Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Br:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][C:25]([OH:27])=O>ClCCl>[Br:12][C:13]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[C:15]2[C:14]=1[CH2:23][CH2:24][C:25]2=[O:27]
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2c1ccc(C(F)(F)F)c2Br
Temperature: 25 °C

Procedure:
Oxalyl chloride (6.8 mL) and N,N-dimethylformamide (0.1 mL) are added to a solution of 3-(2-bromo-3-trifluoromethyl-phenyl)-propionic acid (15.7 g) in dichloromethane (150 mL) at room temperature. The solution is stirred at reflux temperature for 2 h and then concentrated. Trifluoromethane-sulfonic acid (60 ml) is added to the residue, and the resulting mixture is stirred at 55° C. for 4 h. After cooling to room temperature, the mixture is poured into ice-cold water, and the resulting mixture is stirred for 5 min. The precipitate formed is separated by filtration, washed with water, and dissolved in ethyl acetate. The solution is washed with aqueous NaHCO3 solution, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→80:20) to afford the title compound. LC (method 4): tR=1.04 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:16]([N:6]1[C@H:5]([CH3:8])[CH2:4][N:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:2]([CH3:1])[CH2:7]1)[CH:15]=[CH2:14]
Reactant: CCOC(=O)N1C[C@@H](C)NC[C@@H]1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodium carbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated at reflux for 1.5 hours. The reaction was cooled to room temperature, filtered, and the solvent removed under vacuum. The residue was dissolved in 4000 mL of dichloromethane and washed with two 500 mL portions of 1 M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate and the solvent was removed to give 630 g (81%) of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl.[C:22]([C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[C:33]([CH2:34]Cl)=[CH:32][N:31]=[CH:30]2)=[CH:26][CH:25]=1)#[N:23].C(N(C(C)C)CC)(C)C>C(#N)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]([CH2:34][N:11]3[CH2:10][CH2:9][C:8]([C:6](=[O:7])[C:5]4[CH:18]=[CH:19][CH:20]=[C:3]([CH3:2])[CH:4]=4)([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]3)=[CH:32][N:31]=[CH:30]2)=[CH:36][CH:37]=1)#[N:23]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: COC(=O)C1(C(=O)c2cccc(C)c2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1(C(=O)c2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
A solution of methyl 4-(3-methylbenzoyl)piperidine-4-carboxylate hydrochloride salt (58 mg, 0.2 mmol), l-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (52 mg, 0.19 mmol), and diisopropylethylamine (174 μL, 1 mmol) in anhydrous acetonitrile (4 mL) was heated at 60° C. overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2.5% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][CH:8]([OH:18])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH:8]([OH:18])[CH2:7][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)CNc1ccc(Cl)cc1
Product: OC(CNc1ccc(Cl)cc1)Cn1ccnc1

Procedure:
Reaction of imidazole and N-(3-chloro-2-hydroxypropyl)-4-chloroaniline [Current Sci. (India) 4, 142-4 (1959)] yields 1-[3-(4-chloroanilino)-2-hydroxypropyl]-imidazole, M.P. 123°-125° C., which is in turn reacted with 2,4-dichlorobenzyl chloride to yield 1-[3-(4-chloroanilino)-2-(2,4-dichlorobenzyloxy)-propyl]-imidazole; M.P. of oxalate salt is 134°-135° C.; M.P. of hydrochloride salt is 161°-163° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCCCC1>CO>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21](/[CH:28]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:20]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C1COc2c1ccc(O)c2CN1CCOCC1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1/C(=C/c2c[nH]c3ncccc23)Oc2c1ccc(O)c2CN1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A solution of 6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.170 g, 0.684 mmol) obtained in Example A41, Step 1 in methanol (3 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.100 g, 0.684 mmol) and piperidine (0.00582 g, 0.0684 mmol), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed. The solid was collected by filtration to obtain the objective (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.135 g, 52%).
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].S(=O)(=O)(O)O>>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:16]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CCCCCN1
Agent: O=S(=O)(O)O
Product: NCCCCCc1nc2ccccc2[nH]1

Procedure:
339.5 g (3 mols) of caprolactam, 430 g (4 mols) of o-phenylene diamine and 30 g of 50 % by weight sulphuric acid are reacted in the same way as described in Example 3, giving 510 g (83.7 % of the theoretical) of 2-(5'-aminopentyl)-benzimidazole with a boiling point at 0.1 Torr of 210° to 220°C, and a melting point of 101°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][CH:5]([C:7]([O:9]C)=[O:8])[CH:4]([CH3:11])[O:3]1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([CH3:11])[O:3]1
Reactant: COC(=O)C1OC(C)(C)OC1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1OC(C)(C)OC1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of methyl 2,2,5-trimethyl-1,3-dioxolane-4-carboxylate (1 mL) in tetrahydrofuran (10 mL) was added 1N aqueous lithium hydroxide (10 mL) and the mixture was stirred at room temperature for an hour. The reaction mixture was poured into iced 10% citric acid, then extracted with ethyl acetate. The obtained organic layer was washed with brine, dried and concentrated to give the title compound (425 mg) having the following physical data.
Reaction SMILES: [CH2:1]([OH:12])[C:2]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C@@H:6]([OH:9])[CH:7]=O)=O.[CH:13]([NH2:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:7]1[N:26]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:2]([CH2:1][OH:12])[C@@H:4]([OH:11])[C@H:5]([OH:10])[C@H:6]1[OH:9]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a -78° C. solution of 5-keto-D-glucose (Formula V, 4.00 g, 0.0225 mol) in 100 mL of methanol was added a cooled solution (-78° C.) of benzhydrylamine (3.29 g, 0.018 mol) and acetic acid (1.08 g, 0.018 mol) in 100 mL of methanol. Sodium cyanoborohydride (2.82 g, 0.0449 mole) was added, and the mixture was stirred at -78° C. for 2 h and then slowly warmed to ambient temperature. After 18 h, the solution was concentrated, saturated aqueous sodium carbonate was added, and the product was extracted into chloroform. The chloroform extracts were combined, dried (sodium sulfate), and concentrated to afford a yellow foam. Chromatographic purification on flash silica gel (5-10% gradient of methanol in chloroform) afforded 4.06 g (69%) of the title compound as a very pale yellow foam. 1H NMR and reversed-phase analytical HPLC showed that this substance was >95% stereochemically pure (ca. 4.5% of the iditol isomer). Recrystallization from MEOH afforded white needles, mp 101°-104° C. (corrected). Both 1H and 13C NMR in CDCl3 and D3CC(O)CD3 confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[NH:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[N:21][C:23](=[O:25])[CH3:24])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=N)n(C)c2n1
Solvent: CCOCC
Product: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=NC(C)=O)n(C)c2n1

Procedure:
A mixture of 0.161 g (0.46 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3 -d]pyrimidin-7-ylideneamine from Example 19 and 1.0 mL of acetic anhydride was heated to solution at the boiling point. After 2 minutes of reflux, the solution was concentrated to one-half volume, whereupon crystals formed. The mixture was cooled, 2 mL of ether was added, and the product was filtered and washed with ether; mp 229°-231° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C@@H:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C@@H:30]([C:32](=[O:49])NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])C>>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:32](=[O:49])[CH2:30][O:29][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][C@H:18]([O:17][CH3:15])[C:19]([OH:21])=[O:20])=[CH:28][CH:27]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(Cc3ccc(F)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-ropionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-fluoro-benzyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H27FN2O5 [M+H]+: 431.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)[CH3:18]>>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([N:19]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)[CH2:17][CH3:18])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1sccc1OCc1ccccc1
Reactant: CCNc1ccc(C(=O)OCC)cc1
Product: CCOC(=O)c1ccc(N(CC)C(=O)c2sccc2OCc2ccccc2)cc1

Procedure:
3-Benzyloxy-2-thienylcarboxylic acid was converted to the corresponding acid chloride which was reacted with ethyl 4-ethylaminobenzoate using a similar method to that of Example 4 to give ethyl 4-[N-(3-benzyloxy-2-thienoyl)-N-ethylamino]benzoate.
Reaction SMILES: CS([C:5]1[C:18]2[O:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[N:8]=[C:7]([NH2:19])[N:6]=1)(=O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>COCCO>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:5]2[C:18]3[O:17][CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[N:8]=[C:7]([NH2:19])[N:6]=2)[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)c1nc(N)nc2c1OCc1ccccc1-2
Reactant: CN1CCNCC1
Solvent: COCCO
Product: CN1CCN(c2nc(N)nc3c2OCc2ccccc2-3)CC1

Procedure:
A mixture of Example 41C, 1-methyl-piperazine (0.5 mL) and 2-methoxy-ethanol (1 mL) was heated at 110° C. for 60 hours, cooled, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of 2, 3.5 and 5% (9:1 MeOH: saturated aqueous NH4OH) to provide the title compound. 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.52 (t, J=4.75 Hz, 4H), 3.83 (t, J=4.75 Hz, 4H), 4.61 (s, 2H), 5.06 (s, 2H), 7.12 (m, 1H), 7.34-7.44 (m, 2H), 8.05 (m, 1H); MS (M+H)+ m/z 298.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:18]=[CH:17][C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:18]=[C:17]([Br:33])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c3ccccc3n(-c3ccccc3)c2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c3ccccc3n(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to that of Example 103(a) from 4-hydroxy-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 411 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[NH:27][C:28](=[NH:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COCCC(=N)NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 134 mg (0.910 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 185 mg (49% of theory)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39].C(N(CC)CC)C>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Yield: 44.1 %

Procedure:
The title compound was prepared by a similar method to example 3 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol), 1-propanesulphonyl chloride (28 mg, 0.19 mmol) and triethylamine (0.1 ml, 0.72 mmol). The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as a solid (50 mg). MS: 597 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:20][C:19]2[C:14]([CH3:13])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1ncccc1O
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2cccnc2C)cc1
Temperature: 150 °C
Reaction time: 1.33 h

Procedure:
A reaction tube containing a magnetic stirrer bar was charged with ethyl-4-fluorobenzoate (1 mmol), 2-methyl-3-pyridol (1.0 mmol), potassium carbonate (1.08 mmol) and DMF (2 ml). The reaction tube was then sealed and heated by microwave irradiation (100 W, 4 mins) to 150° C. and held at that temperature for 80 mins. The solution was filtered to remove the insoluble potassium carbonate and then concentrated in vacuo. The residue was purified by preparative HPLC and freeze dried to give 4-(2-Methyl-pyridin-3-yloxy)-benzoic acid ethyl ester as a white solid which was hydrolysed by 6N aqueous HCl solution heated by microwave irradiation (200 W) for 3 mins at 150° C. The solution was freeze dried to give to 63 mg of hydrochloride salt of the title compound as a white powder m/z=229 in MS ES+, which was characterised by HPLC and MS.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](#[N:18])[CH3:17].O>C1(C)C=CC=CC=1>[C:5]([CH2:17][C:16]#[N:18])(=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a suspension of sodium ethoxide (34.0 g. 0.500 mole) in dry toluene (200 mL were added ethyl benzoate (71.4 mL, 0.500 mole) and dry acetonitrile (32 mL, 0.60 mole). The mixture was mechanically stirred under nitrogen at 105°-110° C. for 29 hours, during which time it became quite viscous. After cooling to room temperature, water (300 mL) was added and the mixture was washed with ethyl ether (2×100 mL). The aqueous layer was then acidified to pH 5-6 with con. aq. HCl (required 30-35 mL) and the resulting crystalline precipitate was collected by suction filtration, washed twice with water, and air-dried. This subtitled material (49.23 g, 68%, m.p. 72°-73°) was sufficiently pure to be used in further transformations (lit., m.p. 80°-81°, Long, R. S., J. Am. Chem. Soc., (1947), 69, p. 990. 1NMR (CDCl3, δ) 7.95 (dd, 2H, J=7, 2 Hz, o-aryl), 7.6 (m, 3H, aryl), 4.1 (s, 2H, CH2). This benzoyl acetonitrile intermediate is also now commercially available but we prepared ours as above.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]COCC>>[NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CCOCC
Reactant: Nc1cc(Br)ccc1C(=O)O
Product: COC(=O)c1ccc(Br)cc1N
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 2-amino-4-bromobenzoic acid (500 mg, 2.3 mmol) in 20 mL of Et2O was cooled to 0° C. by ice water, and a solution of CH2N2 (145 mg, 3.5 mmol) was added. The reaction was warmed to r.t and stirred for 12 hours. The reaction mixture was concentrated to give methyl 2-amino-4-bromobenzoate 1H-NMR (400 MHz, CDCl3) δ 11.45 (s, 1H), 7.95-8.05 (in, 2H), 7.72 (d, J=8.0 Hz, 1H), 3.31 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN1CCN([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)CC1>>[CH2:2]1[C:42]2[C:41](=[CH:47][CH:46]=[C:44]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-(4-methyl-1-piperazinyl)aniline by a procedure similar to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.48-2.54 (m, 4H overlapping with d6-DMSO), 3.02-3.10 (m, 4H), 6.52 (d, 1H, J=5.2 Hz), 6.88 (d, 2H, J=8.8 Hz), 7.15 (t, 1H, J=6.0 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.46-7.66 (m, 5H), 7.85 (d, 1H, J=8.7 Hz), 8.04 (s, 1H), 8.25 (d, 1H, J=5.2 Hz), 8.45 (bd, 1H, J=8.9 Hz), 8.97 (d, 1H, J=6.9 Hz), 9.31 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=617.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[S:16][S:15][C:14](=[S:17])[CH:13]=1>>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:11][C:12]2[S:16][S:15][C:14](=[S:17])[CH:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(=S)ss1
Reactant: O=CC=Cc1ccccc1
Product: S=c1cc(C=CC=Cc2ccccc2)ss1

Procedure:
In the same manner as in Example 1, a corresponding cinnamaldehyde derivative (i.e., 4-chloro-cinnamaldehyde, 4-methoxy-cinnamaldehyde, 4-dimethylamino-cinnamaldehyde, p-methyl-cinnamaldehyde, o-chloro-cinnamaldehyde or m-methyl-cinnamaldehyde) was reacted with 5-methyl-1,2-dithiol-3-thione to prepare the following compounds.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][CH2:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]1=[O:21].[CH2:22]([CH:24]1[O:26][CH2:25]1)[Br:23].[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:2]1[C:3]2([O:26][CH:24]([CH2:22][Br:23])[CH2:25][O:21]2)[C:4]2[CH:5]=[CH:6][N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:8]=2[CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C3=O)cc1
Reactant: BrCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CBr)O2)cc1
Reaction time: 19 h
Yield: 72.3 %

Procedure:
A mixture of 5-bromo-1-p-toluenesulfonyl-4-oxo-4,5,6,7-tetrahydroindole (100 parts), epibromohydrin (1.2 molar equivalents) and stannic chloride (0.1 molar equivalent in carbon tetrachloride (1500 parts) is kept at 0° C. to 2° C. for 19 hours. The reaction mixture is carefully mixed with 5N-sodium hydroxide to adjust at pH 10, shaken and organic layer separated. By washing with water, drying and concentration, the organic layer gives 72.3% yield of 5-bromo-4'-bromomethyl-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane diastereomer mixture. Amounts show ratios to the starting 5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindol-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1.Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[N:10]=[C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)[N:8]=1
Reactant: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(C3CCCCN3)n2)c1
Yield: 5.9 %

Procedure:
To a solution of 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.144 mmol) in methanol (20 ml) was added concentrated hydrochloric acid (200 ul). The mixture was hydrogenated over palladium (5 wt % on activated carbon) at 50 psi for 6 h. The mixture was filtered through Celite. The filtrate was rotary evaporated to dryness and purified by column chromatography to give a brown oil (3 mg, 6%). 1H NMR (CDCl3): 7.83 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 6.90–6.85 (m, 3H), 6.77 (dd, J=1.8, 7.8 Hz, 1H), 3.90 (dd, J=3.0, 10.5 Hz, 1H), 3.81 (s, 3H), 3.29 (d, J=11.4 Hz, 1H), 2.88–2.80 (m, 2H), 2.25 (d, J=10.5 Hz, 1H), 1.92 (s, 1H), 1.69–1.56 (m, 4H).