Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>O1CCOCC1>[CH:28]1([NH:31][C:2]2[N:7]=[CH:6][C:5]([N:8]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:11][C:10]([C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[O:20])=[N:9]3)=[CH:4][CH:3]=2)[CH2:30][CH2:29]1
Reactant: CN1CCN(C(=O)c2cc(-c3ccccc3)n(-c3ccc(Cl)nc3)n2)CC1
Reactant: NC1CC1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)c2cc(-c3ccccc3)n(-c3ccc(NC4CC4)nc3)n2)CC1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 1-[1-(6-chloro-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-methylpiperazine (200 mg) obtained in Example 110 in dioxane (1.0 mL), cyclopropylamine (1.0 mL) was added. The mixture was stirred at 100° C. for 3 days in a sealed tube, and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated aqueous sodium hydrogencarbonate, and then dried over magnesium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1 mL). The solution was purified through preparative high-performance liquid chromatography (eluent: water-acetonitrile), to thereby give the title compound as an oily product (19.6 mg, 9%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[OH-].[Na+].[C:9](#[N:12])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1>[C:9]([CH2:10][CH2:11][N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])#[N:12]
Reactant: O=C1NCCO1
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCCN1CCOC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Compound 18 was prepared by modification of a reported procedure by Lynn (U.S. Pat. No. 2,975,187). To a vigorously stirred mixture of 2-oxazolidinone (87 g, 1 mol), 50% sodium hydroxide (w/w, 4 g) and toluene (250 mL) maintained at 55°-60° C., acrylonitrile (106 g, 2 mol) was added dropwise over a period of 30 min. The mixture was then stirred at 80° C. for 1 h and refluxed for 3 h. Additional acrylonitrile (50 mL) was added towards the end of the reaction to drive it to completion. Excess acrylonitrile was removed by distillation, and the residue was left at room temperature overnight. The mixture was filtered, cooled in an ice bath and acidified with concentrated H2SO4 to ~ pH 1. The salt was removed by filtration, and the filtrate was dried over anhydrous MgSO4. The residue obtained after removal of the solvent under vacuum was dried under high vacuum overnight to give 117 g (84%) of 18 as a colorless oil: 1H NMR (CDCl3) δ 2.68 (t, 2, CH2CH2CN), 3.57 (t, 2, NCH2CH 2), 3.75 (t, 2, NCH2CH2O) and 4.39 (t, 2, CH2H2O--).
Reaction SMILES: [F:1][CH2:2][C@H:3]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=2)=[C:15]([NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:14]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OC(=O)NC1C=CC(SC2C=CC(C(=O)N[C@H](C3C=CC=CC=3)C)=CC=2NC2C3C=CC(C(C)C)=NC=3N=CN=2)=CC=1)(C)(C)C>>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]([NH:10][C@H:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:2][F:1])=[O:12])=[CH:14][C:15]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](CF)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](CF)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Yield: 71 %

Procedure:
The title compound was prepared (yield 71%) by the procedure of Example 385G substituting the product of Example 448B for the product of Example 385F. 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 3.23 (septet, J=7.0 Hz, 1H), 4.48-4.79 (m, 2H), 5.32-5.49 (m, 1H), 6.62 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.5 Hz, 2H), 7.28 (t, J=7.0 Hz, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.43 (d, J=7.0 Hz, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.73 (br-d, J=8.4 Hz, 1H), 7.88 (br-s, 1H), 8.61 (br-s, 1H), 8.89 (d, J=8.1 Hz, 1H), 9.00 (d, J=8.1 Hz, 1H), 10.45 (br-s, 1H) MS ESI+ m/z: 553 (M+H), ESI− m/z: 551 (M+H).
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][N:14]=2)=[C:3]1[OH:26].C(O)(C)C>C(O)(=O)C.[Fe]>[OH:26][C:3]1[NH:2][C:10]2[C:5]([C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:15][N:14]=1)=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(CN3CCOCC3)cn1)c(O)n2O
Agent: [Fe]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a solution of 1,2-Dihydroxy-3-(5-morpholin-4-ylmethyl-pyridin-2-yl)-1H-indole-5-carbonitrile (1.0 g, 94% pure, 10.73 mmol) in acetic acid (60 ml) at 60° C. was added iron powder (1.8 g, 32.19 mmol) and the resulting dark green solution stirred at 60° C. for 3 hrs. The suspension was removed from the oil bath and cooled to room temperature. Celite® (10 g) was added and the mixture concentrated to dryness. The mixture was then purified by silica column chromatography eluting with dichloromethane/methanol (1% ammonium hydroxide) 5:1 to give an orange solid; which was reslurried with isopropanol, filtered and then washed with isopropanol. After drying at 50° C. under vacuum gave, 2.89 g, 81% yield of 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile as a yellow powder. 1H NMR (400 MHz; CDCl3,): δ 14.76 (br s, 1H), 10.9 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.77 (m, 2H), 7.26 (dd, J=1.08, 7.97 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.55 (m, 4H), 3.35 (s, 2H), 2.35 (br s, 4H); 13C NMR: (100 MHz, CDCl3): δ 169.2, 148.9, 142.5, 1367.5, 136.4, 125.7, 124.5, 122.8, 121.8, 121.5, 119.3, 118.8, 101.8, 84.9, 66.6, 58.8, 53.3 ppm; MS (ESI) m/z [M+1]+ 335.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(c1ccc(O)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(c1ccc(OCCCCBr)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A solution of 6.63 g (20 mmol) of N-(4-Hydroxy-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide in 150 ml of DMF was treated with 7.1 ml (60 mmol) of 1,4-dibromobutane and with 1.00 g (23 mmol) of 55% NaH (in small portions) at 0° C. The reaction mixture was stirred for 4 h at RT, poured into cooled aqueous saturated NH4Cl and extracted (Et2O 3×). The organic phase was washed with aqueous 10% NaCl, dried (NaSO4) evaporated and purified by flash silica gel column (first with hexane to remove the dibromobutane and then Hexane/EtOAc 95:5) to yield 7.7 g (83%) of N-[4-(4-Bromo-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, mp: 91-92° C.; MS: 465 (M, 1 Br).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([N:14]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16][CH2:15]3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[N:14]([C:12]1[O:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)=[N:10][N:11]=1)[CH2:15][CH2:16]2
Reactant: COc1ccc(-c2nnc(N3CCN4CCC3CC4)o2)cc1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: Oc1ccc(-c2nnc(N3CCN4CCC3CC4)o2)cc1
Temperature: -63 °C

Procedure:
A mixture of 4-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane (1.0 g, 3.3 mmol) and chloroform (20 ml) was cooled to −63° C. A mixture of boron tribromide (5.4 g, 21.6 mmol) and chloroform (10 ml) was added at 60° C. The mixture was allowed to reach room-temperature. The crude mixture was purified by column chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent and gave the title compound. LC-ESI-HRMS of [M+H]+ shows 287.1514 Da. Calc. 287.150801 Da, dev. 2.1 ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:20]([O:30][CH3:31])[CH:19]=3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:32]>C(Cl)Cl.C(OCC)C>[ClH:32].[ClH:32].[ClH:32].[CH3:31][O:30][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[S:16][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[N:14]=2)[CH:23]=[CH:22][C:21]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1
Reactant: COc1cc(Nc2nc3c(s2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
1347 mg (3.05 mmol) 2-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester was suspended in methylene chloride (30.5 ml) and 2M HCl in diethyl ether (15.3 ml) was added at room temperature. Initially a clear solution was obtained and then a solid precipitated. The reaction was stirred at room temperature over night. The reaction was diluted with diethyl ether, stirred for 15 minutes and the solid was filtered off, washed with diethyl ether and dried to yield 1370 mg (100%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride as a light yellow solid. MS ISP (m/e): 342.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.91 (s, 1H), 9.68 (br, 2H), 9.31 (s, 1H), 7.66 (s, 2H), 7.48 (d, 1H), 7.45 (d, 1H), 4.22 (br s, 2H), 3.84 (s, 3H), 3.38 (m, 2H), 2.88 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[C:7](=[O:13])[NH:6][N:5]=1)[CH2:2][CH3:3].C[O-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19].Cl>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:19]([N:5]1[CH:4]([CH2:1][CH2:2][CH3:3])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[C:7](=[O:13])[NH:6]1)[CH:18]=[CH2:17]
Reactant: CCCc1n[nH]c(=O)c2cncn12
Reactant: C=CCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCN1NC(=O)c2cncn2C1CCC
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of 4-n-propyl-imidazo[1,5-d]-as-triazin-1(2H)-one (0.01 mol) in dimethylformamide (50 ml) is added sodium methoxide (0.01 mol) followed by the addition of allyl bromide (0.012 mol). The reaction mixture is stirred at 20° C. for 16 hours, then heated at 40° C. for 45 minutes, cooled and poured on a mixture of ice and dilute hydrochloric acid. The product is isolated by extraction with chloroform and evaporation. It is purified by recrystallization from cyclohexane or a cyclohexane-benzene mixture; or by silica gel dry column chromatography in chloroform.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)c2ccccc2)nn1
Yield: 65 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using benzoyl chloride instead of methoxyacetyl chloride, to the title compound (250 mg, 65%) which was obtained as a white solid. MS: m/e=387.4 [M+H]−.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:19][CH2:18]1)[CH3:3].[CH3:36][S:37]([C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[CH:44][C:40]=1[C:41](O)=[O:42])=[O:38]>>[CH3:36][S:37]([C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[CH:44][C:40]=1[C:41]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:18][CH2:19]2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26]1)=[O:42])=[O:38]
Reactant: CS(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4S(C)=O)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoic acid to give the title compound.
Reaction SMILES: C[O:2][C:3]1([O:9][CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:11][C:12]([O:16]O)([CH3:15])[CH2:13][CH3:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>[CH3:10][O:9][C:3]1([O:2][O:16][C:12]([CH3:15])([CH3:11])[CH2:13][CH3:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(OC)CCCCC1
Reactant: CCC(C)(C)OO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: CCC(C)(C)OOC1(OC)CCCCC1
Yield: 77.4 %

Procedure:
A mixed solution consisting of 15.9 g of dimethyl sulfoxide and 1.2 g of p-toluenesulfonic acid was kept at 20° C., into which was added dropwise another solution consisting of 29.1 g of cyclohexanone-dimethylacetal and 21.1 g of 1,1-dimethylpropyl hydroperoxide. The resulting solution had an acid concentration of 0.1 mol/kg of the solution. The solution was treated in the same manner as described in Example 1 to obtain 33.8 g (yield: 67%) of crude 1-methoxy-1-(1,1-dimethylpropylperoxy)cyclohexane having a purity of 86%. The resulting crude peroxyketal was distilled at 43°-45° C. under a vacuum of 0.1 mmHg to obtain a purified peroxyketal having a purity of 98%.
Reaction SMILES: [CH2:1]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].CS(O[CH2:27][C:28]1[C:29]([CH3:41])=[N:30][C:31]([CH3:40])=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH2:1]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:27][C:28]3[C:29]([CH3:41])=[N:30][C:31]([CH3:40])=[CH:32][C:33]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(-c2ccccc2)c(COS(C)(=O)=O)c(C)n1
Reactant: CCCCN1Cc2cc(O)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN1Cc2cc(OCc3c(-c4ccccc4)cc(C)nc3C)ccc2C1=O
Yield: 19.6 %

Procedure:
2-Butyl-5-hydroxyisoindolin-1-one (366 mg, 1.78 mmol), K2CO3 (493 mg, 3.57 mmol) and KI (296 mg, 1.78 mmol) were added to a solution of (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate (520 mg, 1.78 mmol) in DMF (18 mL). After stirring overnight at room temperature (rt), water was added and the pH was adjusted to 13-14 using aqueous NaOH (1 M). The reaction mixture was extracted with EtOAc, the combined organic layers were washed with water, dried with MgSO4 and the solvent was removed in vacuo. Purification by flash chromatography (DCM/MeOH, gradient 1-5% MeOH) provided 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one (140 mg, 19%). ESI-MS [M+H]+=401.2.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12].CN(C)C(N(C)C)=N>C1COCC1>[F:9][C:10]([F:17])([F:16])[C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C(O)[C@H]1CCCN1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCN1C(=O)C(F)(F)F

Procedure:
(R)-proline (20 g, 0.174 mol) was placed in a 500 mL round-bottom flask. To this was added 100 mL THF and ethyl trifluoroacetate (50 g, 0.34 mol). The solution was purged with argon and 1,1,3,3-tetramethylguanidine (30 g, 0.261 mol) was added dropwise. The solution was allowed to stir until all the (R)-proline had dissolved (approximately 35 minutes). The solvent was removed in vacuo and the residue dissolved in CH2Cl2 (200 mL). The solution was washed with 6N HCl (aqueous, 2×100 mL). The organic layer was separated and dried with Na2SO4, filtered and the solvent removed in vacuo to give as an oil which crystallized upon standing; yield 29 g (79%), m.p. 48°-51° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:15].[NH2:16]O>N1C=CC=CC=1>[ClH:15].[CH3:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:16])[CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCC(=O)c1ccc(C(=O)O)c(C)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCC(N)c1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a mixture of methyl 4-propionyl benzoic acid (0.50 g) and pyridine (5.0 mL) was added hydroxylamine hydrochloride (0.54 g) under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, to the residue were added ethyl acetate and a 10% aqueous citric acid solution and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, and washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and to the residue was added ethanol (15 mL). To the reaction mixture were added a suspension of Raney nickel (2.0 mL) in ethanol (15 mL), and concentrated aqueous ammonia (3.0 mL), followed by stirring at room temperature for 14 hours under a hydrogen atmosphere of 3 atm. The insoluble materials in the reaction mixture were separated by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether (10 mL), and a 4 M-hydrogen chloride/dioxane solution (1.0 mL) was added thereto under ice-cooling. The precipitated crystal was collected by filtration and washed with diethyl ether to obtain methyl 4-(1-amino propyl)benzoic acid hydrochloride (0.51 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C@H:9]1[CH2:14][O:13][CH2:12][CH2:11][N:10]1S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH3:8].BrC1C=CC(S)=CC=1.[Br:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][C@@H:9]2[CH2:7][CH3:8])=[O:41])=[CH:38][CH:37]=1
Reactant: CC[C@H]1COCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC[C@H]1COCCN1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
Potassium carbonate (49.1 mg, 0.355 mmol) was added to a solution of 89 mg (0.296 mmol) of the title compound produced in step (iii) of Reference Example 9 in N,N-dimethylformamide (1.0 ml), and the mixture was stirred at room temperature for 5 min. 4-Bromobenzenethiol (56.0 mg, 0.296 mmol) was added thereto, and the mixture was stirred at room temperature for 5 hr. Thereafter, N,N-dimethylformamide (1.0 ml), 119.0 mg (0.592 mmol) of 4-bromobenzoic acid, 80.0 mg (0.592 mmol) of 1-hydroxybenzotriazole, and 119.0 mg (0.592 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were successively added thereto, and the mixture was stirred at room temperature for 4.5 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto to stop the reaction, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure and was then purified by preparative thin layer chromatography (hexane:ethyl acetate=1:4) to give 64 mg (2 steps, yield 72%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:43][CH2:44][O:45][CH2:46][CH3:47])[CH3:42])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][N:41]([C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)[CH3:42])[CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCN(C)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-[N-(2-ethoxyethyl)-N-methylamino]phenyl borate (168 mg) and potassium carbonate (176 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give yellow crystals of 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 70) (235 mg).