Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14](=[O:22])[CH:13]=1.C(N(C(C)C)CC)(C)C.C(OC([NH:39][C:40](N1C=CC=N1)=[N:41]C(OC(C)(C)C)=O)=O)(C)(C)C>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:22]=[C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:40]([NH2:41])=[NH:39])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCCOc1cc(=O)oc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N=C(N)NCCOc1cc(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
4-(2-Amino-ethoxy)-1-benzopyran-2-one trifluoroacetate (0.313 mmol, 100 mg) is placed in a small vial along with 2 mL of acetonitrile. Diisopropylethylamine is added dropwise until the pH of the solution is ˜9 by pH paper. N,N′-Bis(tert-butoxycarbonyl)-1-H-pyrazole-1-carboxamidine (0.24 mmol, 74.5 mg) is added and the reaction is mixed at ambient temperature for 5 hrs. The reaction mixture is concentrated in vacuo, then is redissolved in neat TFA and is stirred at ambient temperature for 30 min. The TFA is removed under reduced pressure and the residue is purified by reversed-phase HPLC to afford the title compound as the trifluoroacetic acid salt (35.0 mg, 31%). 1H NMR (DMSO-d6, 300 MHz) δ 7.88 (1H, dd, J=1.5, 8 Hz), 7.81 (1H, br t), 7.68 (1H, m), 7.39 (2H, m), 7.28 (3H, br s), 5.49 (1H, s), 4.30 (2H, t, J=5 Hz), 3.67 (2H, q, J=5.5 Hz); MS (ESI, Pos.) calcd for C12H13N3O3 m/z [M+H]=248.1, found 248.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[NH3:13].C(OCC)(=O)C.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:13])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 4-bromo-2-chlorobenzenesulfonyl chloride (2.50 g, 8.45 mmol) in THF (25 ml) was added a solution of ammonia (25%, 6.3 ml, 84.5 mmol). The reaction mixture was stirred for 4 h at RT. Ethyl acetate (70 ml) and water (50 mL) were added. The organic phase was separated and washed with hydrochloric acid (1 M, 50 ml) and brine (2×30 ml) and dried over sodium sulfate. After evaporation the product was obtained as a white solid (2.05 g, 90%) which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].C(O[C:11]([NH:13][CH:14]1[N:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[NH:16][C:15]1=[O:28])=[O:12])C1C=CC=CC=1.Br[CH2:30][C:31]([N:33]1[CH2:39][CH:38]2[CH2:40][CH2:41][CH:35]([CH2:36][CH2:37]2)[CH2:34]1)=[O:32].CN(C)[CH:44]=[O:45]>>[CH:35]12[CH2:41][CH2:40][CH:38]([CH2:37][CH2:36]1)[CH2:39][N:33]([C:31]([CH2:30][N:16]1[C:17]3[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=3[C:19]([CH:21]([CH3:22])[CH3:23])=[N:20][C:14]([N:13]=[C:11]=[O:12])([O:45][CH2:44][C:17]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:18]=3)[C:15]1=[O:28])=[O:32])[CH2:34]2
Reactant: CN(C)C=O
Reactant: O=C(CBr)N1CC2CCC(CC2)C1
Reactant: CC(C)C1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CC(C)C1=NC(N=C=O)(OCc2ccccc2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2ccccc21
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.123 g of a 65% dispersion in mineral oil) in dry N, N-dimethylformamide (10 ml) was added dropwise a solution of (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (1.00 g) in dry N,N-dimethylformamide (5 ml) under cooling in an ice-bath. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. To the mixture was added dropwise a solution of N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.77 g) in dry N,N-dimethylformamide (5 ml) and stirred at the same condition for 2 hours. The reaction mixture was concentrated in vacuo and the residue was taken up with ethyl acetate (100 ml) and a saturated aqueous sodium hydrogen carbonate (100 ml). The organic layer was washed with a brine (50 ml) and dried over anhydrous magnesium sulfate. Filtration and evaporation gave (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxy-carbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[OH:11][CH:12]([CH3:16])[C:13](=O)[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[OH:11][CH:12]([CH3:16])[CH:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)[CH3:14]
Reactant: COC(=O)c1csc(N)n1
Reactant: CC(=O)C(C)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1csc(NC(C)C(C)O)n1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Methyl 2-aminothiazole-4-carboxylate (1.0, 6.32 mmol), 3-hydroxy-2-butanone (1.045 ml, 12.01 mmol) and acetic acid (2.278 g, 37.9 mmol) were dissolved in 1,2-dichloroethane. Sodium triacetoxy borohydride (3.75 g, 17.70 mmol) was added and the reaction mixture was stirred overnight. Sodium triacetoxy borohydride (3.1 g) was added in two portions and the reaction mixture was stirred over two nights. 1M NaHCO3 was added slowly and mixture was extracted twice with DCM. DCM phase was dried and evaporated to afford 68.1% of the title product. m/z [230.3+1].
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[CH3:18][CH:19]1O[CH2:20]1.[CH2:22]1[O:24][CH2:23]1.C1OC1.[CH2:28]1O[CH:29]1[CH3:30]>>[C:22]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:24])[CH2:23][CH2:18][CH2:19][CH2:20][CH:29]([CH3:30])[CH3:28]
Reactant: CC1CO1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C1CO1
Agent: *CCO*
Product: CCCCCCCCCCCCCCCCOC(=O)CCCCC(C)C

Procedure:
The emulsion of cetyl isooctanoate was prepared using a mixture of polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene (5) oleyl ether. The numbers in parentheses are the number of moles of ethyleneoxide or propyleneoxide added.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([N:9]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]([O:17][CH3:18])=[N:11][C:10]1=O)[CH3:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[N:9]([CH2:7][CH3:8])[S:14](=[O:16])(=[O:15])[N:13]=[C:12]([O:17][CH3:18])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN1C(=O)N=C(OC)NS1(=O)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN1C(Cl)=NC(OC)=NS1(=O)=O
Reaction time: 2 h
Yield: 91 %

Procedure:
154 parts of phosphorus pentachloride were added, in the course of 2 minutes, to a stirred mixture of 128 parts of 6-ethyl-3-methoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide and 840 parts of phosphorus oxychloride at 25° C. The reaction mixture was then stirred for 51/2 hours under reflux, after which it was evaporated down under reduced pressure. The oil which remained was taken up in 300 parts of 1,2-dichloroethane and the solution was chromatographed over neutral alumina (Activity I). After evaporating down, 127.5 parts (91% of theory) of 5-chloro-6-ethyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 63°-70° C., were obtained (Compound No. 2).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=O)[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.P(Cl)(Cl)(OC1C=CC(Cl)=CC=1)=O.CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[N:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[N:20]=[N+:21]=[N-:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: c1nc[nH]n1
Agent: O=P(Cl)(Cl)Oc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(-n3cncn3)nc2=O)C[C@@H]1N=[N+]=[N-]
Yield: 60 %

Procedure:
5'-O-Acetyl-3'-azido-3'-deoxythymidine was reacted with 5 equivalents of 1,2,4-triazole and two equivalents of 4-chlorophenyl dichlorophosphate in dry pyridine at ambient temperature for 10 days. Silica gel chromatography of the crude product using 1:1 EtOAc/hexane (v/v) followed by combination and evaporation of the appropriate fractions yielded an oil. Crystallization from EtOAc afforded the title compound as a solid 2.7 g (7.5 mMol; 60%); m.p.=143°-145° C. UV (nm): at pH 1λmax =324,245,215 (ε=9300, 10000, 20500), λmin =282,233 (ε=2100,8200); at pH 13λmax =276 (ε=6000), λmin =242 (ε=2000), H1NMR (DMSO-d6) δ9.34, 8.40(2s,2H, triazolyl), δ8.23(s,1H,H6), δ6.12(t, 1H, H1', J=6.16 Hz), β4.48-4.17(m, 4H, H3', H4', H5'), δ2.35(s, 3H, 5'-acetyl), δ2.07(s, 3H, 5CH3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][C@@H:30]([CH3:34])[CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[C@@H:30]([CH3:34])[CH2:29]1)[CH3:27]
Reactant: CCN1CCN[C@@H](C)C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)[C@@H](C)C1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-3-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.20 Hz, 3 H) 1.38 (d, J=7.07 Hz, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.68-5.32 (m, 9 H) 7.63 (d, J=7.33 Hz, 1H) 7.70-7.80 (m, 1 H) 7.94-8.73 (m, 4 H) 8.97-10.49 (m, 1 H). ESI-MS m/z [M+H]+449.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([O:44][CH:45]([CH2:53][O:54][C:55](=[O:71])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:46][S:47][CH2:48][CH2:49][C:50](O)=[O:51])(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:50](=[O:51])[CH2:49][CH2:48][S:47][CH2:46][CH:45]([O:44][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:53][O:54][C:55](=[O:71])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-aminobenzoylaspartic acid di-t-butyl ester (168 mg) in pyridine (2.3 ml), phosphorus trichloride (0.02 ml) was added, followed by stirring at room temperature for 2 hours. To the mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (150 mg) was added, followed by stirring at room temperature for 64 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate =3:1) to yield the title compound (197 mg, yield 85%) as a wax-like substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@H:17]([C:26](O)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:16][C@H:17]([C:26]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCC[C@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC[C@H](C)C(=O)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
{circle around (1)}: A mixture comprising 2.00 g of 4-benzyloxyphenol, 1.86 g of (S)-1-methylnonylcarboxylic acid, 2.06 g of DCC and 20 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate. The resultant residue was purified by means of silica gel column chromatography, whereby 3.2 g of (S)-4-(1′-methylnonylcarbonyloxy)-1-benzyloxybenzene was obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4-c4ccccc4)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4-c4ccccc4)ccc3c2)cc1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A mixture of methyl 4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoate (235 mg, 0.461 mmol), prepared in the previous step, and 1 N NaOH (692 μL, 0.692 mmol) in 30 mL of THF plus 30 mL of methanol plus 5 mL of water was refluxed under nitrogen for 7 h. The reaction was filtered, cooled to room temperature, acidified by the addition of 2.5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (225 mg, 99%) as a white solid, mp 309–310° C. Elemental Analysis for C34H25NO3.0.05 C4H8O.0.19 H2O Calc'd: C, 81.73; H, 5.17; N, 2.79. Found: C, 81.94; H, 5.02; N, 2.65.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:28]2[CH2:29][CH2:30][N:25]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[N:24]=3)[CH2:26][CH2:27]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nccc(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nccc(N2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Yield: 24.1 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (7.14 g) and 1-(2-methylpyrimidin-4-yl)piperazine dihydrochloride (8.38 g) in methanol/acetic acid (99:1) (150 ml) was added sodium cyanoborohydride (6.32 g) portionwise over 30 minutes and the resultant suspension stirred at arnbient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 1-tert-butoxycarbonyl-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylmethyl]piperidine (3.02 g) as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]O)[N:3]=1.O=S(Cl)[Cl:12]>C(Cl)Cl>[ClH:12].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:12])[N:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-6-(hydroxymethyl)pyridine (0.54 g, 2.87 mmol) in dry CH2Cl2 (10 mL) at 0° C. under N2 in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (4.2 mL, 57.90 mmol) and the mixture was stirred for 2 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CHCl3 (20 mL) before concentration back to dryness at 40° C. under vacuum (done twice) to give 2-bromo-6-(chloromethyl)pyridine hydrochloride CCH 34150-1 as a brown solid (0.65 g, 93% yield).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:29]([OH:31])=[O:30])[CH2:10]1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[CH2:37]([O:36][C:34]([CH2:33][O:30][C:29]([C@H:18]1[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([C:22](=[O:28])[CH2:21][C@:19]12[CH3:20])[C@:24]1([CH3:27])[C@H:11]([CH2:10][C@H:9]([OH:8])[CH2:26][CH2:25]1)[CH2:12][CH2:13]3)=[O:31])=[O:35])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h

Procedure:
Triethylamine (4.5 mmole) was added to a solution of 3α-hydroxy-5α-androstan-11-one 17β-carboxylic acid (1.025g.,) in warm acetone (50 ml.) followed by ethyl bromoacetate (6 mmole) and the reaction mixture stood at room temperature overnight. The reaction was completed by refluxing for 1 hr., evaporating to dryness and partitioning the residue between water and ether. The ethereal solution was washed with water, dried, and evaporated to give a residue (1.61g.) which was purified by preparative t.l.c. to afford the pure title compound; [α]D + 76°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=O.[Cl-].[CH2:14]([O:21][C:22]1[CH:47]=[CH:46][CH:45]=[CH:44][C:23]=1[CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=[CH:24][C:23]1[CH:44]=[CH:45][CH:46]=[CH:47][C:22]=1[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccccc1CCC=O
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccccc1CCC=Cc1ccccc1OCc1ccccc1

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, the whole of the 3-(2-methoxyphenyl)propanal prepared as described above, 1.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 1.01 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were reacted in 30 ml of acetonitrile. The crude product, extracted as described in Preparation 3, was purified by column chromatography through silica gel, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.98 g of benzyl 2-[4-(2-methoxyphenyl)-1-butenyl]phenyl ether as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:21][NH:22][O:23][CH:24]=[C:25]=[O:26])[CH2:14][CH2:13]1.[Cl:32][C:33]1[C:34](=[O:43])[NH:35][N:36]=[C:37]([O:40][CH2:41][CH3:42])[C:38]=1Cl.C(N(CC)CC)C.C(O)CC>O>[Cl:32][C:33]1[C:34](=[O:43])[NH:35][N:36]=[C:37]([O:40][CH2:41][CH3:42])[C:38]=1[N:22]([O:23][CH:24]=[C:25]=[O:26])[CH2:21][C:20]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:13][CH2:14]2)[CH:19]=1
Reactant: COc1ccc(CNOC=C=O)cc1N1CCN(Cc2ccc3ccccc3n2)CC1
Reactant: CCOc1n[nH]c(=O)c(Cl)c1Cl
Solvent: CCCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1n[nH]c(=O)c(Cl)c1N(Cc1ccc(OC)c(N2CCN(Cc3ccc4ccccc4n3)CC2)c1)OC=C=O
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture comprising 2.4 g of 3-[4-(2-quinolylmethyl)-piperazin-1-yl]-carbonylmethoxy-4-methoxybenzylamine, 1 g of 4,5-dichloro-6-ethoxy-3(2H)-pyridazinone, 580 mg of triethylamine, 10 ml of propanol and 10 ml of water, was refluxed under heating with stirring overnight. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=6:1→chloroform:methanol=12:1) and then crystallized from diethyl ether to obtain 1.5 g of the above-identified compound as white crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[O:21])=[CH:15][CH:14]=1.ClS([N:32]=[C:33]=[O:34])(=O)=O.[C:35](O)(=O)[CH3:36].O>C1COCC1>[C:33]([NH:22][C:20](=[O:21])[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:18][CH:17]=1)[CH:23]1[CH2:36][CH2:35][CH2:24][CH2:25][CH2:26][CH2:27]1)(=[O:34])[NH2:32]
Reactant: CC(=O)O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Temperature: 100 °C

Procedure:
10 g (0.0257 mol) of the compound from Example III are suspended in 100 ml of THF at 0° C., and 2.5 ml (4 g/0.028 mol) of chlorosulphonyl isocyanate are added, with exclusion of moisture. The mixture is allowed to after-react for 15 minutes, while stirring, 120 ml of glacial acetic acid/water (2/1) are added and the temperature is allowed to rise to room temperature. To bring the reaction to completion, the mixture is heated at 100° C. for a further 15 minutes, during which a uniform solution forms. The solution is evaporated to dryness in vacuo, and the residue is extracted by stirring with 50 ml of water for 15 minutes and recrystallised from THF/ethylene chloride.