Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]([C:55]1[CH:62]=[CH:61][C:58]([C:59]#[N:60])=[CH:57][CH:56]=1)[CH2:28][O:29][CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=1)(C(C)(C)C)(C)C>O1CCCC1.O>[OH:26][CH:27]([C:55]1[CH:56]=[CH:57][C:58]([C:59]#[N:60])=[CH:61][CH:62]=1)[CH2:28][O:29][CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 mmol of tetrabutylammonium fluoride (1M solution in tetrahydrofuran) are added to a solution of 1 mmol of 4-[1-(tert-butyldimethylsilanyloxy)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile in 5 ml of tetrahydrofuran, and the solution is stirred at room temperature for 1 hour. The reaction solution is then diluted with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:16]2[CH:12]([O:13][C:14]([CH3:18])(C)[O:15]2)[O:11][C:10]1([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])(C1C=CC=CC=1)C1C=CC=CC=1)[CH:19]=[CH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:43][C:44](=[O:46])[CH3:45])(=O)C.OS(O)(=O)=O.[C:52](O)(=O)[CH3:53]>>[C:44]([O:43][CH:16]1[CH:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([C:21]([C:53]2[CH:52]=[CH:19][CH:10]=[CH:9][CH:16]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:22][SiH2:23][C:36]([CH3:37])([CH3:39])[CH3:38])([CH:19]=[CH2:20])[O:11][CH:12]1[O:13][C:14](=[O:15])[CH3:18])(=[O:46])[CH3:45]
Reactant: C=CC1(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC2OC(C)(C)OC2C1OCc1ccccc1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(OC(C)=O)C(OC(C)=O)C1OCc1ccccc1
Yield: 85 %

Procedure:
A flask was charged with (6-Benzyloxy-2,2-dimethyl-5-vinyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-ylmethoxy)-tert-butyl-diphenyl-silane, Acetic acid, acetic acid anhydride, and H2SO4. The reaction was stirred, extracted, and the solvent was evaporated to provide the titled compound in 85% yield.
Reaction SMILES: [F:1][C:2]1([F:13])[C:11](=[O:12])[N:5]2C(C)(C)[O:7][CH2:8][C@@H:4]2[CH2:3]1.Cl>CO.O1CCOCC1>[F:1][C:2]1([F:13])[CH2:3][C@@H:4]([CH2:8][OH:7])[NH:5][C:11]1=[O:12]
Reactant: CC1(C)OC[C@@H]2CC(F)(F)C(=O)N21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1N[C@H](CO)CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 749.9 %

Procedure:
To a solution of (S)-6,6-difluoro-3,3-dimethyl-dihydropyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one (1.35 g, 0.706 mmol) in methanol (10 mL) was added HCl in dioxane (2.65 mL, 4N) under ice-water bath and then stirred at RT overnight. The reaction mixture was concentrated. The resulting residue was dissolved in THF (10 mL) and TEA (5 mL) was added. The resulting solution was stirred for 1 h. The reaction mixture was concentrated to give a crude mixture. Purification by flash column chromatography (hexanes/EtOAc) gave (S)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (0.80 g 75%). LRMS (M+H+) m/z 152.2.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a solution of 2-bromothiazole (0.26 g, 1.6 mmol) and 4-formylphenylboronic acid (0.48 g, 3.2 mmol) in toluene (16 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) and K2CO3 (0.33 g, 2.4 mmol) and the solution stirred at reflux for 16 h. The reaction was cooled to room temperature, diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (2% MeOH/CH2Cl2) to give 4-(2-thiazolyl)-benzaldehyde (45 mg, 15%). 1H NMR (CDCl3) δ 7.45 (d, 1H, J=3.0 Hz), 7.90 (d, 1H, J=3.0 Hz), 7.97 (d, 2H, J=7.8 Hz), 8.15 (d, 2H, J=7.2 Hz), 10.07 (s, 1H (CHO)).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=O)[CH3:2].[C:16]1([C:22](=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:31][C:32]([NH2:34])=[S:33].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:34][C:32](=[S:33])[NH:31]2)[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=S)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 78 °C
Yield: 2.9 %

Procedure:
A mixture of 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (323 mg, 1.53 mmol), 1,2-diphenylethanone (300 mg, 1.53 mmol), thiourea (349.16 mg, 4.59 mmol), concentrated HCl solution (0.8 mL) in ethanol (10 mL) was refluxed at 78° C. for 76 h. After being cooled down to room temperature, the mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give Compound 8 (20 mg, yield 2.9%). 1H NMR (CD3CN): δ 7.68 (s, 1H), 7.65 (s, 1H), 7.31 (m, 4H), 7.21 (s, 1H), 7.09 (m, 3H), 6.94 (m, 2H), 5.34 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 1.43-1.40 (t, J=7.2 Hz, 3H); MS (ESI): m/z 447.9 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.O>O1CCOCC1.ClCCl>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3F)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 25 mg (0.05 mmol) 6-{[6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 1.0 ml dioxan and add 0.16 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.17 ml 1 N hydrochloric acid and then 2 ml water and 5 ml dichloromethane. Separate the organic phase, dry over sodium sulphate, filter, and concentrate by evaporation. 23 mg (92% of theor.) of the target compound is obtained.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:6]([NH:22][C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:9][CH:10]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1

Procedure:
(S)-5-(4-Benzyloxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester (0.86 g, 1.7 mmol) and NaOH solution (4 M, 0.85 mL, 3.4 mmol) in MeOH-THF (1:1, 6 mL) was stirred at room temperature overnight. The solvent was removed, and the residue diluted with water. The solution was washed with Et2O, acidified with 5% aqueous HCl, and extracted with EtOAc. The organic phase was then washed with brine, dried Na2SO4) and the solvent removed under reduced pressure to afford (63), 0.81 g (98%), m.p. 127.7-129.5° C. 1H NMR (DMSO-d6) δ 1.13-1.23 (6H, m, 3×CH2), 1.35-1.44 (2H, m, CH2), 1.47-1.54 (2H, m, CH2), 1.95-2.00 (2H, m, CH2), 2.14-2.22 (2H, m, CH2), 3.86 (1H, br s, H58□ 5.02 (2H, s, OCH2Ph), 6.89 (2H, d, J=8.6 Hz), 7.08 (2H, d, J=8.5 Hz), 7.15-7.44 (10H, m, 10×Ar—H), 7.50 (1H, br d, J=8.6 Hz, NH), 12.01 (1H, br s, CO2H). 13C NMR (DMSO-d6) δ 25.3, 28.4, 28.5, 29.3, 30.5, 31.0, 35.2, 35.5, 49.3, 114.3, 125.6, 127.7, 127.8, 128.2, 128.4, 130.1, 131.1, 137.2, 142.3, 156.7, 171.7, 174.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1>CCOC(C)=O.CCO.CCCCCC.O=[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CS(=O)(=O)OCCCCCc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Yield: 95 %

Procedure:
432 mg (1 mmol) Methanesulfonic acid 5-[1-(4-bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester in 30 ml EtOAc/EtOH/hexane (1:1:1) was hydrogenated in the presence of 20 mg PtO2, the solution was filtered and evaporated. Column chromatography on silica gel with hexane/EtOAc 4:1 yielded (95%) Methanesulfonic acid 5-[1-(4-bromo-phenyl)-1H-indol-5-yl]-pentyl ester as colorless viscous oil, MS: 435 (M, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].N1CCCC[CH2:10]1.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:6]([C:5](=[CH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:10])[C:4]([O:3][CH2:1][CH3:2])=[O:8])#[N:7]
Reactant: C1CCNCC1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)=Cc1ccccc1C
Yield: 59 %

Procedure:
O-Tolylaldehyde (10 g, 83.2 mmol), ethylcyanoacetate (9.4 g, 83.2 mmol), and piperidine (1.1 mL, 11 mmol) were heated in toluene at reflux for 1 hour. The reaction was washed with H2O and brine, dried over MgSO4, and concentrated, with the resulting residue purified by chromatography (10-50% EtOAc, petroleum ether) to give ethyl 2-cyano-3-o-tolylacrylate (10.6 g, 59%).
Reaction SMILES: [CH2:1]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9](C=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.CO.[O:26]1[CH2:31][CH2:30][O:29][CH2:28]C1>>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][NH:14][C:31](=[O:26])[CH:30]([O:29][CH3:28])[C:9]2[CH:8]=[CH:7][C:6]([N:4]3[CH2:3][CH2:2][CH2:1][CH2:5]3)=[CH:11][CH:10]=2)=[CH:17][CH:18]=1)#[N:21]
Reactant: O=Cc1ccc(N2CCCC2)cc1
Reactant: C1COCCO1
Reactant: N#Cc1ccc(CN)cc1
Solvent: CO
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(N2CCCC2)cc1

Procedure:
4-(1-Pyrrolidino)benzaldehyde was reacted according to general procedure A using methanol/dioxane as a solvent. The product of this reaction was subsequently coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(4-pyrrolidin-1-yl-phenyl)-acetamide. Off-white solid. MS 350.4 ([M+H]+)
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:39])C.[OH-].[Na+].Cl>C(O)C>[Cl:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:30]#[C:31][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCOCC3)c2)cc1Cl
Reaction time: 16 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-acetic acid ethyl ester (200 mg; 0.33 mmol) was dissolved in ethanol (10 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness, and purified by prep. HPLC (method A). Yield: 46 mg. HPLC-MS: m/z: 572.3 (M+); Rt: 2.03 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)O)=[CH:9][N:10]=2)[N:7]=1.ClC1C=CC2N(C(C(C3C=[C:38]4[C:42](=CC=3F)[N:41]([CH3:46])[N:40]=[CH:39]4)=O)=CN=2)N=1.[CH3:47]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH3:46])[CH:42]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:47]
Reactant: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)c(F)cc21
Solvent: ClCCl
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanone (rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanol (Stage 278.4, 4.2 g, 12.66 mmol) was suspended in DCM (250 mL). Dess-Martin periodinane (10.64 g, 38.0 mmol) was added and the mixture was stirred at rt for 1.5 h. The mixture was evaporated to dryness and the residue was taken in 1 M NaOH and sonicated. After 15 min of stirring, it was filtered. The precipitate was dried under vacuum overnight to afford the title compound (tR 1.13 min (conditions 2), MH+=330)
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][I:17]>CC(C)=O>[I-:17].[C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[N+:9]([CH3:16])[CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CI
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Solvent: CC(C)=O
Product: CC(=O)c1nc(-c2ccc[n+](C)c2)[nH]c1C
Product: [I-]
Reaction time: 24 h

Procedure:
A 3.0 g (0.015 mole) amount of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone in 300 ml of acetone was treated with 3.0 ml of methyl iodide. The reaction mixture was allowed to stand at room temperature for 24 hours. The precipitate formed was collected by filtration and was washed with 50 ml each of acetone and ether then was dried in vacuo at 60° C. to yield 1.9 g of the desired product as a yellow solid, mp 258°-260° C. (dec.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH:15]=[O:16].[CH3:17][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH:15]([OH:16])[CH3:17]
Reactant: C[Mg]Br
Reactant: O=Cc1cccc2cc(-c3nccs3)[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2-(1,3-thiazol-2-yl)-1H-indole-7-carbaldehyde (0.446 g) in anhydrous tetrahydrofuran (10 mL) was added 1.0 M methylmagnesium bromide (4 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. Under ice-cooling, 1.0 M methylmagnesium bromide (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was ice-cooled, 1.0 M methylmagnesium bromide (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.090 g, yield 19%) as colorless crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](O)(=[O:33])[CH2:31][OH:32].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:31](=[O:32])[CH2:30][OH:33])[CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCNC1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@@H]1CCCN(C(=O)CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6) (38.62 g), glycolic acid (9.13 g) and triethylamine (27.90 mL) in THF (500 mL) stirring in an ice bath, was added HATU (45.63 g) in one portion. The reaction was allowed to warm up to room temperature and stirred overnight (16 hrs). Solvent was removed by rotoevaporation. The residue was diluted with dichloromethane (500 mL), washed with aqueous NaOH solution (10%, 300 mL). The solid was filtered off and the bi-layer system was separated. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was triturated with acetonitrile (300 mL) with some heating and cooled to room temperature. The mixture was filtered after sitting at room temperature overnight (16 hrs) and filtered. The solid collected was washed with small amount of acetonitrile and dried under high vacuo to provide the title compound a white powder with slight pink color (34.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:19])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)[CH3:10].[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](O)=[O:25].Cl.C(N(CC)CCCN=C=NCC)C>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([CH3:20])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:19])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH:18][C:24](=[O:25])[CH2:23][C:22]([F:28])([F:27])[F:21])[CH:12]=1)[CH3:10]
Reactant: Cc1nsc(NC(=O)C(C)c2ccc(O)c(N)c2)c1Cl
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nsc(NC(=O)C(C)c2ccc(O)c(NC(=O)CC(F)(F)F)c2)c1Cl
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of N-(4-chloro-3-methylisothiazol-5-yl)-2-(3-amino-4-hydroxyphenyl)propionamide (0.65 g, 0.002 mol), 3,3,3-trifluoropropionic acid (0.267 g, 0.002 mol) and 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.40 g, 0.002 mol) was stirred in N,N-dimethylacetamide (8 ml) at room temperature for 7 hours and was then allowed to stand at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexane 1:1, to give N-(4-chloro-3-methylisothiazol-5-yl)-2-[4-hydroxy-3-(3,3,3-trifluoropropionamido)phenyl]propionamide (0.62 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][C:16]([C:23]([OH:25])=[O:24])=[C:15]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1.O>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][C:16]([C:23]([O:25][CH2:7][CH3:8])=[O:24])=[C:15]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: CCI
Reactant: COc1ccc(-c2c(C(=O)O)[nH]c3cc(OC)c(OC)cc23)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Potassium carbonate (0.139 g) and ethyl iodide (0.13 ml) were added to a solution of 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (0.3 g) in N,N-dimethylformamide (5 ml). The mixture was stirred for 3 hours at room temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give ethyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (0.272 g, 84%) as pale red prisms.
Reaction SMILES: [CH3:1][C:2]([CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([CH2:5][CH3:6])[CH2:3][CH3:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CCC(C)(CC)C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCC(C)(CC)C1CCC(=O)CC1
Temperature: 50 °C

Procedure:
The 4-(3-methylpent-3-yl)cyclohexanol (350 g, 1.9 mol) prepared above was added slowly over a 3 hour period to a stirring solution of sodium dichromate (614 g, 2.06 mol), water (3.0 liters) and 98% sulfuric acid (526 g) while maintaining the batch temperature at 50°-55° C. Upon completion of the addition, the mixture was stirred an additional hour at 50° C. The reaction mixture was cooled and three liters of benzene was added. The layers were separated and the organic layer washed with one liter portions of water until a neutral pH was indicated. The solvent was removed on a rotary evaporator. Distillation of the residual oil under vacuum gave the desired 4-(3-methylpent-3-yl)cyclohexanone: 274 g, 79% theory; bp 105° C. (0.5 mm); mol wt 182 (ms); nmr, 0.75 (3H, s, methyl, 0.8 (6H, t, J=7, methyls), 1.15-2.0 (9H, m, CH, CH2), 2.15-2.5 (4H, m, Hα to carbonyl); ir, 2980, 2890, 1720, 1465, 1390, 1170 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:12][C:11]([F:14])([F:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(c1ccc(N2CCNCC2)cc1)C(F)(F)F

Procedure:
A mixture of 1 mmol 1-Bromo-4-trifluoromethanesulfonyl-benzene [Nodiff et al., J. Org. Chem. 25, 60 (1960)], 3 mmol of piperazine and 2 mmol of potassium carbonate in 5 ml of acetonitrile was refluxed for 2 hours. The resulting mixture was poured into water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography (SiO2; Et2O/cyclohexane) to yield the title compound as a colorless solid. MS (m/e): 295.2 (MH+, 100%)