Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:59][C:60]([O:63][C:64](=[O:85])[NH:65][C:66]1[CH:71]=[CH:70][C:69]([C:72]2[C:84]3[C:83]4[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=4)[NH:77][C:76]=3[CH:75]=[CH:74][CH:73]=2)=[CH:68][N:67]=1)([CH3:62])[CH3:61]>O1CCOCC1.C(OC(C)C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:77]2[C:76]3[CH:75]=[CH:74][CH:73]=[C:72]([C:69]4[CH:70]=[CH:71][C:66]([NH:65][C:64](=[O:85])[O:63][C:60]([CH3:61])([CH3:59])[CH3:62])=[N:67][CH:68]=4)[C:84]=3[C:83]3[C:78]2=[CH:79][CH:80]=[CH:81][CH:82]=3)=[CH:3][C:4]=1[F:10])#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C#N)c(F)c2)cn1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
0.217 g of 4-bromo-2-fluorobenzonitrile, 0.9 g of caesium carbonate, 0.05 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 0.016 g of palladium acetate are successively added, under argon, to a solution of 0.26 g of 2-methylpropan-2-yl[5-(9H-carbazol-4-yl)pyridin-2-yl]carbamate in 15 ml of dioxane. The reaction mixture is refluxed for 5 hours, cooled to ambient temperature and filtered through celite. The filtrate is concentrated under reduced pressure so as to give a brown oil which, after trituration in diisopropyl ether, gives a yellow solid which is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (90/10 by volume). 0.11 g of 2-methylpropan-2-yl {5-[9-(4-cyano-3-fluorophenyl)-9H-carbazol-4-yl]pyridin-2-yl}carbamate is thus obtained, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:30])([F:29])[C:18]1[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:17]([F:16])([F:30])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH:25]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: O=C(O)/C=C\c1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2C(Cc2ccc(C(F)(F)F)nc2)C(=O)O)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, (Z)-3-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N+:12]=2[O-:18])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](Br)[CH2:20][CH2:21][CH3:22].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[C:1]1([CH:7]([S:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N+:12]=2[O-:18])(=[O:10])=[O:9])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc[n+]([O-])c(S(=O)(=O)Cc2ccccc2)c1
Reactant: CCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCCC(c1ccccc1)S(=O)(=O)c1cc(C)cc[n+]1[O-]

Procedure:
To a 100 ml round bottom, 3-necked flask equipped with thermometer, stirrer, were charged 0.5 g (3.2 mmoles) 2-(phenylmethylsulfonyl)-4-methylpyridine 1-oxide, 10 ml CH2Cl2, 0.05 g benzyltriethylammonium chloride and 0.75 ml n-butyl bromide. Said mixture also contained about 5 mg (0.28 mmoles) of water. Immediately, a dark red color formed while the reaction mixture was kept at about 15° while stirring. With time, the color faded, and after 3 hours reaction time, the product (2-(1-phenylpentylsulfonyl)-4-methylpyridine 1-oxide) was isolated, having a melting range of 120°-122° C. The product structure was confirmed by NMR and IR analysis.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:30])([C@H:27]([SH:29])[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>CN(C)C=O.C1C=CC=CC=1>[C:3]([CH2:2][S:29][C@H:27]([CH3:28])[C@:20]([C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12])([OH:30])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:4])[NH2:5]
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C[C@@H](SCC(N)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
58 mg (0.42 mmole) of 2-bromoacetamide and 48 mg (0.35 mmole) of potassium carbonate were added to a solution of 100 mg (0.35 mmole) of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 3 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was diluted with benzene and washed with a saturated aqueous solution of sodium chloride, after which the solvent was removed by distillation under reduced pressure. The virtually pure product thus obtained was recrystallized from a mixture of acetone and hexane to afford 90 mg of the title compound, melting at 144°-145° C.
Reaction SMILES: [ClH:1].C([O:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH:18]([OH:34])[CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:21]2)[NH:9][N:8]=1)(=O)C>>[ClH:1].[ClH:1].[OH:34][CH:18]([CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:25]1)[CH2:17][O:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:6][OH:5])=[N:8][NH:9]2
Reactant: CC(=O)OCc1n[nH]c2cccc(OCC(O)CN3CCC(COc4ccccc4)CC3)c12
Agent: Cl
Product: OCc1n[nH]c2cccc(OCC(O)CN3CCC(COc4ccccc4)CC3)c12
Yield: 48 %

Procedure:
Excess ethanolic hydrochloric acid is allowed to act upon 3-acetoxymethyl-4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-indazole, followed by precipitation with diethyl ether and recrystallization of the precipitate from ethanol. There is obtained, in a yield of 48% of theory, 4-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-3-hydroxymethylindazole dihydrochloride in the form of pale yellow crystals; m.p. 183° C. (decomp.).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH:29]=[CH2:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.O>C(Cl)Cl>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([CH:29]=[CH2:30])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: C=Cc1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C=Cc1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 0.5 h
Yield: 106 %

Procedure:
A mixture of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-vinylpyrimidin-2-yl)thiophene-2-sulfonamide (80 mg, 0.17 mmol) and BCl3 (3 mL) in DCM (10 mL) was stirred for 0.5 h, Water was added and extracted with EA. The combined organic layers were dried (NaHSO4), filtered. The filtrate was concentrated to afford the compound 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-vinylpyrimidin-2-yl)thiophene-2-sulfonamide (Compound 209) (70 mg, 90%). LC-MS (m/z)=389 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.80-0.81 (m, 2H), 1.01-1.04 (m, 2H), 1.96-2.02 (m, 1H), 5.50 (d, J=11.6 Hz, 1H), 5.96 (d, J=17.2 Hz, 1H), 6.43 (s, 1H), 7.08-7.15 (m, 1H), 7.63 (d, J=4 Hz, 1H), 7.87 (bs, 2H), 8.00 (bs, 1H), 8.56 (s, 1H), 10.13 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].C>CCOCC>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)=CC(O)C(Cl)(Cl)Cl
Yield: 59.2 %

Procedure:
1,1,1-Trichloro-4-methyl-4-penten-2-ol (74 g, 0.36 mole) was heated at 140°-150° for 18 hours. After cooling, the alcohol was diluted with ether, and the ethereal solution was treated with activated charcoal. The ether was removed by evaporation to afford crystalline 1,1,1-trichloro-4-methyl-3-penten-2-ol (43.4 g, 59% yield) after recrystallization from petroleum ether.
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][CH2:24][C:25]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.ClCCl.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(OCC)(=O)C.O>[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][CH2:24][C:25]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][N:28]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:27][CH2:26]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(CNC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(CNC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 150 mg of methyl 4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]piperidine-4-carboxylate dihydrochloride, 150 μl of triethylamine, and 5 ml of dichloromethane was added 35 μl of methanesulfonyl chloride under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 85 mg of methyl 4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]-1-(methylsulfonyl)piperidine-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])[CH3:2].Br[CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:15][CH2:16][Cl:17])[CH3:2]
Reactant: ClCCBr
Reactant: CCOC(=O)c1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc(C)ccc1OCCCl

Procedure:
This compound was prepared following the procedure described in Example 1 (part C) starting with 5 g (27.8 mmol) of 2-hydroxy-5-methyl-benzoic acid ethyl ester, 7.9 mL (55.5 mmol) of 1-bromo-2-chloro-ethane and 7.7 g (55.5 mmol) of potassium carbonate. After the work-up and purification, 4.5 g (68% of yield) of the desired product was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH3:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[Cu][C:13]#[N:14]>CN(C)C=O>[CH3:11][C:9]1[N:8]=[C:6]2[NH:7][C:2]([C:13]#[N:14])=[CH:3][CH:4]=[C:5]2[N:10]=1
Reactant: N#C[Cu]
Reactant: Cc1nc2nc(Br)ccc2[nH]1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C#N)[nH]c-2n1
Temperature: 150 °C
Reaction time: 9 h
Yield: 64.7 %

Procedure:
To a solution of 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (1.92 g) in N,N-dimethylformamide (48 ml) was added Copper (I) cyanide (2.04 g), and the mixture was stirred for 9 hr at 150° C. After evaporation of the solvent under reduced pressure, water (45 ml) and ethylenediamine (2.7 g) were added to the residue, and the mixture was heated at 70° C. for 15 min. The solution was concentrated under reduced pressure and the residue was purified by a short silica gel column to give the objective compound (927 mg) as a brown powder. Purification by silica gel column chromatography (dichloromethane/methanol=10/1) gave a purer compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:53]([F:56])([F:55])[F:54])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([N:16]([CH2:20][C@@H:21]4[C@H:25]5[O:26]C(C)(C)[O:28][C@H:24]5[C@H:23]([N:31]5[C:35]6[N:36]=[CH:37][N:38]=[C:39]([NH:40]CC7C=CC(OC)=CC=7OC)[C:34]=6[CH:33]=[CH:32]5)[CH2:22]4)[CH:17]([CH3:19])[CH3:18])[CH2:13]3)[NH:7][C:6]=2[CH:52]=1.C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O.O>[NH2:40][C:39]1[C:34]2[CH:33]=[CH:32][N:31]([C@@H:23]3[CH2:22][C@H:21]([CH2:20][N:16]([CH:14]4[CH2:13][CH:12]([CH2:11][CH2:10][C:8]5[NH:7][C:6]6[CH:52]=[C:2]([Cl:1])[C:3]([C:53]([F:55])([F:54])[F:56])=[CH:4][C:5]=6[N:9]=5)[CH2:15]4)[CH:17]([CH3:19])[CH3:18])[C@@H:25]([OH:26])[C@H:24]3[OH:28])[C:35]=2[N:36]=[CH:37][N:38]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (525 mg, 0.683 mmol) was dissolved in a mixture of Trifluoroacetic Acid (9 ml) and Water (1 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to RT. After 4 h at RT, the mixture was concentrated. The residue was taken up in 20 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 15 ml MeOH (gave a slurry) and was treated with 500 mg K2CO3 and 15 drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a fine frit, the solids were washed with 10 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight. The crude material was purified by flash chromatography (SiO2, eluting with 12% 7N NH3 in CH3OH/CH2Cl2) to give a colorless glass/stiff foam. 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1H), 7.89 (d, J=2.07 Hz, 1H), 7.69 (d, J=2.28 Hz, 1H), 7.21 (dd, J=3.42, 1.76 Hz, 1H), 6.59 (d, J=3.52 Hz, 1H), 4.33 (t, J=6.84 Hz, 1H), 3.89 (q, J=5.25 Hz, 1H), 3.03 (m, 0.5H), 2.89 (m, 2H), 2.70 (m, 0.5H), 2.49 (m, 1H), 2.40 (m, 2H), 2.27 (br. s., 2H), 2.16 (d, J=7.26 Hz, 4H), 2.06 (m, 2H), 1.91 (m, 2H), 1.62 (m, 1H), 1.52 (m, 1H).
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][CH3:18])[C:14](S)=[N:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH2:17][CH3:18])[CH:14]=[N:13][N:12]=1
Reactant: CCCn1c(S)nnc1CO
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCn1cnnc1CO
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of 90% nitric acid (18 ml) and water (26 ml) was added sodium nitrite (0.07 g) and then 3-hydroxymethyl-5-mercapto-4-propyl-4H-1,2,4-triazole (10 g) was slowly added for 0.5 hours at 45° C. After cooling to room temperature, and sodium carbonate was slowly added thereto to adjust pH to 7 at 0° C. The reaction mixture was concentrated under reduced pressure, methanol was added to the residue, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, the precipitates were removed by filtration, and the filtrate was concentrated to give 3-hydroxymethyl-4-propyl-4H-1,2,4-triazole (5.95 g) as a crude product.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][S:13]C(=O)C)[CH2:8][CH2:7][S:6]1)=[O:4].[OH-].[Na+]>CO>[SH:13][CH2:12][CH:11]([CH3:17])[C:10]([N:9]1[CH2:8][CH2:7][S:6][CH:5]1[C:3]([OH:4])=[O:2])=[O:18]
Reactant: COC(=O)C1SCCN1C(=O)C(C)CSC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CS)C(=O)N1CCSC1C(=O)O

Procedure:
3-(3-Acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester (2.9 g.) is dissolved in methanol (30 ml.) and N sodium hydroxide (30 ml.) is added. The reaction mixture is stirred at rooom temperature, aliquots are withdrawn every hour and checked by paper electrophoresis for the hydrolysis of the methyl ester. When this hydrolysis is completed (ca. three hours), the reaction mixture is neutralized, concentrated in vacuo to eliminate methanol, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 3-(3-mercapto-2-methylpropanoyl)-2-thiazolidinecarboxylic acid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:22])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[N+](C)([O-])=O.C(OCC)C>[C:23]([C:19]1[CH:20]=[CH:21][C:8]2[O:7][C:6]([CH3:22])([CH3:5])[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:9]=2[CH:18]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3)ccc2O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.6 %

Procedure:
264 mg of aluminum chloride were added to an ice-cooled solution of 237 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran in 6 ml of nitromethane. The mixture was stirred for 5 minutes, 349 mg of benzoyl chloride were added and the stirring was continued at 0° C. for 30 minutes and at room temperature for 16 hours. The o reaction mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (2:3) for the elution to give 94 mg of 6-benzoyl-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:44]=2)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:40]3[CH:41]=[N:42][N:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:44]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n2S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (940 mg, 1.651 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (694 mg, 2.476 mmol) in N,N-dimethylformamide (11.5 mL) was added saturated aqueous bicarbonate solution (3.83 mL) followed by bis(triphenylphosphine)palladium dichloride (81 mg, 0.116 mmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 95% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 596.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:60][C@H:59]([CH2:61][O:62]C(=O)C(C)(C)C)[C@@H:51]([O:52]C(=O)C(C)(C)C)[C@H:43]([O:44]C(=O)C(C)(C)C)[C@H:35]3[O:36]C(=O)C(C)(C)C)=[N:27][NH:28][C:29]=2[CH:30]([CH3:32])[CH3:31])=[C:20]([CH3:69])[CH:19]=1)[CH2:9][CH2:10][C:11](=[O:13])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([N:8]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:60][C@H:59]([CH2:61][OH:62])[C@@H:51]([OH:52])[C@H:43]([OH:44])[C@H:35]3[OH:36])=[N:27][NH:28][C:29]=2[CH:30]([CH3:32])[CH3:31])=[C:20]([CH3:69])[CH:19]=1)[CH2:9][CH2:10][C:11](=[O:13])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 61.5 %

Procedure:
To a solution of 4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.25 g) in methanol (13 mL) was added sodium methoxide (28% methanol solution, 0.25 mL), and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (0.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:12][C:13]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:15][C:14]=1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1cccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)c1
Yield: 88.6 %

Procedure:
3-Methoxybenzoyl chloride 179 (0.20 g, 1.17 mmol) and 178 (0.34 g, 1.17 mmol) were stirred in pyridine (15 mL) at rt for 4 hrs then the pyridine was removed by rotary evaporation and the crude material was purified by column chromatography (25% ethyl acetate in hexanes) to provide the title compound 180 (0.44 g, 89% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.88 (s, 1H), 8.72 (s, 1H), 7.80 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.43 to 7.55 (m, 6H), 7.17 (dd, J=7.6, 1.8 Hz, 1H), 7.11 (dd, J=4.9, 3.5 Hz, 1H), 3.84 (s, 3H), 1.46 (s, 9H). MS: (calc.) 424.15; (obt.) 425.1 (MH)+.
Reaction SMILES: CN(C=O)C.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[N:27]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:26]=[CH:25][C:15]([CH2:16][NH:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: BrCCCCOc1ccc(CNCCN2CCCC2)cc1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1cc(OCCCCN2CCCCC2)ccc1CNCCN1CCCC1

Procedure:
An 8 mL DMF solution of [4-(4-bromo-butoxy)-benzyl]-(2-pyrrolidin-1-yl-ethyl)-amine (307 mg, 0.86 mmol) and piperidine (0.22 mL, 2.2 mmol) is stirred at 90° C. for six hours under N2. The reaction mixture is cooled, diluted with CH2Cl2, filtered, washed with brine, dried (Na2SO4), and concentrated. The residue is purified by chromatography (SiO2; 0-6% MeOH/CH2Cl2/1% NH4OH gradient) to give the product (40 mg, 12% yld). MS(ES+)360.4(M+H)+ free base.