Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[NH:23][CH2:22]1.[H-].[Na+]>CN(C=O)C>[CH3:20][C:21]1([CH3:36])[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[N:23]([C:2]2[C:11]3[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH2:22]1
Reactant: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2c(F)cccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (235 mg, 0.86 mmol), 4-(3,3-dimethylindolin-6-yl)morpholine (200 mg, 0.86 mmol), sodium hydride (41 mg, 1.72 mmol) in DMF (2.0 mL) and heating at 130° C. for 4 h. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-8-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.64-8.79 (1H, m), 7.87-7.98 (2H, m), 7.60-7.65 (1H, m), 7.32-7.42 (3H, m), 7.08 (1H, d, J=7.8 Hz), 6.31 (1H, dd, J=8.0, 2.2 Hz), 5.59 (1H, d, J=2.3 Hz), 3.63-3.83 (6H, m), 2.86-3.05 (4H, m), 2.43 (3H, s), 1.52 (3H, s), 1.47 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH:24]=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH2:24][NH:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Cc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of 4-benzyl aniline (200 mg, 1.1 mmol) in dichloroethane (1.5 mL) was added a solution of N-(t-butoxycarbonyl)-D-prolinal (239 mg, 1.2 mmol) in dichloroethane (1.5 mL) at 0-5° C. Sodium triacetoxyborohydride (393 mg, 1.85 mmol) was added to the above solution. Acetic acid (65 mg, 1.1 mmol) in dichloroethane (1 mL) was added dropwise, over a period of 5 min at 0-5° C. The reaction mixture was stirred at 0-10° C. for 3 h. The mixture was diluted with saturated aq NaHCO3 and extracted with dichloromethane. Organic layer was dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (340 mg, 85%).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH:10]1([CH2:9][NH:8][C:6]([C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][N:27]=[C:26]([N:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH:25]=4)[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)=[O:7])[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cn1
Yield: 59.3 %

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1)(25 mg, 0.098 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide (Intermediate 18)(30 mg, 0.074 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 80° C. in DMF (1 ml) for 18 hours. The reaction was absorbed onto silica, applied to a bond-elut (10 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%), then acetone and methanol. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-(3-[5-(cyclopropylmethyl-carbamoyl)-pyridin-2-yl]-4-methyl-phenyl)-2-pyrrolidin-1-yl-isonicotinamide as a white solid (20 mg). LCMS: retention time 2.42 min, MH+ 456. NMR: δH [2H6]-DMSO 10.32,(1H, s), 9.09,(1H, s), 8.82,(1H, t), 8.28,(1H, m), 8.19,(1H, m), 7.85,(1H, t), 7.76,(1H, m), 7.64,(1H, m), 7.31, (1H, m), 6.98,(1H, m), 6.88,(1H, s), 3.43,(4H, m), 3.18,(2H, in), 2.31,(3H, s), 1.95,(4H, m), 1.07,(1H, m), 0.45,(2H, m), 0.25,(2H, m).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H][H].[C:13]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1)=[O:14]>CN(C)C=O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc(O)cc1
Reactant: O=C1OCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a stirred suspension of 24.0 g. (0.5 mole) of a 50% dispersion of sodium hydride in mineral oil in 150 ml. of dimethylformamide under nitrogen was added dropwise 50.4 g. (0.5 mole) of 4-methylphenol in 100 ml. of dimethylformamide. The mixture was stirred until the evolution of hydrogen ceased. A solution of 67.1 g. (0.5 mole) of phthalide in 100 ml. of dimethylformamide was added and the mixture was refluxed two hours then stirred at 25° C. for sixteen hours. The mixture was poured into ice-water and acidified. The precipitated solid was filtered, dried and recrystallized from ethanol to give 2-carboxybenzyl 4-methylphenyl ether. The ether (22.6 g., 0.1 mole) was refluxed in dry xylene with a mixture of 65 g. of Super-cel and 65 g. of phosphorus pentoxide for seventeen hours. The reaction mixture was filtered. The filter cake was washed with xylene and ether. The combined filtrates were concentrated to give a solid which was recrystallized from ethanol to afford crystals of 2-methyldibenzo[b,e]oxepin-11-one, m.p. 100°-103° C.
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=[C:18]2[OH:29])[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:31][C:32]#[N:33]>>[CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=[C:18]2[O:29][CH2:31][C:32]#[N:33])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#CCBr
Reactant: CCCCCc1c(-c2ccc3nc(C(F)(F)F)cc(O)c3c2)oc2ccccc12
Product: CCCCCc1c(-c2ccc3nc(C(F)(F)F)cc(OCC#N)c3c2)oc2ccccc12

Procedure:
To a stirred solution of 6-(3-pentyl-1-benzofuran-2-yl)-4-methoxy-2-(trifluoromethyl) quinoline (0.258 g, 0.624 mmol) in CH2Cl2 (10 mL) cooled to −78° C. was added BBr3 (1.68 mL, 1.0 M in CH2Cl2, 1.68 mmol) dropwise. The reaction was stirred at this temperature for 0.5 hour and then warmed to room temperature for 18 hours. The reaction mixture was then heated at reflux for 4 hours. At this point, BCl3 (1.68 mL, 1.0 M in CH2Cl2, 1.68 mmol) and Bu4N+I− (1.24 g, 3.37 mmol) were added and the mixture was allowed to stir at room temperature for 3 days. The reaction mixture was then quenched with MeOH (˜5 mL) followed by dilution with H2O (20 mL) and EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was dried under high vacuum to afford the product (0.247 g, 99%) as an oil. Mass spectrum (+ESI, (M+H]+) m/z 400. Reaction of this intermediate [6-(3-Pentyl-1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl) quinoline] with bromoacetonitrile according to the procedure described in Step 2 of Example 1; afforded the title compound as a solid. Mass spectrum (+ESI, [M+H]+) m/z 439. 1H NMR (500 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.18-8.33 (m, 2H), 7.55-7.77 (m, 3H), 7.29-7.42 (m, 2H), 5.68 (s, 2H), 3.04 (t, 2H, J=8.2 Hz,), 1.73-1.86 (m, 2H), 1.31-1.51 (m, 4H), and 0.89 ppm (t, 3H, J=7.6 Hz).
Reaction SMILES: ClC[C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[CH2:27]([NH2:29])[CH3:28].[CH2:30](O)C>ClCCl>[CH2:27]([NH:29][CH2:30][N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:23][CH3:24])=[C:7]([O:25][CH3:26])[CH:6]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[N:12][CH2:3]1)[CH3:28]
Reactant: CCN
Reactant: CCO
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Product: CCNCN1CN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Yield: 55 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (10.0 g), ethylamine (70% aqueous solution, 206 g) and ethanol (200 ml)--dichloromethane (200 ml) was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform - ethanol (5:1, v/v) gave 2-(N-ethylaminomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (5.7 g, 55%). This compound was recrystallized from ethanol. Colorless prisms, mp. 128°-130° C.
Reaction SMILES: O[C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(S(F)(F)[F:19])CC)C>ClCCl.O>[F:19][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1ccc(C#N)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(F)c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 4-(2-hydroxypropan-2-yl)benzonitrile (1.00 g, 6.20 mmol; obtained from 4-(propan-2-yl)benzonitrile according to literature procedure: Synth. Comm. 2006, 36, 2145-2155) in dichloromethane (20 mL) was added diethylamino sulfur trifluoride (DAST; 1.20 g, 7.44 mmol) at a temperature of 0° C. The reaction mixture was allowed to stirr at rt for 2 h, whereupon it was diluted with water and extracted with dichloromethane. The organic extract was washed with water, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 95:5) to afford the title compound (675 mg, 67%): 1H NMR (400 MHz, CDCl3) δ 7.57 (d, 2H), 7.48 (d, 2H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 163, HPLC RT (Method F) 2.12 min.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: Nc1nccs1
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)Nc1nccs1)=C1SCS1
Yield: 62.9 %

Procedure:
The solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate (10 g) and 2-aminothiazole (4.0 g) in methylene chloride (100 ml) was stirred at room temperature for 24 hrs. The reaction mixture was washed with 10% aqueous sodium hydroxide solution and water and then evaporated. The residue was chromatographed on silica gel column using methylene chloride as an eluent to afford the titled compound as a white solid (6.5 g, 63%).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[OH:20][C:21]1([CH2:31][NH2:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[OH:20][C:21]1([CH2:31][NH:32][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(O)CCCc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(O)CCCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 86.8 %

Procedure:
A reaction mixture of 1.7 g of 6-chloropurine riboside, 1.7 g of (1,2,3,4-tetrahydro-1-hydroxynaphthyl)methyamine as prepared in Example B hereinafter and 2.0 g of triethylamine is refluxed in 150 ml ethanol for 24 hours. Volatiles are evaporated to dryness and residue is treated with 150 ml of cold water. Clear aqueous solution is decanted off. The water treatment is repeated twice followed by dissolving the residue in methanol and evaporating it to dryness. Co-evaporation several times with methanol affords solid material. It is dried under reduced pressure yielding 2.2 g (85%) of N6 -[1,2,3,4-tetrahydro-1-hydroxy-1-naphthalenyl]methyl adenosine having a melting point of 110°-115° C. Anals. calcd. for C21H25N5O5.0.5 C2H5OH, Found: C=58.65; H=6.26, N=15.55, C=59.27; H=6.34; N=15.53.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14].[C:15]([O-:18])(=O)C.[Na+]>C(O)(=O)C>[OH:14][CH2:13][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([CH2:15][OH:18])=[CH:11][N:10]=1
Reactant: C=O
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1cnc(CO)n1Cc1ccccc1
Yield: 24 %

Procedure:
Using the procedure of S. Zimmerman et al. (S. C. Zimmerman, K. D. Cramer and A. A. Galan J. Org. Chem. 1989, 54, 1256-1264) N-Benzylimidazole (15 g, 95 mmol) was treated with formaldehyde (60 mL of a 37% aqueous solution), to which glacial acetic acid (8 mL) and sodium acetate (10.5 g) were added. The resulting mixture was stirred until homogeneous, then was transferred to a thick-walled glass tube, which was sealed and placed in a 140° C. oil bath for 12 hours. The tube was then cooled, concentrated, made basic with 10N NaOH, and extracted twice with a 10:1 isopropanol:chloroform mixture. The combined organic fractions were then dried over anhydrous sodium sulfate and concentrated. Purification by chromatography on silica gel (7% methanol in dichloromethane) gave 2,5-bis-(hydroxymethyl)-N-benzylimidazole as a white crystalline solid (4.9 g, 24%). 1H NMR (CDCl3) δ4.41 (s, 2H), 4.48 (s, 2H), 5.36 (s, 2H), 6.77 (s, 1H), 7.00 (m, 2H), 7.28 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29][C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH:38]1(O)[CH2:44][CH2:43]C[CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:36])[O:29][CH:27]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:44][CH2:43]2)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: OC1CCCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCCC4)c([N+](=O)[O-])c3)c2cc1OC
Yield: 99.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cycloheptanol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (140 mg, yield 100%).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
A mixture of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (59 mg, 0.099 mmol), N1,N1-dimethylethane-1,2-diamine (0.13 ml, 1.2 mmol), sodium triacetoxyborohydride (104 mg, 0.493 mmol) and AcOH (0.023 ml, 0.394 mmol) in DCE (3 ml) was stirred at rt for 12 h. The solvent was removed in vacuo. LCMS showed desired product and some imine not reduced yet. The residue was redissolved in DCE (3 ml) and treated again with sodium triacetoxyborohydride (104 mg, 0.493 mmol) and AcOH (0.023 ml, 0.394 mmol) at rt for 48 h. Solvent removed in vacuo and the residue redissolved in methylene chloride and purified by silica gel column (0-10% MeOH/CH2Cl2) to afford the title compound as a white solid (65 mg, 98% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 5.30 (dd, J=6.1, 1.6 Hz, 1H), 4.72 (d, J=1.5 Hz, 1H), 4.63 (s, 1H), 3.17-2.95 (m, 3H), 2.72 (t, J=5.9 Hz, 2H), 2.54 (d, J=12.3 Hz, 1H), 2.48-2.41 (m, 1H), 2.40 (s, 6H), 2.21-1.10 (m, 22H), 1.72 (s, 3H), 1.61 (s, 9H), 1.12 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.95 (s, 6H).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CC1C=CC(S(O[CH:17]2[O:21][C:20]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:19][CH2:18]2)(=O)=O)=CC=1.[CH3:36]C(C)=O>>[C:1]([S:3][CH2:36][CH:17]1[O:21][C:20]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:19][CH2:18]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(C)=O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OC(OS(=O)(=O)c2ccc(C)cc2)CS1
Agent: [K+]
Product: CCOC(=O)CCC1(CCC(=O)OCC)OC(CSC(C)=O)CS1
Yield: 72 %

Procedure:
A stirred slurry of potassium thioacetate (0.50 g) in a solution of the tosylate produced in Example 62 (2.0 g, 0.0042 mol) in acetone (20 ml) was refluxed under nitrogen for 5 hrs. The reaction mixture was filtered and the filtrate concentrated on the rotary evaporator. The residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate. The drying agent was filtered, the solvent removed using the rotary evaporator and the residue chromatographed on silica gel using 10% ethyl acetate/hexane as eluent to give 1.1 g (72%) of the title compound as a light yellow oil.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N[C@H]2CC[C@H](C)CC2)[CH2:35]CCC[CH2:31]1.[CH3:44]OC(C1(NS(C2SC(N)=NC=2)(=O)=O)CCC1)=O>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH3:44])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][C:19]3([C:20]([OH:22])=[O:21])[CH2:35][CH2:30][CH2:31]3)(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: COC(=O)C1(NS(=O)(=O)c2cnc(N)s2)CCC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NC3(C(=O)O)CCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and 1-(2-amino-thiazole-5-sulfonylamino)-cyclobutanecarboxylic acid methyl ester to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (353 mg, 1.05 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (200 mg, 1.05 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (302 mg, 1.58 mmol) and 1-hydroxy-1H-benzotriazole (161 mg, 1.05 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (166 mg, 31%).