Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])=[O:23])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1F)[CH:10]=2)[CH3:2].[CH3:46][O:47][CH2:48][CH2:49][OH:50].CC(C)([O-])C.[K+].[Cl-].[OH:58][NH3+:59]>N1C=CC=CC=1.O>[CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:23])[C:24]3[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:50][CH2:49][CH2:48][O:47][CH3:46])=[N:59][OH:58])[CH:10]=2)[CH3:2]
Reactant: [NH3+]O
Reactant: COCCO
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3F)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(CC)Cn1c2ccc(C(=NO)c3ccccc3OCCOC)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 71 %

Procedure:
To 11-(2-Ethylhexyl)-8-(2-fluorobenzoyl)-11H-benzo[a]carbazole-5-yl-(2,4,6-trimethylphenyl)-methanone (5.98 g; 10.0 mmol) in pyridine (10 mL) are added 2-methoxyethanol (2.28 g; 30.00 mmol) and potassium tert-butoxide (1.68 g; 15.00 mmol) at room temperature. The mixture is heated at 80° C., and it is stirred for 3.5 hours. To the reaction mixture is added hydroxylammonium chloride (2.08 g; 30.00 mmol), and then the mixture is stirred at 100° C. overnight. After it is cooled at room temperature, the reaction mixture is poured into 200 ml of water. The precipitated solid is collected by filtration, and then it is washed with CH3OH. The desired compound is obtained in 71% yield (4.73 g) as a white solid. The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.81 (t), 0.87 (t), 1.17-1.43 (m), 2.18 (s), 2.26-2.28 (m), 2.36 (s), 2.39 (s), 2.96 (s), 3.08 (t), 3.11 (t), 3.45 (t), 3.81 (t), 4.08 (t), 4.65-4.75 (m), 6.87 (d), 6.93 (s), 7.03-7.12 (m), 7.24-7.26 (m), 7.36-7.47 (m), 7.50-7.51 (m), 7.57 (br), 7.67-7.76 (m), 8.27 (d), 8.30 (d), 8.33 (s), 8.62 (d), 9.55 (dd), 9.59 (dd)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.I[CH2:12][CH:13]([O:15][CH2:16][CH2:17]I)[CH3:14].FC1C=C(CC#N)C=C(F)C=1.ClCCOCCCl>>[C:9]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[CH2:17][CH2:16][O:15][CH:13]([CH3:14])[CH2:12]1)#[N:10]
Reactant: N#CCc1cccc(I)c1
Reactant: CC(CI)OCCI
Agent: N#CCc1cc(F)cc(F)c1
Solvent: ClCCOCCCl
Product: CC1CC(C#N)(c2cccc(I)c2)CCO1

Procedure:
The titled compounds were prepared according to the procedure described in Example 25A except that 3-iodophenyacetonitrile and 1-iodo-2-(2-iodoethoxy)propane were used in place of 3,5-difluorophenylacetonitrile and bis-(2chloroethyl)ether. The diastereomers were separated by silica gel column chromatography to afford 1.46 g (38%) of a less polar isomer, (2SR, 4RS)-4-cyano-4-(3-iodophenyl)-2-methyl-3,4,5,6-tetrahydr o-2H-pyran; and 1.31 g (34%) of a more polar isomer, (2SR, 4SR)-4-cyano-4-(3-iodophenyl)-2-methyl-3,4,5,6-tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)O.CCN(CC)CC.CS([Cl:50])(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:38])[C:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[C:21]([Cl:50])[C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])=[CH:5][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1
Reactant: COC(=O)C(NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(O)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=Cc1ccc(Cl)c(Cl)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionic acid methyl ester (42 mg, 0.068 mmol) in DCM (1.5 mL) was added Et3N (38 μL, 0.273 mmol) and the mixture was cooled to 0° C. MsCl (8 μL, 0.102 mmol) was added and the mixture was warmed to rt and stirred for 1.5 h. The mixture was heated to 50° C., treated with catalytic DMAP, and stirred overnight. The mixture was diluted with satd. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylic acid methyl ester. The crude product was hydrolyzed as in Example 2, Part E, to provide the title compound (25% for two steps). HPLC: RT=9.97 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 618.30; m/z found, 581/583 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.82 (s, 1H), 9.37 (d, J=5.1, 1H), 8.48 (d, J=7.1, 1H), 8.34 (dd, J=8.8, 0.9, 1H), 7.96-7.86 (m, 2H), 7.82-7.75 (m, 2H), 7.64-7.55 (m, 3H), 7.11 (dd, J=8.5, 2.0, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH3:24])[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:24][N:12]([CH2:11][C:10]1[CH:25]=[CH:26][CH:27]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[N:7][CH:6]=2)[CH:9]=1)[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: C1CC(N2CCOCC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCC(N4CCOCC4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
tert-butyl (2-{[3-(2-Chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (250 mg) was dissolved in DMF (5 ml), and 4-piperidin-4-ylmorpholine (218 mg) and K2CO3 (265 mg) were added thereto, followed by stirring at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl3) to obtain tert-butyl [2-(methyl{3-[2-(4-morpholin-4-ylpiperidin-1-yl)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (285 mg).
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]([CH3:34])[C:31]([NH2:33])=[O:32])[C:19]([C:35]([F:38])([F:37])[F:36])=[CH:18][N:17]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1>CCO>[CH2:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]([CH3:34])[C:31]([NH2:33])=[O:32])[C:19]([C:35]([F:37])([F:36])[F:38])=[CH:18][N:17]=3)[CH:12]=[N:11]2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CC=O
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Solvent: CCO
Product: CCN1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C(C)C(N)=O)n3)cn2)CC1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Acetaldehyde (17 μL, 0.31 mmol) was added to a solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide A67 (50 mg, 0.10 mmol) in EtOH (20 mL). After 10 minutes, NaHB(OAc)3 (86 mg, 0.41 mmol) was added and the mixture was stirred for 3 hours. The reaction was quenched with water (20 mL) and the volatiles were removed in vacuo. The resultant solid was suspended in water (25 mL), sonicated for 10 minutes, collected by filtration and then dissolved in acetone (3 mL). Addition of petroleum benzine 40-60° C. gave a precipitate that was collected by filtration to give the title compound 59 as a tan solid (42 mg, 79%). LCMS-A: rt 4.808 min; m/z 516.3 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=[C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]1=[N:20]O)([OH:3])=[O:2].[CH:22](OC)=[O:23]>[Pt]=O.CO>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[NH:20][CH:22]=[O:23])([OH:3])=[O:2]
Reactant: CN1C(=O)C(=NO)C(=NCCCCCC(=O)O)N(C)C1=O
Reactant: COC=O
Agent: O=[Pt]
Solvent: CO
Product: Cn1c(NCCCCCC(=O)O)c(NC=O)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A mixture of 15.8 g (0.05 mol) of the oxime (III), 200 ml of methanol, and 100 mg of platinum oxide was shaken under 4 atmospheres H2 for 15 minutes at room temperature. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure (35° C.) to give a red oil. Methyl formate (200 ml) was added and the resulting mixture refluxed under argon for 20 hours. It was then cooled in an ice bath and the white solid collected by filtration. Recrystillization from methanol gave 9.82 g (63% yield) of the formamido uracil (IV) as white crystals, mp 152°-153° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH2:61][CH2:60][CH2:59][C:58]1=[O:62].C(Cl)[Cl:64]>>[ClH:64].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH2:61][CH2:60][CH2:59][C:58]4=[O:62])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: O=C1CCCN1CCO
Reactant: ClCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCN1CCCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Diethyl azodicarboxylate (283 μl, 1.8 mmol) was added dropwise to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (218 mg, 0.6 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (95 μl, 0.84 mmol) and 1-(2-hydroxyethyl)-2-pyrrolidinone (95 μl, 0.84 mmol) in methylene chloride (8 ml) under nitrogen. The mixture was stirred for 4 hours at ambient temperature, and then purified by pouring it directly on to a column of silica and eluting with methylene chloride/acetonitrile/methanol (60/32.5/7.5). The purified product was triturated with ether and collected by filtration. The solid was dissolved in methylene chloride/methanol (1/1) and 2M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline hydrochloride (182 mg, 60%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:9]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][NH:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:18])[CH2:16][N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)[CH:9]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CCN1CCNCC1
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CCl)c2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(CC(=O)Nc2cc(Oc3ccc(NC)c([N+](=O)[O-])c3)ccn2)CC1

Procedure:
The mixture containing N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide (1 eq), 1-ethylpiperazine (3 eq), and potassium carbonate (4 eq) was stirred in dimethylformamide at 60° C. for 1 hour. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with water then brine, dried over sodium sulfate and concentrated to give orange solid. Purification on silica gel with 20% methanol in methylene chloride gave N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide as a red solid. HPLC=3.26 min; MS: MH+=415.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1([CH2:22][C:23](=[O:26])[O:24][CH3:25])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19](O)=[O:20])[CH2:6]1.[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:25][O:24][C:23](=[O:26])[CH2:22][C:5]1([CH2:4][C:3](=[O:27])[O:2][CH3:1])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19]([N:28]2[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:20])[CH2:6]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COC(=O)CC1(CC(=O)OC)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)CCc2ccc(O)cc2C2=NOC(CC(=O)OC)(CC(=O)OC)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-(5,5-bis(2-methoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (820 mg), ethyl piperidine-4-carboxylate (0.366 mL), WSC (497 mg), HOBt (350 mg), triethylamine (0.362 mL), and DMF (8 mL) was stirred overnight at room temperature. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (760 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:18]=[CH:17][C:12]2[CH2:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[NH:19]C(=O)OC(C)(C)C.O.C(=O)(O)[O-].[Na+]>C(OCC)C>[NH2:19][C:10]1[C:11]2[O:16][CH2:15][CH2:14][CH2:13][C:12]=2[CH:17]=[CH:18][C:9]=1[F:8]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc2c1OCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(F)ccc2c1OCCC2
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Trifluoroacetic acid, 50 mL, was stirred and cooled in an ice-water bath, and 6.1 grams (0.023 mole) of 1,1-dimethylethyl N-(3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)carbamate was added portionwise. Upon completion of the addition, the reaction mixture was stirred for one hour, then stirred with water and diethyl ether and neutralized with solid sodium bicarbonate. The water layer was separated and extracted with diethyl ether. The extract was combined with the organic layer, and the combination was washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.7 grams of 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:47])[CH2:21][N:22](CC2C=CC=CC=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([OH:50])C>C(OCC)(=O)C.[Pd]>[C:30]([OH:50])(=[O:29])[CH3:31].[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:47])[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2N1
Reactant: CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)O
Product: O=C1COc2c(C(O)CNCCCCCCOCCCCc3ccccc3)ccc(O)c2N1

Procedure:
A solution of 5-(benzyloxy)-8-(2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2H-1,4-benzoxazin-3(4H)-one (82 mg) in ethanol (10 ml) and ethyl acetate (2 ml) was stirrer under hydrogen in the presence of palladium on charcoal (50 mg) for 8 h. The reaction mixture was filtered and concentrated in vacuo. Mass directed auto-preparative chromatography afforded the title compound (13.7 mg). LCMS RT=2.62 min ES+ve 456 (MH)+
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[NH2:8][C:3]1[C:2]([C:14]2[CH:13]=[CH:12][C:11]([C:25]3[CH:30]=[N:29][C:28]([NH2:31])=[N:27][CH:26]=3)=[C:10]([F:9])[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1ncccc1Br
Product: Nc1ncc(-c2ccc(-c3cccnc3N)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 3-bromopyridin-2-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C15H12FN5, 281.11; m/z found, 282.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.64-8.54 (m, 1H), 8.00-7.89 (m, 1H), 7.74-7.64 (m, 1H), 7.46-7.36 (m, 1H), 7.09-7.03 (m, 1H).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(F)cc1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Solvent: CCO
Product: O[C@@H]1C[C@@H](C(c2ccccc2)c2ccccc2)OC[C@H]1NCCc1ccc(F)cc1

Procedure:
(1S, 4S, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.025 g, 0.094 mmol) was reacted with 2-(4-fluoro-phenyl)-ethylamine (0.26 g, 1.88 mmol) in ethanol (Procedure E) to yield (2S, 4R, 5R)-2-benzhydryl-5-[2-(4-fluorophenyl)-ethylamino]-tetrahydropyran-4-ol, (−)-29c, 0.04 g (98%, [α]D=(−)62.9, c=1, MeOH).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30]=O.[OH-].[Na+]>CCOCC.C(O)C.C(N(CC)CC)C>[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[C:7]([CH2:30][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C=O
Reactant: Sc1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(CSc5ccccc5)C(=O)CC[C@@]43CO)[C@@H]1CCC2=O

Procedure:
A mixture of 19-hydroxy-4-androstene-3,17-dione, thiophenol, 40% aqueous formaldehyde, triethylamine and ethanol are heated at the reflux temperature for about 48 hours. The cooled solution is poured into an aqueous sodium hydroxide solution and the product isolated by ether extraction. The ether extract is washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is triturated with hot hexane to remove the condensation products derived from the thiophenol and formaldehyde. The 19-hydroxy-4-phenylthiomethyl-4-androsten-3,17-dione so obtained is desulfurized by dissolving in acetone and adding to a suspension of Raney Nickel in refluxing acetone. The mixture is heated at its reflux temperature while stirring for about 5 hours. The hot solution is filtered and the nickel washed with boiling ethanol and water. The combined filtrates are concentrated under vacuum whereupon the product separates as a solid. Recrystallization from an acetone-hexane solution yields 19-hydroxy-4-methyl-4-androstene-3,17-dione.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=2[CH:29]=1)=[O:8]>C(#N)C>[N:1]([CH2:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=2[CH:29]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CCl)cc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(C(=O)CN=[N+]=[N-])cc2[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Sodium azide (1.79 g, 27.48 mmol) was added in one portion to a solution of (S)-tert-butyl 2-(6-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (10.0 g, 27.48 mmol) in acetonitrile (200 mL) and stirred at 60° C. for 16 h. The reaction mixture was concentrated to ⅕ volume, diluted with EtOAc, and washed with water and brine prior to being dried (Na2SO4) and filtered. Concentration gave J4 (S)-tert-butyl 2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (6.8 g, 48%) as a golden orange foam. 1H NMR (500 MHz, DMSO-d6) δ: 8.22/8.03 (s, 1H), 7.80-7.75 (m, 1H), 7.65/7.56 (d, J=8.5 Hz, 1H), 4.99-4.93 (m, 3H), 3.60 (br s, 1H), 3.46-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.01-1.89 (m, 3H), 1.40/1.06 (s, 9H). LC (D-Cond. 2): RT=1.97 min; LC/MS: Anal. Calcd. for [M+H]+ C18H23N6O3: 371.19. found: 371.32. HRMS: Anal. Calcd. for [M+H]+ C18H23N6O3: 371.1832. found: 371.1825.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]([C:16]([Cl:20])=[C:17]([Cl:19])[Cl:18])=[C:13](Cl)[Cl:14])([O-:11])=[O:10].CO>CCOCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:13]([Cl:14])=[C:12]([N+:9]([O-:11])=[O:10])[C:16]([Cl:20])=[C:17]([Cl:18])[Cl:19])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C(=C(Cl)Cl)C(Cl)=C(Cl)Cl
Reactant: Cc1ccc(S)cc1
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(SC(Cl)=C(C(Cl)=C(Cl)Cl)[N+](=O)[O-])cc1
Reaction time: 20 h

Procedure:
At room temperature, 4.72 g (38 mmol) of 4-methylthiophenol are added to a solution of 10.00 g (36.9 mmol) of 2-nitropentachloro-1,3-butadiene in 20 ml of ether, and the mixture is stirred for 20 h. The ether is then removed under reduced pressure, and the crystal slurry which is formed after addition of 20 ml of methanol is filtered off, washed with cold MeOH (2×10 ml) and dried under reduced pressure, yield 9.9 g (75%), Rf=0.72 (Et2O: petroleum ether=1:3), m.p. 110-111° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[BrH:9].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:5]=1)[CH3:8]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1nnc(N)s1
Solvent: ClC(Cl)Cl
Product: Br
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Yield: 146.1 %

Procedure:
To 10 ml of chloroform, 2.7 g of 2-amino-5-ethyl-1,3,4-thiadiazole and 1.3 g of 4'-bromomethyl-2-cyanobiphenyl were added, followed by heating under reflux for 2 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration, washed successively with chloroform and diethyl ether and then dried, whereby 2.80 g of the title compound was obtained.