Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:34]1[CH:35]=[C:36]2[C:49]3([CH2:53][O:52][C:51]([N:54](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:50]3)[C:45]3([CH2:48][O:47][CH2:46]3)[C:41]3([CH2:44][CH2:43][CH2:42]3)[O:40][C:37]2=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+].C>O1CCOCC1.C1(C)C=CC=CC=1.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.O>[F:9][C:3]1[C:2]([C:34]2[CH:35]=[C:36]3[C:49]4([CH2:53][O:52][C:51]([NH2:54])=[N:50]4)[C:45]4([CH2:46][O:47][CH2:48]4)[C:41]4([CH2:44][CH2:43][CH2:42]4)[O:40][C:37]3=[CH:38][CH:39]=2)=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Reactant: Cc1cnc(F)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(F)c(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C2(CCC2)O3)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
A mixture of 3-bromo-2-fluoro-5-methylpyridine (202 mg, 1.06 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (300 mg, 1.17 mmol), potassium acetate (208 mg, 2.12 mmol) and PdCl2(PPh3)2 (37 mg, 0.053 mmol) in dioxane (4 mL) was stirred for 3 hours at 100° C. To the mixture was added di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (300 mg, 0.531 mmol), sodium carbonate (225 mg, 2.12 mmol) and H2O (1 mL), and the mixture was stirred for 1.5 hours at 100° C. The mixture was treated with charcoal, and filtered off. The filtrate was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated to give a pale brown oil. The oil was dissolved in toluene (5 mL) and to the mixture was added silicagel (neutral; 600 mg). The mixture was refluxed for 1 hour. The solvent was evaporated off. Silicagel column chromatography (CHCl3-EtOH, linear gradient of EtOH from 0 to 20%) afforded a solid. The solid was triturated in Et2O and collected by filtration, washed with Et2O and dried in vacuo at 70° C. to give 6′-(2-fluoro-5-methylpyridin-3-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (130 mg).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>C(Cl)Cl.CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][CH:14]=1
Reactant: OCCc1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of pyridinium chlorochromate (6.9 g, 21.4 mmol) in CH2Cl2 (100 ml) was added a solution of 2-(4-fluorophenyl)ethanol (3.0 g, 21.4 mmol) in CH2Cl2 (10 ml). The resulting suspension was stirred for 2 hours at room temperature and was then diluted with ether. The resulting suspension was filtered through a pad of Celite and washed with ether.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[F:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:4]2[C:3]([CH2:2][NH:30][C:29]3[CH:31]=[CH:32][C:26]([CH3:25])=[CH:27][CH:28]=3)=[C:12]3[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]3)=[CH:6][CH:5]=2)[CH:21]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(F)cc1-c1ccc2c(c1CCl)NC(=O)C(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccc2c(c1CNc1ccc(C)cc1)NC(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 8-chloromethyl-7-(5-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 4-2, 50.7 mg, mmol), 4-methylaniline (19.3 mg, 0.18 mmol), and potassium carbonate (60.6 mg, 0.44 mmol) was suspended in anhydrous N,N-dimethylformamide (1 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (30 mL) and water (30 mL) were added and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (48.2 mg) as a pale yellow solid. (Yield 80%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]1[CH2:8][CH:7]([N:9]=[N+]=[N-])[CH2:6][N:5]1[C:12](=[O:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:17][CH:16]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]1[CH2:8][CH:7]([NH2:9])[CH2:6][N:5]1[C:12](=[O:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(=O)CCc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CC(N)CN1C(=O)CCc1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 93 %

Procedure:
6.27 g (14.5 mmol) of 4-azido-1-[3-(4-tert-butyloxycarbonylaminomethylphenyl)propionyl]proline methyl ester (starting compound A5) are dissolved in 200 ml of methanol and, after addition of 0.6 g of Pd/C (10%), hydrogenated. After the reaction is complete, the catalyst is filtered off with suction and the filtrate is concentrated in vacuo. Drying under high vacuum results in 5.47 g of the title compound as a colorless solidified foam. The mass spectrum shows the molecular peak MH+ at 406 Da.
Reaction SMILES: C([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C:10]([NH:21][CH2:22][C:23](=[O:37])[NH:24][CH:25]2[CH2:28][N:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35]#[N:36])[CH2:31][CH2:30]3)[CH2:26]2)=[N:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:35]([CH:32]1[CH2:33][CH2:34][CH:29]([N:27]2[CH2:26][CH:25]([NH:24][C:23]([CH2:22][NH:21][C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=4)[N:8]([C:6]([NH2:5])=[O:7])[N:9]=3)=[O:37])[CH2:28]2)[CH2:30][CH2:31]1)#[N:36]
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(C#N)CC3)C2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCC(N2CC(NC(=O)CNc3nn(C(N)=O)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from de-protection of 3-({[1-(4-cyano-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-amino)-5-trifluoromethyl-indazole-1-carboxylic acid tert-butylamide (as prepared in Example 86) with TFA using the procedure described in Example 81.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:20])=[O:12])[NH:8]2)=[C:4]([CH3:21])[CH:3]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C(O[K])(C)(C)C.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1(C)C(C)=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][C:4]1[CH:3]=[C:2]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[CH3:20])=[O:12])[NH:8]2
Reactant: Cc1cc(Br)cc2[nH]c(C(=O)N[C@@H]3CCCC[C@@H]3C)cc12
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1C
Product: Cc1cc(Nc2ccccc2)cc2[nH]c(C(=O)N[C@@H]3CCCC[C@@H]3C)cc12
Temperature: 100 °C
Yield: 31 %

Procedure:
To a stirred solution of 6-bromo-4-methyl-N-((1R,2S)-2-methylcyclohexyl)-1H-indole-2-carboxamide (4AH: 500 mg, 1.43 mmol) in xylene (7.5 mL) were added Pd(OAc)2 (58 mg, 0.26 mmol), JohnPhos (51 mg, 0.17 mmol), tBuOK (644 mg, 5.74 mmol) and aniline (802 mg, 8.62 mmol). The resulting mixture was purged with argon for 10 minutes and then heated at 100° C. for 3 h in sealed tube. The reaction mixture was partitioned between ethyl acetate and water. The organic layer separated and washed with brine and dried over Na2SO4, concentrated. The crude product was purified by column chromatography followed by preparative HPLC to obtain 160 mg of 4-methyl-N-((1R,2S)-2-methylcyclohexyl)-6-(phenylamino)-1H-indole-2-carboxamide (6A: 30%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N+:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](Cl)=[C:11]([C:20]([O:22]CC)=O)[CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][NH2:40].CN(C)C=O>O.COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:40][N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH3:32])[C:20](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1c[n+](Cc2ccc(Br)cn2)c2ccccc2c1Cl
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)cn3)cc-2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[(5-Bromopyridin-2-yl)methyl]-4-chloro-3-(ethoxycarbonyl)quinolinium salt (1.55 g, 3.51 mmol), potassium carbonate (2.63 g, 19.1 mmol, 5.4 equiv), and (2-methylphenyl)hydrazine hydrochloride (1.33 g, 8.38 mmol, 2.4 equiv) were combined in a mixture (1:1) of N,N-dimethylformamide:1,2-dimethoxyethane (25 mL) and placed into an oil bath preheated at 80° C. for 3 hours. The mixture was cooled to ambient temperature, poured into water (100 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound as a yellow solid: 1H-NMR (400 MHz, CD3OD) δ 8.97 (1H, s), 8.59 (1H, s), 8.33 (1H, d, J=7.8 Hz), 8.02-8.00 (1H, m), 7.78 (1H, d, J=9.0 Hz), 7.66-7.56 (2H, m), 7.48-7.37 (5H, m), 5.85 (2H, s), 2.28 (3H, s), ppm; low resolution mass spectrometry (ES+) m/z 446.8 [(M+H)+; calculated for C23H17BrN4O: 446.3].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:20]1[CH:24]=[CH:23][CH:22]=[N:21]1.CC(C)([O-])C.[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccnc(-c2ccc(-n3cccn3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
212 mg of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and 68 mg of pyrazole were dissolved in 4 ml of DMSO, and 102 mg of potassium tert-butoxide was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=67:33) to obtain 251 mg of methyl 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinate. (2) 236 mg of this compound was dissolved in a mixture liquid of 10 ml of methanol and 5 ml of THF, and 1.16 ml of aqueous 1 M sodium hydroxide solution was added, followed by heating at 80° C. for 40 minutes. The reaction liquid was cooled to room temperature, washed with water, and the organic solvent was evaporated away under reduced pressure. The reaction liquid was washed with diethyl ether to obtain an aqueous layer. The aqueous layer was neutralized with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure, and the resulting residue was recrystallized from a mixture of ethanol and water to obtain 103 mg of 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinic acid. (3) 92 mg of this compound was dissolved in ethanol, and 0.317 ml of aqueous 1 M sodium hydroxide solution was added thereto, followed by stirring at room temperature for 15 minutes. The reaction liquid was concentrated, the residue was suspended in 2-propanol, and the precipitate was collected by filtration to obtain 93 mg of sodium 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[N:41][N:40]=[CH:39]2)[CH:33]=1)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:29](=[O:28])[CH2:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:39]=[N:40][N:41]=[CH:42]2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (434 mg, 1.2 mmol) and 3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid ethyl ester [CAS-No. 335255-97-5] (259 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white solid (372 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:30][CH2:29][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])=[O:19])[C:9]3=[O:28])[C:6]=2[CH:7]=1.BrC1C=CC2C3(COC=2C=1)C1C(=CC=CC=1)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])C3=O>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:6]3[CH:7]=[C:2]([C:50]4[CH:51]=[N:40][CH:47]=[CH:48][CH:49]=4)[CH:3]=[CH:4][C:5]=3[O:30][CH2:29]2)[C:9]1=[O:28]
Reactant: O=C(CN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21)Nc1ccccc1F
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Product: O=C(CN1C(=O)C2(COc3ccc(-c4cccnc4)cc32)c2ccccc21)Nc1ccccc1F
Yield: 55 %

Procedure:
Following the procedure as described in EXAMPLE 37, and making non-critical variations using 2-(5-bromo-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide to replace 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (55% yield) was obtained as a white solid: mp 98-100° C.; 1H NMR (300 MHz, CDCl3) δ 8.60-8.53 (m, 2H), 8.14 (dd, 1H), 7.65 (dd, 1H), 7.41 (dd, 1H), 7.32-6.90 (m, 11H), 5.02 (d, 1H), 4.76 (d, 1H), 4.72 (d, 1H), 4.56 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 177.9, 164.8, 160.9, 154.2, 151.0, 147.1, 141.7, 134.2, 131.7, 131.5, 129.9, 129.4, 129.1, 125.1, 124.6, 124.5, 124.2, 124.0, 122.5, 122.2, 115.1, 114.8, 111.0, 109.1, 80.0, 58.1, 44.6; MS (ES+) m/z 466.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][CH:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@@H:5]([OH:12])[C@@H:4]1[OH:13].O(C)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.O(C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[C:40](O)(=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]CC>>[C:40]([O:10][CH2:9][C@H:7]1[O:8][CH:3]([O:2][CH3:1])[C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]1[OH:11])(=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCC(=O)OC[C@H]1OC(OC)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 79 %

Procedure:
Methyl-D-glucopyranoside (19.8 g, 0.10 mol, a 1:1 mixture of methyl α-(D)-glucopyranoside and methyl β-(D)-glucopyranoside, both Sigma Chemicals) was esterified with dodecanoic acid (31 g, 0.15 mol) by the procedure described in Example 1, using 3 g of an immobilized lipase (derived from Candida antarctica). The reaction was complete in 24 hours (HPLC showed>90% conversion) and the enzyme was removed by filtration. Purification by chromatography provided the title compound in a yield of 79% (30 g) as a crystalline powder, m,p. 70°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.CS([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncccc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methoxy-pyridin-3-yl)-methanol (0.38 g, 2.74 mmol) from example 42 step A and triethylamine (0.5 mL, 3.56 mmol) in 6 mL of CH2Cl2 was added methanesulfonyl chloride (0.26 mL, 3.29 mmol) at 0° C. After 1 hr, the reaction was warmed to room temperature and stirred overnight. The reaction mixture was brought to the usual work-up to give the crude product, which was purified by chromatography (silica gel, 25% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) 8.15 (m, 1H), 7.67 (m, 1H), 6.91 (m, 1H), 4.60 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:13]([C:15]1[S:27][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]([CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:37])[C:17]=2[C:16]=1[O:38][CH3:39])=[O:14])[CH3:12])=[O:7])(=O)C.[OH-].[Na+].CO>C1COCC1.C(=O)([O-])O.[Na+]>[OH:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:12])[C:13]([C:15]1[S:27][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]([CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:37])[C:17]=2[C:16]=1[O:38][CH3:39])=[O:14])=[O:7]
Reactant: COc1c(C(=O)N(C)CCNC(=O)COC(C)=O)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)N(C)CCNC(=O)CO)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 58.2 %

Procedure:
A mixed solution of the compound of Example 504 (120 mg, 0.22 mmol) and 4N aqueous sodium hydroxide solution (2 mL) in THF (4 mL)-methanol (4 mL) was stirred at room temperature for 2 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Recrystallization of the crude solid from ethyl acetate-hexane gave the title compound (65 mg, 58%) as white crystals.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20]C=[CH:18][N:17]=3)[CH2:12][CH:11]2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.COC1C(N2CCNCC2)=[N:44]C=NC=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20][N:44]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cncnc1N1CCNCC1
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCCc2csc3ccccc23)CC1

Procedure:
The title compound was prepared (1.03 g, 74%, mp 209°-212° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thienepropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[F:19][C:17]1[CH:18]=[C:13]2[CH:12]=[C:11](/[C:20](/[C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=3)=[CH:21]/[CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (405 mg, 0.75 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 15 mL, 15 mmol) was stirred for 12 h at room temperature. The mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 5-fluoro-2-[(E)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (300 mg, 100%) as a solid: LC/MS m/e calcd for C21H21FN2O3S [M+H]+ 401.48, observed 401.2; 1H NMR (400 MHz, CDCl3) δ ppm 10.24 (br. s., 1H), 7.98 (br. s., 1H), 7.76-7.95 (m, 3H), 7.40-7.56 (m, 2H), 6.54 (s, 1H), 6.17 (d, J=10.1 Hz, 1H), 3.93-4.03 (m, 2H), 3.33-3.48 (m, 2H), 2.95-3.09 (m, 3H), 2.79-2.90 (m, 1H), 1.64-1.83 (m, 4H).
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH3:2].[CH3:15][NH:16][NH2:17]>C(O)(=O)C>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]1[C:12]([CH3:13])=[N:17][N:16]([CH3:15])[C:1]=1[CH3:2])[CH3:11]
Reactant: CNN
Reactant: CCOC(=O)CCC(C(C)=O)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(C)nn(C)c1C
Yield: 92.8 %

Procedure:
Dissolve ethyl 4-acetyl-5-oxohexanoate (2.00 g, 9.99 mmol) in acetic acid (21 mL). Add methyl hydrazine (589 μL, 10.99 mmol) and stir at room temperature for 18 hr. Concentrate and dissolve residue in ethyl acetate. Wash ethyl acetate layer with saturated aqueous sodium bicarbonate solution. Extract aqueous layer twice with ethyl acetate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 100% ethyl acetate:hexanes) to give 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-propionic acid ethyl ester (1.95 g, 93%). MS (ES): m/z=211 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:34][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:9]=3[N:10]=[C:2]([Cl:1])[N:3]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC1CCCC1
Product: CCOC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-ethyl-β-D-ribofuranosyl)-purine (63, 505 mg, 1.16 mmol) and cyclopentylamine (1.74 mmol, 172 μL). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 323 mg (0.81 mmol, 70%), mp 114–116° C.; Rf 0.55 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.34 (s, 1H, H-8), 8.32 (bs, 1H, NH), 5.82 (d, 1H, J=5.15 Hz, H-1′), 5.53 (d, 1H, J=5.18 Hz, OH-2′), 5.29 (d, 1H, J=5.15 Hz, OH-3′), 4.47–4.37 (m, 2H, CH, H-2′), 4.11–4.10 (m, 1H, H-3′), 4.00 (q, 1H, J=4.47 Hz, H-4′), 3.62–3.58 (m, 2H, H-5′), 3.47 (q, 2H, J=7.21 Hz, CH2CH3), 2.00–1.83 (m, 2H, cyclopentyl), 1.71–1.51 ((m, 4H, cyclopentyl), 1.12 (t, 3H, J=7.21 Hz, CH3); MS m/z 399 (M+H)+; Anal. (C17H24ClN5O4) C, H, N.