Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]#[N:16])[CH:9]=1.Br[C:18]([CH3:22])([CH3:21])[CH:19]=[O:20]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[C:10]([C:15]#[N:16])[CH:9]=1
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: CC(C)(Br)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C=O)Oc1ccc(Cl)cc1C#N
Temperature: 4 °C
Yield: 94.7 %

Procedure:
Anhydrous potassium carbonate (2.76 g) was added to a stirred solution of 4-chloro-2-cyanophenol (1.53 g) and 2-bromo-2-methyl propanal (2.26 g) in THF (50 ml) and the mixture heated at reflux for 5 hours. The mixture was then cooled to 4° C., the suspended solid removed by filtration and the filtrate evaporated to give a yellow oil which crystallised on standing. The solid was triturated with hexane and collected by filtration to give 2-(4-chloro-2-cyanophenoxy)-2-methylpropanal (2.11 g), m.p. 85°-88° C.;
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[N:11]=[CH:10][CH:9]=[N:8][C:7]=1[S:6]2.[CH3:17][O:18][C:19](Cl)=[O:20].CI>>[C:19]([N:13]1[C:12]2[N:11]=[CH:10][CH:9]=[N:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:15][CH:16]=[CH:3][CH:4]=2)([O:18][CH3:17])=[O:20]
Reactant: COc1ccc2c(c1)Sc1nccnc1N2
Reactant: COC(=O)Cl
Solvent: CI
Product: COC(=O)N1c2ccccc2Sc2nccnc21
Yield: 23 %

Procedure:
By following the conditions of Example 4, but substituting 1,4-diazaphenothiazine for 7-methoxy 1,4-diazaphenothiazine and methylchloroformate for methyl iodide, the title compound, m.p. 137°-138° was obtained in a 23% yield.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].Cl[C:16]1[C:21]2=[N:22][O:23][N:24]=[C:20]2[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][CH:3]([CH2:2][S:1][C:16]1[C:21]2[C:20](=[N:24][O:23][N:22]=2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][CH:17]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CSc1ccc([N+](=O)[O-])c2nonc12)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
700 Mg of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline, 700 mg of 4-chloro-7-nitrobenzofurazan (10% excess), 1 g sodium bicarbonate, and 10 ml dichloromethane were stirred at 20° C. for 16 hours. The reaction mixture was put in a 4×30 cm Silicar CC4 column, and eluted with C6H6 :CH3COOH (3:1) mixture (v/v).
Reaction SMILES: C(O[C:9]([S:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:35])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[N:24][N:25]([CH3:34])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.ClC[C:38]1[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][N:39]=1.[OH-].[Na+]>C(O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]2[N:25]([CH3:34])[N:24]=[CH:23][C:22]=2/[CH:21]=[CH:20]/[C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([S:11][CH2:9][C:38]3[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][N:39]=3)=[CH:17][CH:16]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: CCCn1cnnc1CCl
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(SC(=O)OCc3ccccc3)cc2)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1cnnc1CSc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Yield: 65 %

Procedure:
A mixture of (2E)-N-{4-[(benzyloxycarbonyl)sulfanyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide (488 mg), 3-(chloromethyl)-4-propyl-4H-1,2,4-triazole (240 mg), a 1N aqueous sodium hydroxide solution (3 ml) and ethanol (30 ml) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio}phenyl)acrylamide (310 mg, 65%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:24][CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)O)[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](\[CH:21]3[CH2:22][CH2:23][CH2:24]3)/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C2CCC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(/c2ccc(F)cc2)C2CCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-cyclobutyl-1-(4-fluorophenyl)ethanol (500 mg, 1.2 mmol) was dissolved in thionyl chloride (5 mL) and the solution was stirred at RT for 3 h. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (3 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (637 mg, 11 mmol) was added and the reaction mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to RT and diluted with water. The precipitate obtained was filtered and washed with hexane, followed by purification by HPLC. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.58 (m, 1H), 7.45 (d, 1H), 7.25 (m, 1H), 7.10 (d, 1H), 7.0 (m, 3H), 6.70 (m, 1H), 4.30-4.20 (m, 3H), 3.65 (m, 2H), 3.50 (m, 2H), 2.90 (m, 2H), 2.80 (s, 3H), 2.20 (m, 2H), 1.80 (m, 1H), 1.60-1.30 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A mixture of 3-(3-tert-butoxycarbonylaminophenyl)propanol (3.24 g, 12.9 mmol), methanesulfonylchloride (1.63 g, 14.2 mmol), triethylamine (1.44 g, 14.2 mmol) and ethyl acetate (50 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with hexane-ethyl acetate (3:1) to give 3-(3-tert-butoxycarbonylaminophenyl)propyl methanesulfonate as a colorless oil (3.50 g, 82%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1)([OH:10])=[O:9].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[CH:1]1([NH:7][C:19]([CH2:18][C:14]2[CH:13]=[C:12]([CH2:11][C:8]([OH:10])=[O:9])[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1cccc(CC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
Cyclohexylamine (510 mg), (3-carboxymethyl-phenyl)-acetic acid (1.0 g), 1-hydroxybenzotriazole (700 mg) and Hunigs base (0.9 mL) were added to a round bottomed flask and dissolved in dichloromethane (40 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (990 mg) was added. The reaction was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane (40 mL) and washed with 2M hydrochloric acid (2×40 mL). The organic layer was isolated and extracted with 2M sodium hydroxide (2×40 mL). The basic extract was isolated, acidified with 2M hydrochloric acid and extracted with dichloromethane (2×40 mL). The dichloromethane extracts were combined, dried over anhydrous sodium sulphate, filtered and concentrated to give 626 mg of the sub-titled product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccsc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccsc3)c3ccccc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.2 g (0.73 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 1.64 mL (0.95 mmol) of a freshly prepared 0.6 M solution of 3-bromomethylthiophene in ethyl ether. After standard work-up, 0.27 g (100% of yield) of 4-(1-thiophen-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([O:29]C)=[O:28])=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([OH:29])=[O:28])=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC(C)(C)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CC(=O)O)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Temperature: 0 °C

Procedure:
A mixture of the product of STEP 7 (0.5 g) in methanol (2 mL) and a solution of NaOH (1 g) in water (6 mL) was heated to reflux for 30 minutes. The mixture was cooled to 0° C., acidified to pH=4 and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated in vacuo to provide the above product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:5]=2[N:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>>[F:12][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:18]([C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)=[O:19])[S:3][C:4]=2[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: Nc1nc2c(F)cc(F)cc2s1
Reactant: O=C(Cl)c1ccco1
Product: O=C(Nc1nc2c(F)cc(F)cc2s1)c1ccco1

Procedure:
Using 2-amino-4,6-difluoro-benzothiazole and furan-2-carboxylicacid chloride the title compound was prepared as a grey solid (81% yield), MS: m/e=280 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH3:21])=[O:18].N1C=CC=CC=1.[C:47]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80](Cl)=[O:81])(=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>C1COCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:80](=[O:81])[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][O:64][C:47](=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH3:21])=[O:18]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OC(C)OC(=O)CCCCCCCCCCCCCCCO
Reaction time: 2 h
Yield: 29.4 %

Procedure:
Ethylidene bis (16-hydroxyhexadecanoate) (4.38 g, 7.67 mmol) was dissolved in THF (80 ml) and pyridine (0.61 g, 7.71 mmol) was added. 16-hexadecanoyloxyhexadecanoyl chloride (4.18 g, 7.90 mmol) was dissolved in THF (20 ml) and added dropwise. After 3 days at room temperature the mixture was filtered and the filtrate was left -20° C. for 2 hours. The precipitated product was filtered and purified by flash chromatography (silicagel, chloroform) to give 2.4 g (29%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 0.85 (t, 3H, CH3), 1.2-1.4 (s, 90H, --CH2 --), 1.45 (d, 3H, --O--CH(CH3)--O--), 1.5-1.7 (m, 14H, --CH2 --), 2.25 (m, 8H, --CH2 --C(O)--O--), 3.60 (t, 2H, --CH2 --OH), 4.05 (t, 4H, --C(O)--O--CH2 --), 6.85 (q, 1H, --O--CH(CH3)--O--). 13C NMR (75 MHz, CDCl3): δ 13.7, 19.1, 22.2, 24.2, 24.6, 25.2, 25.5, 28.2, 28.5, 28.7, 28.8, 29.0, 29.2, 31.5, 32.3, 33.7, 34.0, 62.5, 64.0, 88.0, 171.5, 173.5.
Reaction SMILES: [O:1]1[CH:8]([CH3:9])[CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(=O)(=O)(O)O.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[CH:15]([O:18][CH:8]([CH3:9])[CH:2]([OH:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1OC1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)C(C)OC(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
That is, to ethyl 2,3-epoxybutanoate (13.0 g, 0.1 mol) dissolved in isopropanol (30 ml) was added sulfuric acid (0.5 ml), and the mixture was stirred at 60° C. for 5 hours. Subsequently, excessive isopropanol was removed under reduced pressure to obtain ethyl 3-(isopropoxy)-2-hydroxybutanoate. The product obtained and p-toluenesulfonyl chloride (20.9 g, 0.11 mol) were added to pyridine (50 ml), and the mixture was stirred at room temperature for 5 hours. Subsequently, water was added to the reaction mixture, and the oily product liberated was extracted with toluene. After the toluene layer was washed with water and dried over sodium sulfate, toluene was removed under reduced pressure. The oily product obtained was isolated by silica gel column chromatography (Wako gel C-200 (trade name, produced by Wako Junyaku K.K.), eluted by hexane: ethyl acetate=9:1) to obtain ethyl 3-(isopropoxy)-2-p-toluenesulfonyloxybutanoate (27.5 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11](Cl)=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24].C(N(C(C)C)CC)(C)C>C(O)CCC>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:24][CH2:23][C:22]([O:21][CH3:20])=[O:25])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 150 °C
Reaction time: 19 h
Yield: 17.2 %

Procedure:
9-Benzyl-2-chloroadenine (0.30 g, 1.12 mmol), glycine methyl ester hydrochloride (0.72 g, 5.73 mmol) and diisopropylethylamine (1.48 g, 11.47 mmol) were added to n-butanol (10 ml), and the mixture was stirred in an autoclave at 150° C. for 19 hours. The solvent was removed and the residue was poured into water. The solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-2-methoxycarbonylmethylaminoadenine (0.06 g) as a brown tar. Thus obtained 9-benzyl-2-methoxycarbonylmethylaminoadenine was dissolved in dichloromethane (10 ml) and to the solution was added bromine (0.05 ml) in an ice bath. The mixture was stirred at room temperature for 1 hour. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine (0.06 g) as a yellow solid.
Reaction SMILES: [C:1]12([S:11](Cl)(=[O:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)(=[O:13])=[O:12])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=S(=O)(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanesulfonamide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(N2CCc3ncnc(Nc4ccc(C(F)(F)F)cc4)c3C2)c1
Reaction time: 6 h
Yield: 4.7 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.2 mg, 5%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([OH:26])[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)Cl>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](=[O:26])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCC2)cc2cccnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCCC1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a 250 mL round bottomed flask charged with 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanol (690 mg, 1.86 mmol) was added a 0.3 M solution of Dess-Martin periodinane in methylene chloride (12.4 mL, 3.72 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h before quenching with saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (250 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×3), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (685 mg, quant.) as a light yellow solid which was used for the next step without further purification: LC/MS m/e calcd for C20H21N2O3S [M+H]+ 369.12, observed 369.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24]O)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:52])C(=O)C1>ClCCl>[Br:52][CH2:24][C:22]1[S:23][C:19]([C:4]2[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:20][N:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CO)s2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CBr)s2)c1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
To [5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol (0.13 g, 0.34 mmol) was added dichloromethane (3.5 mL) and triphenylphosphine (0.11 g, 0.41 mmol). The solution was cooled to 0° C. and n-bromosuccinimide (0.067 g, 0.38 mmol) was added and the reaction was allowed to warm slowly to room temperature. Once the reaction was complete, silica gel (1.3 g) was added and the slurry was concentrated. The solid was purified by silica gel chromatography to yield N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.072 g, 49%). MS ESI: [M+H]+ m/z 430.9. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.84 (d, J=4.9, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.49 (s, 1H), 7.29 (d, J=4.9, 1H), 7.21 (s, 1H), 5.04 (s, 2H), 2.32 (s, 3H). rhSYK activity=+++
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]3[CH2:17][CH:18]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:19](=[O:27])[N:20]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:21][C:15]=3[CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.[ClH:36].C(O)C>[C].[Pd].C(O)C>[ClH:36].[O:27]=[C:19]1[CH:18]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:17][C:16]2[CH:34]=[CH:35][C:13]([O:12][CH2:11][CH2:10][C:2]3[N:1]=[C:5]4[NH:6][CH2:7][CH2:8][CH2:9][N:4]4[CH:3]=3)=[CH:14][C:15]=2[CH2:21][N:20]1[CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: CCOC(=O)CC1Cc2ccc(OCCc3cn4cccnc4n3)cc2CN(CC(F)(F)F)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 11 mL of an ethanol solution containing 0.28 g (0.57 mmol) of ethyl 8-[2-(imidazo[1,2-a]pyrimidin-2-yl)ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetra-hydro-1H-2-benzazepin-4-acetate obtained in Example 1-(c) were added 5.5 mL of 3.2M hydrogen chloride/ethanol solution and 0.14 g of 10% palladium carbon, and the mixture was stirred under hydrogen atmosphere at room temperature for 1 hour.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=[N+]([O-])O
Reactant: CCCCC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(Cn1ccnc1)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 40 ml of nitric acid and 10 ml of sulfuric acid, 14.8g (0.0498 mole) of 1-[β-(2,4-dichlorophenyl)hexyl]imidazole in 30 ml of sulfuric acid is added at less than 5°. The reaction is stirred for 1/2 hour and then it is poured into iced water. The oily solid which separates is isolated by decanting off the dilute acid solution. The residue is washed and then treated with ammonium hydroxide solution.