Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:20]=[CH:19][N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[CH:21]=[CH2:22])=[CH:7][CH:6]=1)([CH3:4])=[O:3].[Cl:23][C:24]1[C:29](I)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[C:29](/[CH:22]=[CH:21]/[N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][CH:19]=[N:20][C:12]=3[NH:11][C:8]2[CH:9]=[CH:10][C:5]([P:2]([CH3:1])([CH3:4])=[O:3])=[CH:6][CH:7]=2)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Reactant: Cc1ccnc(Cl)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1ccnc(Cl)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 120 °C

Procedure:
N-(4-(Dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (Example 3, 1 mmol), 2-chloro-3-iodo-4-methylpyridine compound (1.3 mmol), disopropylethyl amine (3 mmol), palladium acetate (0.05 mmol), tri-o-tolylphosphine (0.1 mmol) in DMF (5 mL) was thoroughly purged with argon for 10-15 min. and sealed and heated for 120° C. for 18 h. until the starting materials disappeared. The reaction mix. was passed through celite, and washed with dichloromethane containing 30% methanol. The filtrate was concentrated in vacuo. The residue was purified by Biotage-S column chromatography using 1/1 hexane ethyl acetate, ethyl acetate and 1-10% methanol containing ethyl acetate: MS [M+H]+ 439.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12]C)[CH:8]=[CH:7][CH:6]=2)[CH3:2].B(Br)(Br)Br.C(Cl)Cl>>[CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1
Yield: 53.7 %

Procedure:
By the method used in Example 1, Part D, 3.1 g (11.7 mmol) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole was O-demethylated by treating it with 48.6 mL of 1M BBr3 /CH2Cl2 to give a material that was chromatographed on silica gel (eluted with 20% EtOAc/hexane) to give 1.58 g (54% yield) of 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole, mp, 86-90° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.C[Si](C)(C)[O:31][CH:32]([CH3:35])[CH2:33][NH2:34].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:34][CH2:33][CH:32]([OH:31])[CH3:35])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CC(CN)O[Si](C)(C)C
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(O)CNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 33.5 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), 2-Trimethylsilanyloxy-propylamine (211 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 125° C. for 7 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-TLC (EtOAc/hexanes=2:1) to afford 110 mg of 293. (yield=34%). 1H NMR (CDCl3, 400 MHz): δ8.01 (s, 1H), 7.50-7.45 (m, 1H), 7.06-6.98 (m, 4H), 6.23 (d, J=8.8 Hz, 1H), 4.54-4.50 (m, 1H), 4.17-4.15 (m, 2H), 3.98-3.94 (m, 1H), 3.44-3.40 (m, 1H), 3.15-3.00 (m, 3H), 1.21-1.17 (m, 3H). LC-MS (ESI): m/z=456 [M+H]+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[CH:11][C:12]([OH:14])=[O:13].[CH2:15]([N:17](CC)CC)[CH3:16].CC(C)=O.ClCC#N>O>[C:15]([CH2:16][O:13][C:12](=[O:14])[CH:11]=[CH:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)#[N:17]
Reactant: O=C(O)C=Cc1cc2ccccc2o1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: O
Solvent: CC(C)=O
Product: N#CCOC(=O)C=Cc1cc2ccccc2o1
Yield: 90.1 %

Procedure:
171.8 g of β-(2-benzofuryl)acrylic acid, synthesized in the manner as described in J. Chinese Chem. Soc. sev. II 8, pp. 374-379, and 101.5 g of triethylamine were added to 550 ml of acetone, to the mixture were added dropwise 75.9 g of chloroacetonitrile, and the mixture was refluxed by heating over a period of five hours. After the reaction, 400 ml of water were added to cool the reaction system, and the deposited crystals were filtered by a suction filter and then washed. The obtained crystals were recrystallized from acetone to thereby obtain 187 g of β-(2-benzofuryl)acrylic acid cyanomethyl ester having a melting point between 119° C. and 121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([OH:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](Cl)=[O:30])[CH3:27]>CN(C)C=O>[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](=[O:30])[O:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=1)[CH3:27]
Reactant: Cc1ccc(-c2cc3ccccc3c(O)n2)cc1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Oc1nc(-c2ccc(C)cc2)cc2ccccc12
Yield: 9 %

Procedure:
The procedure is as in Example 37, starting with 3-(4-methylphenyl)-1-isoquinolinol (4.7 g), triethylamine (8.1 g) and diethylcarbamoyl chloride (10.8 g) in dimethylformamide (50 cc). After chromatography on silica gel with a cyclohexane/ethyl acetate (4:1 by volume) mixture as eluant and recrystallization in ethyl ether, 3-(4-methylphenyl)-1-isoquinolyl diethylcarbamate (0.6 g), m.p. 98° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20](O)=[O:21])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.FC(F)(F)C(O)=O.[CH3:54][O:55][C:56](=[O:71])[CH2:57][C:58]1([C:64]2[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=2)[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[CH3:54][O:55][C:56](=[O:71])[CH2:57][C:58]1([C:64]2[CH:65]=[CH:66][C:67]([NH:70][C:20](=[O:21])[CH2:19][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]4[N:8]=[C:9]([NH:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH3:18])[O:10][C:6]=4[CH:5]=3)=[CH:68][CH:69]=2)[CH2:59][CH2:60][O:61][CH2:62][CH2:63]1
Reactant: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)O)cc2o1
Reactant: COC(=O)CC1(c2ccc(N)cc2)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1(c2ccc(NC(=O)Cc3cc(C)c4nc(Nc5ccccc5C)oc4c3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A stirred solution of (4-methyl-2-o-tolylamino-benzoxazol-6-yl)-acetic acid [0.44 g, prepared according to the procedure described in International Patent Application No. WO00/61580 for Reference Example 9] in dry dimethylformamide (10 mL), under argon, was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.8477 g) and then with diisopropylethylamine (1.05 mL). After stirring at room temperature for 10 minutes the bright yellow solution was added to a solution of [4-{4-amino-phenyl}-tetrahydro-pyran-4-yl]-acetic acid methyl ester trifluoroacetate (0.444 g, Reference Example 18) in a mixture of dimethylformamide (8 mL) and diisopropylethylamine (1.05 mL). The mixture was stirred at room temperature under argon overnight and then evaporated to low bulk. The residue was dissolved in ethyl acetate and this solution was washed with water, then with aqueous sodium bicarbonate solution, and then with water and then evaporated. The residue was subjected to reverse phase HPLC on a Hypersil Elite C18 column using as the mobile phase a mixture of acetonitrile, water and trifluoroacetic acid (35:65:0.1, v/v/v) followed by a 1% acetonitrile/minute gradient to give the title compound (0.178 g, approximately 90% purity) which was used without further purification. LC-MS: RT=3.71 minutes, MS(ES+): 528(M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15](Br)[C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOC(C)=O.CCCCCCC>O1CCCC1.CN(C)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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3c(Br)cccc3c2CC1
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: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CCc2[nH]c3c(-c4ccccc4)cccc3c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A mixture of 3-benzoyl-7-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.517 g, 1.40 mmol), potassium carbonate (0.77 g, 5.60 mmol), phenylboronic acid (0.194 g, 1.54 mmol), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol) in tetrahydrofuran (7.0 mL) and N,N-dimethylacetamide (7.0 mL) was stirred at room temperature overnight. The mixture was filtered through Celite and the filtrate concentrated in vacuo to give an oil, which was subjected to column chromatography (silica gel, 10-50% EtOAc/heptane) to afford 0.44 g (86%) of the title compound as a solid: mp 198-200° C.; 1H NMR (400 MHz, CDCl3) δ 8.10, 7.67-7.60, 7.55-7.4, 7.47-7.33, 7.18-7.14, 4.04-3.96, 3.72-3.63, 3.20-3.12, 2.93-2.80; IR (drift) 3258, 1602, 1464, 1430, 1327, 1295, 1239, 1185, 930, 761, 749, 740, 711, 703, 696 cm−1; MS (El) m/z 366 (M+); HRMS (FAB) calcd for C25H22N2O+H: 367.1810, found: 367.1805; Anal. Calcd. for C25H22N20: C, 81.94; H, 6.05; N, 7.64. Found: C, 81.37; H, 6.12; N, 7.57.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[S:14][C:15]([Br:19])=[C:16]([Br:18])[CH:17]=2)[CH2:11][N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)=[O:7])(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:20]([N:10]1[CH2:11][CH:12]([C:13]2[S:14][C:15]([Br:19])=[C:16]([Br:18])[CH:17]=2)[CH:8]([C:6]([OH:7])=[O:5])[CH2:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccccc2)CC1c1cc(Br)c(Br)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1cc(Br)c(Br)s1

Procedure:
The product of step b) (2.6 g, 5.2 mmol) in CH2Cl2 (25 ml) and trifluoroacetic acid (TFA) (75 ml) was stirred at 22° C. for 16 hours. Next, the solvent was evaporated and toluene (50 ml) was added and subsequently evaporated in vacuo at 40° C. to remove residual TFA. The crude subtitle product was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.[H][H]>CO.C(O)(=O)C.[Pt](=O)=O>[O:13]1[C:9]2([CH2:14][CH2:15][C:6]3([CH2:16][CH2:17][NH:18][C:4]3=[O:3])[CH2:7][CH2:8]2)[O:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
8-Cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (525 mg, obtained in example 133, step 2) was dissolved in methanol (10 mL) and acetic acid (5 mL). Platinum (IV) oxide (235 mg) was added and an atmosphere of hydrogen was introduced at r.t. The mixture was stirred under hydrogen at room temperature for 18 hours. The reaction was filtered over dicalite speed plus (Acros Organics) and the filtrate was concentrated in vacuo. The residue was poured into ice/water and was basified with 2M aqueous NaOH solution. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless solid (169 mg, 39%). MS (m/e): 212.2 [MH+].
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5](=[O:12])[NH:4][CH:3]=1.[NH3:13].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO.O>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH2:13])=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1nc(F)c[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1nc(F)cnc1O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
In 3.0 mL of methanol was dissolved 0.12 g of methyl 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, gaseous ammonia was introduced into the solution at an ice-cooled temperature for a period of 10 minutes, after which the mixture thus obtained was allowed to stand at room temperature for 2 days. The solvent was removed under reduced pressure, the residue thus obtained was added to a mixture of 30 mL of ethyl acetate and 30 ml of water, pH was adjusted to 7.5 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. After adding 30 mL of ethyl acetate to the remaining aqueous layer, pH was adjusted to 1.0 with 1 mol/L hydrochloric acid, and the whole mixture was extracted with two 15 mL portions of ethyl acetate. The organic layers thus obtained were united, washed successively with 15 mL of water and 15 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The solid product thus obtained was washed with diisopropyl ether to obtain 0.015 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a yellow-colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20]
Reactant: NCc1ccccc1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: O=C(NCc1ccccc1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), benzylamine (0.350 g, 3.27 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-benzyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.584 g, 45.1% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:30])=[C:22]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:23]=3)[C:18](=[O:31])[N:17]([O:32]CC3C=CC=CC=3)[C:16]2=[O:40])=[CH:11][CH:10]=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:30])=[C:22]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:23]=3)[C:18](=[O:31])[N:17]([OH:32])[C:16]2=[O:40])=[CH:13][CH:14]=1
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(O)cc2)c(=O)n1O
Yield: 96.7 %

Procedure:
Using the General Method 6B, the reaction of 1 M TFA solution of B(TFA)3 (0.5 mL, 0.44 mmol) with 1-(4-hydroxyphenyl)-6-fluoro-3-benzyloxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example K-1, 0.05 g, 0.11 mmol) afforded 0.038 g of the title compound as a solid, mp 264-268° C. (decomp.).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.O>C(OCC)C.CO.Cl>[CH2:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:16]=[N:15]2)[CH2:12][CH2:13]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccccc3)nn2)CC1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: c1ccc(CN2CCC(n3cc(-c4ccccc4)nn3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.9 %

Procedure:
To a solution of N-t butyloxycarbonyl-4-((4-phenyl)triazol-1-yl)piperidine (2.5 g) in a 1:1 mixture of diethyl ether and methanol (10 ml) was added a solution of hydrogen chloride in methanol (10 ml, ~5 mol) and the reaction mixture was stirred at room temperature for 72 hrs. The solid was filtered off and dried then redissolved in N,N-dimethylformamide (20 ml), to which was added benzyl bromide (0.4 ml, 3.4 mmol) and ethyldiisopropylamine (0.55 ml, 3.4 mmol). The reaction mixture was stirred at room temperature for 18 hrs under nitrogen, then poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash silica chromatography using methanol in dichloromethane (0-4%) and ammonia (0.5%). The product obtained was redissolved in a 1:1 mixture of diethyl ether and methanol (5 ml) with hydrogen chloride in methanol (10 ml, ~5 mol). After 5 mins the solvent was removed under vacuum and the residue was recrystallized from methanol and ethyl acetate to give the required product as a white solid (85 mg). M.p 206-280° C. 1H NMR (DMSO) δ 2.11 (4H,m), 2.60 (2H,m), 2.77 (2H,m), 3.04 (2H,m), 4.52 (1H,m), 7.18-7.85 (11H,m). MS (CI) m/e 319 [MH]+. Anal. Found C, 64.90; H, 6.43; N, 15.05. C20H22N4.HCl.0.75H2O requires C, 65.21; H, 6.70; N, 15.21%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=2)[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(Cl)c2)CC1
Yield: 7.9 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-chloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.6 mg, 7.9%) as light yellow oil. MS m/e=525.4 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([S:23][CH2:24][C@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([S:23][CH2:24][C@@H:25]([CH3:29])[C:26]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CNC1Cc2ccccc2C1
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
By reacting N-(2-indanyl)glycine with 3-benzoylthio-2(S)-methylpropionyl chloride in a similar manner to that of Example 37, there is obtained N-(3-benzoylthio-2(S)-methylpropionyl)-N-(2-indanyl)glycine. Colorless needles.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].Cl[S:10]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)(=[O:12])=[O:11]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:10]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccsc1Cc1ccc2c(c1)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2Cc2ccc3c(c2)OCO3)c1Br
Yield: 37 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 by reacting 5-amino-4-bromo-3-methylisoxazole and 3-chlorosulfonyl-2-[(3,4-methylenedioxy)benzyl]thiophene. The crude product was purified by HPLC, 37% yield.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(O)[C@H]1[O:35][C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO>>[OH:35][C:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])([CH3:1])[CH3:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h

Procedure:
Fifty ml of the conversion culture medium described in Examples 1-9 was placed in a 250 ml Erlenmeyer flask and autoclaved at 120° C. for 20 minutes. This medium was inoculated with 1 ml of the seed culture solution prepared as in Examples 1-9 and shaking culture was carried out at 220 rpm for 48 hours at 28° C. To this culture were added cholesterol in the form of powder and 5.6 ml of a 1. 5% aqueous solution of partially methylated β-cyclodextrin (methylation rate 74%: Mercian Corp.) which was sterilized beforehand, and the cultivation continued for further 40 hours. By the same method as Examples 1-9, 25-hydroxycholesterol in the culture solution obtained was quantified. The conversion rates into 25-hydroxycholesterol from cholesterol were summarized in Table 3.