Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[OH:6][CH2:7][C@H:8]([CH3:35])[C@@H:9]([NH:16][C:17]1[C:18](=[O:34])[N:19]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28]C)=O)[CH:20]=[CH:21][N:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([NH:39][C:26](=[O:28])[C:25]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:17]([NH:16][C@@H:9]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C@@H:8]([CH3:35])[CH2:7][OH:6])[C:18]3=[O:34])[CH:24]=2)[CH2:38][CH2:37]1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3ccccc3)[C@@H](C)CO)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CO)c1=O

Procedure:
A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 5.5 mL) was added dropwise to a stirred mixture of 3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 136c, 500 mg), cyclopropylamine (0.3 mL) and tetrahydrofuran (20 mL) at 0° C. After 15 min the reaction was quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give a crude title product (525 mg). Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[N:4][C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.N#N>CO.[Pd]>[NH2:8][CH2:7][C:6]1[C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[N:4][C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[C:2]([F:1])[CH:9]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reaction time: 6 h
Yield: 66.4 %

Procedure:
A solution of (R)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 11; 0.60 g, 1.44 mmol), conc. HCl (0.3 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.3 g) in MeOH (8 ml) was flushed with N2, evacuated, and then placed under of H2 (40 psi) for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml) and treated with a saturated aqueous Na2CO3 solution (100 ml). The resulting mixture was shaken vigorously for 30 min and allowed to separate. The aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were dried, filtered and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.40 g, 66%). 1H NMR (400 MHz, CD3OD) δ 7.47-7.44 (m, 2H), 7.37 (d, J=10.7 Hz, 1H), 7.06-7.02 (m, 2H), 5.10-5.06 (m, 1H), 4.57-4.51 (m, 1H), 4.28 (d, J=14.2 Hz, 1H), 4.07 (d, J=14.2 Hz, 1H), 3.92-3.80 (m, 2H), 1.32 (d, J=3.7 Hz, 6H). MS: Calcd.: 418. Found: [M+H]+ 419.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.CO[CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([I:25])[CH:23]=2)[C:18](=[O:26])[NH:17][C:16]1=[O:27]>CN(C)C=O>[I:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:26])[NH:17][C:16](=[O:27])[C:15]2=[CH:14][NH:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: COc1cnc(CN)cc1O
Solvent: CN(C)C=O
Product: COc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-methoxy-pyridin-4-ol (116 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (247 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness and treated with acetonitrile, the solid filtered and dried to give a pink solid, 293 mg, (87%); MS (ES+): m/z 451.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH2:30]([N:14]1[CH2:15][CH2:16][CH:11]([N:8]2[C:9]3[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:5]=3[CH:6]=[N:7]2)[CH2:12][CH2:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide (1 equiv.) and benzaldehyde (1.5 equiv.) in methanol (5 mL per 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 5 h. Then NaBH3CN (1 equiv.) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the residue purified by column chromatography (27%). LCMS: 548.10 (M+1)+; HPLC: 99.16% (@ 254 nm) (Rt; 5.349); 1H NMR (DMSO-d6, 400 MHz) δ 11.51 (s, 1H), 8.59 (t, 1H, J=4.8 Hz), 8.36 (s, 1H), 8.25 (s, 1H), 7.69 (d, 1H, J=1.2 Hz), 7.34 (d, 4H, J=4.4 Hz), 7.27-7.24 (m, 1H), 5.87 (s, 1H), 4.70 (m, 1H), 4.33 (d, 2H, J=4.8 Hz), 3.55 (s, 2H), 2.93 (d, 2H, J=10 Hz), 2.30-2.20 (m, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 2.09 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: COc1ccccc1CBr
Product: COc1ccccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-methoxybenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:15]4[C:14](=[O:25])[NH:13][C:12](=[O:26])[C:11]=4[C:10]=3[C:6]=2[CH:5]=[C:4]([O:27]C)[CH:3]=1.B(Br)(Br)Br>>[Br:1][C:2]1[C:7]2[O:8][C:9]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:15]4[C:14](=[O:25])[NH:13][C:12](=[O:26])[C:11]=4[C:10]=3[C:6]=2[CH:5]=[C:4]([OH:27])[CH:3]=1
Reactant: COc1cc(Br)c2oc3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Agent: BrB(Br)Br
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1oc3c(Br)cc(O)cc3c21
Yield: 98 %

Procedure:
Demethylation of (861) prepared as described in example 442 with BBr3 using the procedure described in example 80 gave (862) (98%) which was used without further purification. 1H NMR δ [(CD3)2SO] 8.04 (d, J=2.3 Hz, 1H), 7.91 (s, 1H), 7.56 (d, J=8 Hz, 1H), 7.45 (m, 3H), 7.2 (d, J=2.5 Hz, 1H). MH−:443.9, 441.9, 439.9.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(-c2cnn(C)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (52 mg, 0.11 mmol), β-alanine (596 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 26 mg of the title compound. MS: (+) m/z 524.37 (M+1).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:36]C(Cl)(Cl)Cl>>[Cl:36][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Product: ClC#Cc1ccccc1
Temperature: 24 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
In a 10 mL round-bottom flask, a mixture of 0.51 g phenylacetylene (5 mmol), 0.7 g potassium carbonate (5 mmol), 165 mg tetra-n-butylammonium fluoride trihydrate, and 3 mL tetrachloromethane was stirred at 24° C. for 10 min. After filtration of the solids, the filtrate was found to contain 0.68 g of 1-chloro-2-phenylacetylene (99% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:11]([C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([O:9][CH3:10])=[C:2]([CH3:1])[CH:7]=1)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COc1c(C)cccc1C
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)c1cc(C)c(OC)c(C)c1

Procedure:
2,6-Dimethylanisole and n-hexanoyl chloride were treated in the same way as in step (a) of Example 30 to give 4-n-hexanoyl-2,6-dimethylanisole.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Reaction time: 18 h
Yield: 70.6 %

Procedure:
To a solution of tetrahydro-3-furanmethanol (6.2 g, 60.8 mmol) in 60 mL tetrahydrofuran was added p-toluenesulfonyl chloride (11.6 g, 60.9 mmol) in one portion, followed by the drop-wise addition of triethylamine (9.2 mL, 66.4 mol) over 10 min. The resulting mixture was stirred at reflux for 16 h and then treated with triethylamine (1.6 mL, 11.5 mmol). Heating was continued for an additional 18 h. The cooled mixture was diluted with diethyl ether, washed with water and brine, and dried over MgSO4. The mixture was then filtered and concentrated under reduced pressure. The resulting residue was placed on a column of silica gel (30 g) and eluted with 5% to 80% ethyl acetate in hexanes to give 11.0 g (72%) of the title compound as an orange oil.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([CH3:8])[N:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([CH:22]=[O:23])[N:4]([CH3:8])[N:3]=1
Reactant: CN(C)C=O
Reactant: Cn1nc(Br)nc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nc(Br)nc1C=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To a solution of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (500 mg, 2.08 mmol, Eq: 1.00) in tetrahydrofuran (5 ml) was added dropwise at −45° C. under argon atmosphere n-butyllithium 1.6 M in hexane (1.56 ml, 2.49 mmol, Eq: 1.2). The resulting mixture was stirred for 30 minutes at −45° C. and was then cooled to −70° C. Then dimethyl formamide (197 mg, 209 μl, 2.7 mmol, Eq: 1.3) was added dropwise. After 15 minutes the cooling bath was removed and the mixture was allowed to reach 25° C. The mixture was stirred for additional 2 hours at 25° C. The mixture was poured on water and extracted twice with ethyl acetate, the organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtrated and evaporated, affording 5-bromo-2-methyl-2H-[1,2,4]triazole-3-carbaldehyde (218 mg/55.3%) as an orange semi solid. MS: m/e=189 (M+H+)
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.C([Li])CCC.[I:19]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[I:19][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:11]=[CH:10][N:9]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1ccnc1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1I
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 34.3 %

Procedure:
A solution of Example 191E (1.50 g, 7.56 mmol) in dry tetrahydrofuran (38 mL) at −40° C. was treated dropwise with a solution of n-butyllithium in hexanes (2.5 M, 3.93 mL, 9.83 mmol). After addition of the n-butyllithium, the solution took on a distinct light orange color. The solution was stirred at −40° C. for 45 minutes, followed by dropwise addition of a solution of iodine (2.69 g, 10.59 mmol) in dry tetrahydrofuran (18 mL) followed by warming to room temperature for 20 minutes. The solution was treated with water and with vigorous stirring, solid sodium sulfite was added to discharge the iodine color. The mixture was diluted with ethyl acetate and extracted with water and saturated sodium chloride solution. Drying (Na2SO4), filtration, and concentration in vacuo afforded an oil, which was chromatographed over a 220 g silica gel cartridge, eluting with 0-20% acetonitrile in chloroform. These procedures afforded the title compound (840 mg, 34%) as a colorless oil that crystallized upon pumping under high vacuum. MS (ESI+) m/z (rel abundance) 325 (100, M+H)+, 326 (12).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]=1[C:8]#[N:9].[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:23][CH2:22]1)(=O)[CH3:19]>>[F:13][C:12]([F:14])([F:15])[CH2:11][O:10][C:6]1[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=[C:2]([N:1]=[C:18]([N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[O:29])[CH2:23][CH2:22]2)[CH3:19])[C:7]=1[C:8]#[N:9]
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 95 %

Procedure:
The subtitle compound was prepared from 3-amino-4-cyano-5-(2,2,2-trifluoroethoxy)-anisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following a similar procedure to that described in Example 10(g) allowing the reaction to stir for 60 hours at room temperature. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 to 95:5, v/v). The product was dissolved in a minimum volume of dichloromethane and an excess of ethereal hydrogen chloride added. The resulting precipitate was filtered off and partitioned between saturated aqueous sodium hydroxide solution (100 ml ) and dichloromethane (200 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound (1.83 g, 95%). Rf 0.58 (dichloromethane:methanol:0.880 aqueous ammonia 92:7:1, v/v). MS m/z 484 (MH)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:17]1[N:18]([CH3:30])[C:19](=[O:29])[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][N:24]=2)[N:22]=1.O>CN(C)C=O>[CH2:3]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]2[N:18]([CH3:30])[C:19](=[O:29])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)[N:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1ccc(O)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(Oc2nc(-c3ccncn3)cc(=O)n2C)cc1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of sodium hydride (60 wt % in mineral oil, 202 mg, 5.05 mmol) in N,N-dimethylformamide (1.0 ml) was added 4-hexylphenol (899 mg, 5.04 mmol) at room temperature, and stirred for one hour. 2-Chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (935 mg, 4.20 mmol) was added to the solution. The mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=50/50) to afford 2-(4-hexylphenoxy)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (1.14 g, 3.13 mmol, 75%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH:18]([C:24](O)=[O:25])[CH2:17]2.C(N(CC)CC)C.ClC(OCC)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O1CCCC1>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH:18]([C:24]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:25])[CH2:17]2
Reactant: C1COCCN1
Reactant: CCN1CC(C(=O)O)Cc2cccc(CSc3nc4ccccc4[nH]3)c21
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CC(C(=O)N2CCOCC2)Cc2cccc(CSc3nc4ccccc4[nH]3)c21
Yield: 45.3 %

Procedure:
To a solution of 8-(2-benzimidazolyl)thiomethyl-1-ethyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (1.3 g) in tetrahydrofuran (50 ml) were added dropwise triethylamine (0.4 g) and ethyl chloroformate (0.4 g) with stirring under ice-cooling and the mixture was stirred for 30 minutes. Moreover morpholine (0.4 g) was added dropwise thereto and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off and the resulting residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:dichloromethane-methanol (200:1)], and recrystallized from ethyl acetate-ethanol to give 8-(2-benzimidazolyl)thiomethyl-3-morpholinocarbonyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.7 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1>>[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@@H:27]([NH:30][CH2:2][CH2:3][OH:4])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: Cc1cncc2cccc(N[C@H]3CC[C@@H](N)CC3)c12
Agent: Cl
Product: Cc1cncc2cccc(N[C@H]3CC[C@@H](NCCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 120 to obtain the title compound.
Reaction SMILES: [S:1](OCCOC1C=CC(C)=CC=1)(=[O:4])(=[O:3])[NH2:2].[CH3:16][C:17]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH2:18][OH:19].S(Cl)(=O)(=O)N.ClS(N=C=O)(=O)=O.C(N(CC)CC)C.O>C(#N)C>[S:1]([O:19][CH2:18][C:17]([CH3:16])([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])(=[O:4])(=[O:3])[NH2:2]
Reactant: Cc1ccc(OCCOS(N)(=O)=O)cc1
Reactant: CC(C)(CO)Oc1ccccc1
Agent: NS(=O)(=O)Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(COS(N)(=O)=O)Oc1ccccc1
Yield: 28 %

Procedure:
This compound was prepared by the procedure used to synthesize 2-(4-methylphenoxy)ethanol sulfamate in Example 33. Thus, 13.2 g (0.0794 mole) of 2-methyl-2-phenoxypropanol was reacted with sulfamoyl chloride prepared from 26.5 ml (0.298 mole) of chlorosulfonyl isocyanate (98%, Aldrich), 33.9 g (0.336 mole) of triethylamine, and 5.3 g (0.294 mole) of water in 250 ml of acetonitrile. The 12.4 g of a viscous, oily residue obtained was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrePAK 500® silica; methylene chloride), then by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride). Fractions containing title compound were combined and the solvent was evaporated under reduced pressure to give 5.4 g (28%) of a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.COC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC=CC=3)=C2C(OCC)=O)=CC=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Reaction time: 24 h

Procedure:
Ethyl (1RS,2SR,3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylate. To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-phenylindene-2-carboxylate (5.75 g, 15 mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg). The resulting suspension was stirred under an atmosphere of H2 for 1 d, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound, which was used without further purification.
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][NH:9][CH2:10]2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([OH:13])[CH2:5]1.[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33](O)=[O:34])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[OH:2][CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9]([C:33](=[O:34])[CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:10]2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([OH:13])[CH2:5]1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Reactant: OCC1CC2CNCC2C(O)(c2ccccc2F)C1
Agent: Cl
Product: O=C(Cc1ccccc1N1CCCC1)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Yield: 18.3 %

Procedure:
The procedure is as described for Example 14, starting from 0.73 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)perhydroisoindol-4-ol hydrochloride and 0.68 g of 2-(1-pyrrolidinyl)phenylacetic acid, and gives 0.2 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol in the form of a thick white foam.