Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH2:21]([N:28]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(C(=O)N3CCC(=NCc4ccccc4)CC3)ccc2N1

Procedure:
0.8 Gram of 6-(4-oxo-1-piperidyl)carbonyl-3,4-dihydrocarbostyril, 1.6 ml of benzylamine and 1 g of Molecular Sieve 3A (a trademark for synthetic feldspar manufactured by Linde Co., U.S.A.) were dispersed in 15 ml of chloroform and refluxed by heating for 6 hours. Molecular Sieve 3A was removed by filtration, the filtrate was concentrated, then the residue obtained was washed several times with diethyl ether, next, purified by means of a silica gel column chromatography to obtain 6-(4-benzylimino-1-piperidyl)carbonyl-3,4-dihydrocarbostyril.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][CH2:13][CH:14]1[O:16][CH2:15]1.O.[OH-].[Li+]>C(OCC)(=O)C>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:15][CH:14]([OH:16])[CH2:13][CH3:12]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCC1CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(O)COc1cccc(C(F)(F)F)c1

Procedure:
40.5 g of 3-hydroxybenzotrifluoride, 18.0 g of α-butylene oxide and 1.0 g of lithium hydroxide monohydrate are heated in a bomb tube (pressure reactor) for 16 hours to 140° C. After cooling the reactor, the reaction mixture is dissolved in 200 ml of ethyl acetate and the organic phase is washed with water and then dried over sodium sulfate and concentrated. The desired product, 1-(3-trifluoromethylphenoxy)-2-butanol, is obtained in a yield of 54.0 g and in high purity. The product can be used in the subsequent reaction without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5].[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH3:30])[NH:25]1>C(O)(C)C>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH3:30])[N:25]1[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5]
Reactant: CC1CCCC(C)N1
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCCl)c2ccccc21
Solvent: CC(C)O
Product: CC1CCCC(C)N1CCC(=O)N1c2ccccc2C(=O)N(C)c2ccccc21

Procedure:
6.3 gm (0.02 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 8.4 (0.075 mol) of 2,6-dimethyl piperidine were refluxed in 100 ml of isopropanol for 6 hours. The reaction mixture was worked up as described in Example 13. After recrystallization from ethyl acetate by addition of a little ether, 4.2 gm (54% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][CH2:7][C:6]1=[S:26]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: c1ccncc1
Product: COC(=O)CN1C(=S)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A mixture of 6.35 g. (0.0186 mole) of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 4.42 g. (0.0199 mole) of phosphorus pentasulfide and 185 ml. of pyridine is heated under reflux for about 19 hours. The pyridine is evaporated, 100 ml. of cold water is added, and the product is extracted with four 100-ml. portions of methylene chloride. The extracts are combined, washed with sodium bicarbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated to give 2.5 g. of residue. The residue thus obtained is extracted with eight 250-ml. portions of boiling ether. The extracts are combined and concentrated. On standing 2.1 g. of 7-chloro-2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester of melting point 180°-182° c. crystallizes from solution; recrystallization from ether raises the melting point to 185°-187° C.
Reaction SMILES: [CH:1]([CH:5]1[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[CH:2][CH2:3][CH3:4].F[B-](F)(F)F.[CH3:18][O+](C)C>>[CH3:18][O:12][C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:1]=[CH:2][CH2:3][CH3:4])[N:11]=1
Reactant: CCC=CC1CCCCC(=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: CCC=CC1CCCCC(OC)=N1
Yield: 103.4 %

Procedure:
The product of Example 326 (1.34 g, 8 mmol) was reacted with trimethyloxonium tetrafluoroborate (1.63 g, 11 mmol) by the method of Example 26 to yield 1.5 g (100%) of the title material.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)=[C:17]([C:22]([O:24]C)=[O:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)=[C:17]([C:22]([OH:24])=[O:23])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:33][CH:34]=1
Reactant: COC(=O)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3c2c2ccccc2n3Cc2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
A mixture of methyl 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylate (625 mg, 1.375 mmol) in Methanol (10 mL) and Tetrahydrofuran (THF) (10.00 mL) was treated with 2M LiOH (20 mL, 40.0 mmol) and then refluxed overnight. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and then filtered to afford 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid as a white solid (595 mg, 1.35 mmol, 98% yield). A suspension of 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (595 mg, 1.35 mmol) in thionyl chloride (10 mL, 137 mmol) was heated at 70° C. for 2 hours and then concentrated. The residue was dissolved in Tetrahydrofuran (THF) (10.00 mL), treated with sodium borohydride (520 mg, 13.75 mmol) and then heated at 70° C. for 2 hours. Additional NaBH4 (15 eq.) was added and then mixture was heated at 70° C. overnight. The mixture was concentrated, treated with NH4Cl (sat. aq) slowly at 0° C. and then extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated to afford 9-(4-fluorobenzyl)-3-(hydroxymethyl)-2-methyl-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (520 mg, 1.22 mmol, 90% yield) as a white solid which was used in the next step without any further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.30-7.44 (m, 7H) 7.19-7.27 (m, 3H) 6.95 (s, 4H) 6.62-6.70 (m, 1H) 6.14 (s, 3H) 4.57 (s, 2H) 3.92 (s, 3H) 2.52 (s, 3H); LCMS (m/z) ES+=427 (M+1).
Reaction SMILES: O(C(C)(C)C)[K].[CH2:7]([OH:10])[CH2:8][OH:9].Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1>C(Cl)Cl>[N:14]1[CH:13]=[C:12]([O:9][CH2:8][CH2:7][OH:10])[CH:17]=[N:16][CH:15]=1
Reactant: OCCO
Reactant: Brc1cncnc1
Agent: CC(C)(C)O[K]
Solvent: ClCCl
Product: OCCOc1cncnc1
Yield: 6 %

Procedure:
KO-t-Bu (7.70 g, 68.6 mmol) was added to ethylene glycol (10.45 g, 168.4 mmol) under stirring. The mixture was gently heated in order to consume all KO-t-Bu. 5-Bromopyrimidine (8.45 g, 53.1 mmol) was added to the light brownish mixture. After 8 h of stirring at 130° C., CH2Cl2 (50 mL) was added to the brownish reaction mixture and two layers were formed. The CH2Cl2 layer was saved and the other layer was extracted with additional portions of CH2Cl2. The combined CH2Cl2 layers were concentrated in vacuo and the oily residue purified by column chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give 0.45 g (6%) of the title product as an oil sufficiently pure for the next step. HRMS m/z calcd for C6H8N2O2(M)+140.0586, found 140.0589.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1.[CH:13](O)=[O:14]>>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([NH:11][CH:13]=[O:14])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1
Reactant: Nc1c(Cl)ncnc1NCCO
Reactant: O=CO
Product: O=CNc1c(Cl)ncnc1NCCO

Procedure:
The starting 4-β-hydroxyethylamino-5-formamido-6-chloropyrimidine was prepared by heating in 80% formic acid, 4-β-hydroxyethylamino-5-amino-6-chloropyrimidine, M.P. (Koffer) 139° C, itself prepared according to the method of SCHAEFFER and BHARGAVA, Biochemistry (1965) 71.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)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>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:34]4[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=[C:32]([C:31]([F:30])([F:46])[F:45])[CH:33]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a solution of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.21 mmol) and 3,5-bis(trifluoromethyl)phenylboronic acid (0.86 g, 3.32 mmol) in dioxane (25 mL) heated to 90° C. was added tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) and potassium phosphate (0.94 g, 4.42 mmol). The reaction mixture was allowed to stir at 90° C. for 12 h. The reaction mixture was allowed to cool and was diluted with diethyl ether (100 mL), filtered (celite), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethylacetate:hexanes 1:9) afforded 0.75 g (66%) of (±)-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.49 (silica, ethyl acetate:hexanes 1:3); mp 100-105° C.; Anal. calcd. for C24H18F6O4S2: C, 55.82; H, 3.51. Found: C, 55.75; H, 3.35.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:33])[C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][C@H:6]([CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:13][CH:12]=1)[CH:7]([CH3:9])[CH3:8].[CH3:34][C:35]([CH3:43])([CH2:39][CH2:40][CH2:41][CH3:42])[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][C:35]([CH3:43])([CH2:39][CH2:40][CH2:41][CH3:42])[C:36]([NH:1][CH2:2][C@H:3]([OH:33])[C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][C@H:6]([CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:13][CH:12]=1)[CH:7]([CH3:8])[CH3:9])=[O:37]
Reactant: CCCCC(C)(C)C(=O)O
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@H](C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a solution of tert-butyl (2S,3S,5S)-1-amino-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (350 mg, 0.76 mmol) in CH2Cl2 (15 mL), 2,2-dimethylhexanoic acid (176 mg, 1.22 mmol), HOBt (290 mg, 2.1 mmol) and EDCl (400 mg, 2.1 mmol) were added. The mixture cooled to 0° C. and DIEA (700 mg, 5.4 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 5 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl (2S,3S,5S)-1-(2,2-dimethylhexanamido)-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (335 mg, 75%). 1H NMR (400 MHz, CDCl3): 0.86 (m, 3H), 0.92 (m, 3H), 0.99 (m, 3H), 1.13 (s, 6H), 1.16 (m, 2H), 1.27 (m, 3H), 1.49 (m, 2H), 1.70 (m, 3H), 1.88 (m, 1H), 2.11 (m, 2H), 2.62 (m, 1H), 2.85 (m, 1H), 2.97 (m, 1H), 3.10 (m, 1H), 3.28 (s, 3H), 3.36 (m, 1H), 3.62 (m, 1H), 4.48 (m, 2H), 7.06 (m, 1H), 7.39 (s, 1H), 7.67 (m, 1H), 7.99 (s, 1H); MS: 588 (M++1)
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[C:11]#[N:12].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.ClCCl>[C:20]([NH:12][CH2:11][C:10]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=1[NH2:8])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc([N+](=O)[O-])cc1CNC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (116 ml, 0.835 mol) and DMAP (2.0 g, 0.016 mol) are added to 2-amino-5-nitrobenzonitrile (68 g, 0.33 mol) in dichloromethane (1 litre). The mixture is cooled to +5° C., and benzoyl chloride (38.8 ml, 0.33 mol) in dichloromethane (50 ml) is added. The resulting mixture is stirred for 2 hours and then concentrated. The residue is taken up in 10/1 water/ethanol (550 ml) and the product is filtered off and recrystallized from isopropyl ether. Yield: 88.5 g (97%); IR (KBr): 3375, 3213, 1638, 1547, 1319 cm−1; 1H-NMR (d6-DMSO) 8.15 (m, 1H); 7.85 (m, 4H); 7.51 (m, 4H); 6.68 (m, 3H); 4.30 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:3]1.[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH:23]([CH3:25])[CH3:24])[C:5](=[O:7])[C:4]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
A mixture of tert-butyl 2,4-dioxo-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (4.18 g, 15.5 mmol), 60% sodium hydride in oil (0.68 g, 17 mmol), and DMF (25 mL) was stirred approximately one hour at 25° C.; then 2-iodopropane (2.7 g, 16 mmol) was added and stirring was continued for three days. The solvent was removed under reduced pressure, and the residue was stirred with water (80 mL) for a few minutes. The insoluble solid was collected and purified by chromatography, eluting with ethyl acetate/hexane (60:40). tert-Butyl 2,4-dioxo-3-(1-methylethyl)-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (0.66 g, 2.1 mmol), m.p. 206°-208° C. was obtained as fine needles.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH:3]([CH3:5])[CH3:4].[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:30]1[CH2:31][O:32][CH:6]([CH2:7][C@H:8]([C@@H:10]2[C@:28]3([CH3:29])[C@H:13]([C@H:14]4[C@H:25]([CH2:26][CH2:27]3)[C@:23]3([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]3)[OH:20])=[CH:16][CH2:15]4)[CH2:12][CH2:11]2)[CH3:9])[CH:2]([CH:3]([CH3:5])[CH3:4])[O:1]1
Reactant: OCCO
Reactant: CC(C)C(=O)CC[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
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C1OCCOC1C[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
Temperature: 105 °C

Procedure:
27 g of 24-oxocholesterol was dissolved in 717 ml of anhydrous benzene. To the solution were added 179 ml of ethylene glycol and 358 mg of p-toluen sulfonic acid. The mixture was stirred and heated at a bath temperature of 105° C. for 20 hours in a flask equipped with receiver capable of mesuring water in which was added a molecular sieve. Water was added to separate the reaction mixture into layers. The aqueous layer was extracted with benzene.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[C:18]([CH:11]1[C:10](=[O:21])[C@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NNc1ccccc1Cl
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.7 %

Procedure:
Triethylamine (1.7 mL, 12.1 mmol) was added dropwise to a cooled (0° C.) solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 1.00 g, 4.66 mmol) in dichloromethane (10 mL), yielding a thick slurry. Dichloromethane (5 mL) was added to facilitate stirring. The reaction mixture was stirred at 0° C. for 5 min and then N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 936 mg, 3.85 mmol) was added in small portions over 2-3 min. The reaction mixture was allowed to warm to room temperature and stir overnight, then it was cooled again to 0° C. and triethylamine (0.5 mL, 3.6 mmol) and a solution of N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 241 mg, 1.12 mmol) in dichloromethane (1 mL) were added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 6 h. Again triethylamine (0.8 mL, 5.7 mmol) and a solution of N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 431 mg, 2.0 mmol) in dichloromethane (1 mL) were added at 0° C. and the reaction mixture was allowed to warm to room temperature and stir over the weekend. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with water (25 mL), 1 M HCl (50 mL), and brine (2×50 mL). The organic layer was dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RediSep-40 g silica gel column, eluting with 5-50% ethyl acetate/hexanes, to give N′-(2-chloro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (1.275 g, 79%) as a pale yellow foam.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]4[CH:27]=3)=[CH:14][CH:13]=2)=O)[CH2:6][CH2:5][CH2:4]C[CH2:2]1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]4[CH:27]=3)=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:2]1
Reactant: Cc1cccn2cc(-c3ccc(NC(=O)CCN4CCCCC4)cc3)nc12
Solvent: Cc1ccccc1
Product: Cc1cccn2cc(-c3ccc(NCCCN4CCCC4)cc3)nc12
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of the product of Step C (122 mg) and borane-methylsulfide complex (0.5 mL of a 2M solution in toluene) in toluene (3.5 mL) was stirred and heated at reflux for 18 hours. The mixture was cooled to ambient temperature and evaporated. The residue was treated with 1M HCl (10 mL) and heated to reflux. The aqueous mixture was cooled to ambient temperature and treated with solid sodium hydroxide until the pH of the mixture was 8. The aqueous mixture was extracted three times with dichloromethane (10 mL each). The combined organic layers were dried over sodium sulfate, decanted and evaporated. The residue was purified via silica gel chromatography (methanol/dichloromethane) to yield the title compound (60 mg). 1H-NMR (CD3OD) δ 8.16 (d, J=7.0 Hz, 1H), 7.90 (s, 1H), 7.72 (m, 2H), 7.00 (m, 1H), 6.71 (m, 3H), 3.16 (t, J=7.0 Hz, 2H), 2.59 (m, 9H), 1.86 (m, 2H), 1.65 (m, 4H), 1.50 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=O)[CH3:2].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>O>[CH3:9][C:7]1[S:8][C:4]([C:1](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2])=[C:5]([CH3:10])[N:6]=1
Reactant: CC(=O)c1sc(C)nc1C
Reactant: NNC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=NNC(=O)c1ccccc1)c1sc(C)nc1C
Yield: 54 %

Procedure:
A mixture of 5.0 gm (0.322 mole) of 5-acetyl-2,4-dimethylthiazole, 4.38 gm (0 0322 mole) of benzhydrazide, 10 drops of glacial acid and 100 ml of ethanol is refluxed 48 hrs. The reaction mixture is diluted with water to the cloud point then chilled. The product is collected and dried to give 4.75 gm (54%) of the title compound having a melting point of 138.4° C.