N:58]=[C:57]([NH:56][CH2:52][CH2:53][CH2:54][CH3:55])[N:65]=[C:64]2[C:60]=1[NH:61][C:62](=[O:78])[N:63]2[CH2:66][CH2:67][CH2:68][CH:69]([N:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH3:70]
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCCN3CCCCCC3)c2n1
Reactant: C1CCCNCC1
Agent: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: ClCCCCCBr
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCC(C)N3CCCCCC3)c2n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (192 mg, 0.547 mmol) and potassium carbonate (189 mg, 1.368 mmol) were suspended in DMF (3 ml) and heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and 1-bromo-5-chloropentane (0.072 ml, 0.547 mmol) was added and the reaction stirred for a further 18 hours. Hexahydro-1H-azepine (54.2 mg, 0.547 mmol) and triethylamine (0.076 ml, 0.547 mmol) were added and the reaction mixture heated to 70° C. for 24 hours. LCMS showed a major peak with MH+ 404 consistent with the formation of N2-butyl-9-[5-(hexahydro-1H-azepin-1-yl)pentyl]-8-(methyloxy)-9H-purine-2,6-diamine. The solvent was removed in vacuo and the residue partitioned between DCM (2 ml) and water (2 ml). The aqueous was extracted again with DCM (2 ml) and the combined organic extracts were concentrated and the residue was dissolved in 1:1 MeOH:DMSO (2 ml) and purified by MDAP (Method C). Evaporation of the product containing fractions gave a residual TFA salt which LCMS indicated had undergone hydrolysis of the 8-methoxy group, presumably on concentration in the presence of TFA. This crude material was dissolved once more in 1:1 MeOH:DMSO (2 ml) and re-purified by MDAP (Method A). Product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a white solid (39 mg).
Reaction SMILES: [Cl-].[CH3:2][CH:3]1[NH2+:7][C:6]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:5]=2[Te:4]1.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:2][C:3]1[Te:4][C:5]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1ccc2c(c1)[NH2+]C(C)[Te]2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2[te]c(C)nc2c1
Yield: 55.8 %

Procedure:
2,5-Dimethylbenzotellurazolium chloride (Example 14) (3.5 g) was treated in an aqueous suspension with sodium bicarbonate in excess of that stoichiometrically required. The free base product was isolated by extraction with diethyl ether and evaporation to dryness. The residue was recrystallized from ≃50 ml isopropanol to yield 1.7 g colorless needles, m.p. 126°-128° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[OH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:7]=1[CH:8]=[O:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:6]([O:5][CH2:1][CH2:2][CH3:3])[C:7]=1[CH:8]=[O:9]
Reactant: COc1cccc(O)c1C=O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOc1cccc(OC)c1C=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Propyl bromide (1 ml) was added to a mixture of 2-hydroxy-6-methoxybenzaldehyde (0.45 g), potassium carbonate (0.83 g) and a small amount of potassium iodide in a mixed solvent of N,N-dimethylformamide (10 ml) and acetone (5 ml). After being stirred for 5 hours at 100° C., the mixture was poured into ice-water (20 ml) and extracted with ethyl acetate. The extract was washed with brine (10 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of 2-methoxy-6-propoxybenzaldehyde (0.3 g).
Reaction SMILES: CS([O:5][CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[CH2:7]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>C(#N)C>[O:25]=[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][N:19]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][CH:6]([O:5][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[CH2:7]1
Reactant: CS(=O)(=O)OC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OC2CCN(CCc3ccccc3N3CCCCC3=O)C2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl methanesulfonate a10-2 (0.183 g, 0.5 mmol, 1 eq) in acetonitrile (4 ml) is added K2CO3 (0.138 g, 1 mmol, 2 eq) and 4-hydroxybenzonitrile (0.060 g, 0.5 mmol, 1 eq). The solution is stirred overnight at 85° C. After filtration and solvent removal, the residue is purified by basic reverse phase chromatography on silicagel (gradient: CH3CN/H2O/NH4OH from 40/60/0.1 to 70/30/0.1) to give 85 mg of pure 4-[(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)oxy]benzonitrile 50.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:34][CH2:33][C:32]([F:36])([F:35])[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31][C:32]([F:36])([F:35])[CH2:33][CH2:34]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
TFA (0.5 mL, 6.490 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4,4-difluorocyclo hexane carboxamide (10 mg) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.67 (s, 1H), 7.80 (m, 2H), 7.69 (d, 1H, J=9.2 Hz), 7.52 (m, 3H), 2.57 (m, 1H), 2.18 (m, 2H), 2.01 (m, 2H), 1.97-1.87 (m, 3H); ESI-MS [M+H]+: 396.3.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1>>[CH3:18][C:16]1[N:17]=[C:13]([NH:12][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[S:14][CH:15]=1
Reactant: Clc1nccc2cccnc12
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2nccc3cccnc23)n1

Procedure:
The title compound, MS: m/e=243.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-[1,7]naphthyridine and 2-amino-4-methylthiazole.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9]4)=[N:6][CH:7]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(N2CCC(N3CCCC3)C2)nc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(N4CCC(N5CCCC5)C4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from 1′-(5-iodo-pyridin-2-yl)-[1,3′]bipyrrolidinyl (172 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][CH:11]([CH2:16]C)[CH:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[C:21]1([CH:20]2[O:15][CH:12]([CH:11]([O:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:19][CH:18]=3)[CH3:16])[CH2:13][O:14]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCC(C)Oc1ccc(OC(CC)C(O)CO)cc1
Reactant: O=Cc1ccccc1
Solvent: CC(C)=O
Product: CCC(C)Oc1ccc(OC(C)C2COC(c3ccccc3)O2)cc1

Procedure:
In the same manner, 3-[4-(1-methylpropoxy)phenoxy]-1,2-pentanediol is reacted with each of acetone and benzaldehyde to give, respectively,
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[CH3:31])=[N:8][CH2:7]1)C.CO.[OH-].[K+]>O1CCCC1>[CH3:31][C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:7][N:8]=1)=[CH:19]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(C)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To a solution of ethyl[2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (2.59 g), methanol (25 mL), and tetrahydrofuran (25 mL) was added an aqueous solution (15 mL) of potassium hydroxide (1.0 g), and the mixture was stirred at room temperature for 6 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (2.33 g, yield 96%) as pale-yellow crystals.