Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: NCc1cc(Cl)ccc1Cl
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cc(Cl)ccc1Cl)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.06 (s, 1H), 7.32 (d, J 8.4, 1H), 7.44 (d, J 8.4, 1H), 7.51 (s, 1H), 7.78 (t, J 7.8, 1H), 7.90 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.26 (d, J 6.4, 1H), 8.60 (d, J 6.2, 1H), 8.65 (t, J 5.8, 1H), 9.49 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[N:3]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=2)[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)n(-c2ccc(C(=O)O)cc2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C)n(-c2ccc(C(=O)Cl)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
To a suspension of 4-(3,5-dimethylpyrazol-1-yl)benzoic acid (1.34 g) in dichloromethane (25 ml) was added oxalyl chloride (1.0 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo yielded 4-(3,5-dimethylpyrazol-1-yl)benzoyl chloride (0.80 g), which was used without further purification.
Reaction SMILES: ICCO[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7](=[O:15])[C:6]=1OCCI.[C:20](=[O:23])([O-])[O-:21].[Na+].[Na+].[C:26](#N)[CH3:27]>>[C:20]([C:6]1[C:7](=[O:15])[O:8][C:9]2[C:14]([CH:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:21][CH2:26][CH3:27])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2ccccc2c(OCCI)c1OCCI
Reactant: CC#N
Agent: [Na+]
Product: CCOC(=O)c1cc2ccccc2oc1=O

Procedure:
A 1.0 g (1.8 mmol) sample of bis-iodoethoxy-coumarin (from Example 32 or Example 34) and 0.47 g (1.8 mmol) of 1,4,10,13-tetraoxa-7,16-diazacycloctadecane (i.e., 4,13-diaza-18-crown-6) were separately dissolved in 50 ml portions of dry acetonitrile. The combined solutions (100 ml total) were refluxed under nitrogen for six days in the presence of 5 equivalents (0.94 g) anhydrous sodium carbonate. During the reaction, the coarse sodium carbonate was converted to an extremely fine powder. The cooled reaction mixture was filtered and the solution was evaporated to dryness in vacuo. The residue was dissolved in methylene chloride, and the solution was filtered. Evaporation of the methylene chloride using the rotary evaporator at aspirator pressure, followed by oil pump pressure, gave a yellow foam (>100% of the calculated yield). The crude product was purified by chromatography on deactivated neutral alumina first using methylene chloride to elute unreacted starting materials, followed by a 1-5% ethanol/methylene chloride mixture to elute the product. About 50% of calculated amount of the product was recovered, consisting essentially of the desired product (VI). LRMS FAB (triethanolamine) calculated m/e for C28H40N2O10 was 564.27, whereas the observed m/e was 587, [VIII(Na)] +; free [VII]+ was not observed. UV (phosphate buffered saline) Imax =374 nm, 312 nm. Fluorescence (phosphate buffered saline) showed Iex =371 nm and Icm =453 nm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30][CH3:31])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH3:34])[C:43]([CH3:44])=[O:45])=[CH:20][CH:21]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 127.6 %

Procedure:
The compound (182.6 mg) obtained in Example 21-4 was dissolved in chloroform (7.0 ml) and added with triethylamine (0.133 ml) and acetic anhydride (73.5 mg) and the whole was stirred at room temperature for 24 hours. The reaction solution was added with water, subjected to extraction with chloroform, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (253.2 mg) as a colorless oily substance.
Reaction SMILES: [CH2:1]1C2[C:5](=[CH:6][CH:7]=[CH:8]C=2)[CH:4]=[CH:3][CH2:2]1.C[N+]1([O-])[CH2:17][CH2:16][O:15]CC1.CC(C)=[O:21]>O=[Os](=O)(=O)=O.O>[C@@H:16]1([OH:15])[C:17]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2][C@@H:1]1[OH:21]
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1=Cc2ccccc2CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O[C@@H]1c2ccccc2CC[C@@H]1O

Procedure:
Alternatively, 1,2-dihydronaphthalene (V) is treated with OsO4 and NMMO in a suitable solvent, such as a mixture of acetone and water, at -60° to +20° C., preferably at about 0° C., for 10 to 48 hours, preferably about 26 hours, to give cis-1,2,3,4-tetrahydro-1,2-napthalenediol. The treatment with OsO4 and NMMO can optionally be carried out in the presence of hydroquinine 4-chlorobenzoate, as described in Sharpless, et al, J. Org. Chem., 57, 2768-2771 (1992), in which case predominantly one enantiomer of the cis-diol is produced. The diol is treated with (C6H5)3 PBr2 in the presence of a tertiary amine base, preferably triethylamine, in a suitable solvent, such as CH3CN, at 0° to 50° C., preferably at about 25° C., for 10 to 30 hours, preferably about 20 hours, to form predominantly one enantiomer of the epoxide XI, having the absolute stereochemistry indicated in Reaction Scheme C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([NH2:38])[CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH:30]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:38][C:27]4[CH:28]=[C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)[CH:30]=[C:25]([Cl:24])[CH:26]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1CCN(c2cc(N)cc(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(Cl)cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)c2)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (88.0 mg, 0.263 mmol), 3-chloro-5-(4-methylpiperazin-1-yl)-phenylamine (71.2 mg, 0.316 mmol), trifluoroacetic acid (203 μL, 2.63 mmol), and DMF (2 mL) was stirred in a sealed tube at 70° C. for 18 h. The mixture was concentrated in vacuo, sodium bicarbonate (221 mg, 2.63 mmol), di-tert-butyldicarbonate (86.1 mg, 0.394 mmol), and DMF (2 mL) were added to the residue, and the resulting mixture was stirred at rt under N2 for 16 h. After that time, the mixture was filtered, and the filtrate was concentrated in vacuo and submitted for MS-directed purification. One obtained the title compound as light-brown solid. 1H NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (brs, 2H), 2.86 (s, 3H), 3.29 (brs, 4H), 3.46 (brs, 4H), 3.67 (brs, 2H), 4.13 (brs, 2H), 6.29 (brs, 1H), 6.68 (s, 1H), 6.74 (s 1H), 7.44 (s, 1H), 7.47 (s, 1H), 8.28 (s, 1H). M (ES+): m/z 523.99/525.95(100/40) [MH+]. HPLC: tR (polar—5 mins)=2.28 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[C:17]1[C:21]([CH3:22])=[CH:20][NH:19][N:18]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[Cl:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[C:17]1[C:21]([CH3:22])=[CH:20][N:19]([CH:2]([CH2:8][CH3:23])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[N:18]=1
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1ccc(-c2n[nH]cc2C)c(Cl)c1
Reactant: Cc1c[nH]nc1-c1ccccc1
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccc(C)cc2Cl)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-(2-chloro-4-methylphenyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole there is obtained 3-(2-chloro-4-methylphenyl)-α-ethyl-N,N,4-trimethylpyrazole-1-acetamide isolated as an oil.
Reaction SMILES: [K+].[CH3:2][S:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([C:17]([O-:19])=O)=[CH:6][N:5]=1.[C:20]1([C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][C:27]=2[NH2:40])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]1([C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH:29]=[CH:28][C:27]=2[NH:40][C:17]([C:7]2[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[C:4]([S:3][CH3:2])=[N:5][CH:6]=2)=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: Nc1ccc(CCN2CCOCC2)cc1C1=CCCCC1
Reactant: CSc1ncc(C(=O)[O-])n1COCC[Si](C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2ccc(CCN3CCOCC3)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 2-methylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylate potassium salt (90 mg, 0.28 mmol)(as prepared in the previous step), 2-cyclohex-1-enyl-4-(2-morpholin-4-yl-ethyl)-phenylamine (81 mg, 0.28 mmol)(as prepared in Example 33, step (c)), PyBrOP (170 mg, 0.37 mmol), and DIEA (0.10 mL, 0.57 mmol) in 1.5 mL of DCM was stirred for 8 h at RT. The mixture was diluted with 20 mL of DCM and washed with NaHCO3 (2×30 mL) and brine (30 mL) and dried over Na2SO4. Flash chromatography of the residue on Si gel with 100% EtOAc gave the title compound as a white solid (107 mg, 70%). Mass spectrum (ESI, m/z): Calcd. for C29H44N4O3SSi, 557.3 (M+H). found 556.8.
Reaction SMILES: [Mg].II.[CH:4]1(Br)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:11][N:12]1[CH2:35][CH2:34][C:15]2[N:16]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:26])[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.C1([Mg]Br)CCCCC1>C1COCC1>[CH:4]1([C:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)([OH:26])[CH2:24][N:16]2[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=3[C:14]3[CH2:13][N:12]([CH3:11])[CH2:35][CH2:34][C:15]2=3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Reactant: BrC1CCCCC1
Agent: Br[Mg]C1CCCCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccc(F)cc2)C2CCCCC2)CCN(C)C1
Reaction time: 0.25 h

Procedure:
Activated magnesium turnings (480 mg, 20 g/atom) and 2-3 crystals of iodine were stirred under anhydrous conditions. The excess of iodine was removed by heating with a heat gun. The magnesium turnings were now yellow in color. To this was added diethyl ether (15 mL) at 0° C. and stirred for 15 min. (until the color of the magnesium becomes white). To this was added cyclohexyl bromide (2.5 mL, 20 mmol) dropwise with constant stirring. The reaction mixture was stirred until a dark grey-colored solution was obtained. Into a separate flask was placed 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone (168 mg, 5 mmol) in THF under anhydrous conditions. The solution of the prepared cyclohexylmagnesium bromide (5 mL) was added dropwise. After addition, the mixture was allowed to come to RT and stirred at RT for 2 h. The reaction was monitored by TLC and NMR. The reaction was quenched with ice water and the product extracted into EtOAc. The organic extracts were concentrated and the residue purified by silica gel column chromatography (#100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.25 (m, 2H), 7.10 (d, 1H), 6.92 (m, 1H), 6.80 (m, 3H), 4.60 (m, 1H), 4.65 (m, 1H), 4.22 (m, 2H), 3.70 (m, 1H), 3.40 (m, 1H), 3.20 (m, 2H), 3.0 (s, 3H), 2.70 (m, 1H), 2.38 (s, 3H), 2.20 (m, 2H), 1.80 (m, 2H), 1.70 (m, 3H), 1.50-1.20 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][C:31](O)([CH:33]=[CH2:34])[CH3:32]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:31]([CH3:32])([CH3:30])[CH:33]=[CH2:34])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Reactant: C=CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using the procedure of Step A of Example 15, 2 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-carboxy-ethynyl]-cyclopropane-carboxylate, 3 ml of 2-methyl-3-buten-2-ol and 150 mg of 4-dimethylamino-pyridine were admixed at 0° C. with 1.06 g of dicyclohexycarbodiimide in 3 ml of methylene chloride and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 700 mg of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-(1,1-dimethylallyloxycarbonyl)-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 23.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.090 g, 0.190 mmol) obtained in step 2 and methanesulfonamide (0.094 g, 0.951 mmol), the title compound (0.025 g, 24%) was obtained.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:26])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO.C(#N)C.O1CCCC1>[NH2:33][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:26])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(CC(=O)N(C)C)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(CC(=O)N(C)C)CC1
Temperature: 65 °C

Procedure:
A mixture of 2-[4-(7-acetyl-5-chloroquinolin-8-yl)piperazin-1-yl]-N,N-dimethylacetamide (0.019 g, 0.051 mmol) and ammonium acetate (0.0391 g, 0.507 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.12 mL). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H27ClN5O (M+H)+: m/z=376.2; Found: 376.2.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[N:36]1[C:45]2[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([NH:46][C:42]1[CH:41]=[C:40]2[C:45](=[CH:44][CH:43]=1)[N:36]=[CH:37][CH:38]=[CH:39]2)=[O:26])(=[O:7])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: O=C(Nc1ccc2ncccc2c1)[C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 6-quinolinamine the title compound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=533.6.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C@H:14]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[NH2:15]>C(O)C>[CH3:13][C@@H:14]([NH:15][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc2nnnn2c1

Procedure:
A solution of 325 mg of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 300 mg of (R)-α-methyltryptamine in 6 ml of absolute ethanol is heated at reflux under nitrogen for two hours. The reaction mixture is concentrated and the residue purified by silica gel chromatography to give (R)-α-[[(1(R)-methyl-2-(1H-indol-3-yl)ethyl)amino]-methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [NH2:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[O:6][C:7]([CH3:18])([CH3:17])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:14][CH2:13][CH2:12][C:11]3=[O:15])[C:4]=2[CH:3]=1.[N+](C1C(NC(=O)C)=C[C:30]2[O:31]C(C)(C)[C@@H](O)[C@H](N3CCCC3=O)[C:29]=2C=1)([O-])=O.[N+](C1C(N)=CC2OC(C)(C)[C@@H](O)[C@H](N3CCCC3=O)C=2C=1)([O-])=O.C(C1C(N)=CC2OC(C)(C)[C@@H](O)[C@H](N3CCCC3=O)C=2C=1)#N>>[C:30]([NH:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[O:6][C:7]([CH3:17])([CH3:18])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:14][CH2:13][CH2:12][C:11]3=[O:15])[C:4]=2[CH:3]=1)(=[O:31])[CH3:29]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Agent: CC1(C)Oc2cc(N)c(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Agent: CC1(C)Oc2cc(N)c([N+](=O)[O-])cc2[C@@H](N2CCCC2=O)[C@@H]1O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H](O)[C@@H]2N1CCCC1=O

Procedure:
6-amino-7-nitro-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically acceptable salt thereof; 6-nitro-7-acetamido-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol; 6-nitro-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically salt thereof; or 6-cyano-7-amino-3,4-dihydro-trans-4-(2-ketopyrrolidinyl)-2,2-dimethyl-2H-benzo[b]pyran-3-ol or a pharmaceutically acceptable salt thereof.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[N:24]=[C:25]([CH3:28])[S:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.C([O-])(=O)C.[Na+]>O>[CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[N:24]=[C:25]([CH3:28])[S:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)O)cc1

Procedure:
A mixture of methyl Z-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate (0.428 g, 0.65 mmol) and 2N HCl (12 mL) is refluxed for 1 hour in which time all the solid dissolved. Solvents are removed in vacuo and the mixture is evaporated from ethanol (5 mL) three times. The solid that results is treated with 5% aqueous sodium acetate (10 mL) and water (10 mL) to precipitate a gummy solid which is dissolved in methylene chloride (30 mL). The organic layer is dried over Na2SO4 and then evaporated in vacuo. The residue is recrystallized from hot ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:24][C:25]2[C:34]3[C:29](=[C:30]([C:35]([O:37]C)=O)[CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:39])[N:26]=2)[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[NH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:24][C:25]2[C:34]3[C:29](=[C:30]([C:35]([NH2:40])=[O:37])[CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH3:39])[N:26]=2)[CH2:9][N:10]([CH3:23])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c(N[C@H](CN(C)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c3ccc(F)cc3)nc(C)nc12
Reactant: N
Product: Cc1nc(N[C@H](CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(F)cc2)c2cccc(C(N)=O)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Crude methyl 4-[((1S)-1-(4-fluorophenyl)-2-{methyl[(4-nitrophenyl)sulfonyl]-amino}ethyl)amino]-2-methylquinazoline-8-carboxylate (177 mg; 0.32 mmol) was treated with methanolic ammonia (10 ml, 7M), and stirred at 70° C. overnight. The reaction mixture was concentrated to provide the desired crude intermediate. (M+H) 539.1