Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:71]4[CH2:70][CH2:69][N:68]([CH3:67])[CH2:73][CH2:72]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 39.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenyl piperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(4-methylpiperazino)benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (11 mg, 39%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.26 (s, 3H, CH3), 2.49 (s, br, 4H, piperazine N(CH2)2), 2.63 (s, br, 4H, piperazine N(CH2)2), 3.30 (hidden by DMSO peak, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2), 3.65 (t, J=4.2 Hz, 4H, piperazine N(CH2)2), 7.06 (d, J=8.7 Hz, 2H, phenyl H-3 & H-5), 7.40 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.79 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.03 (d, J=8.7 Hz, 2H, phenyl H-2 & H-6), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (d, J=4.5 Hz, 1H, pyridine H-6), 8.57 (s, br, 1H, pyridine H-2), 13.22 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [F:1][CH:2]([F:42])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][OH:9])=[NH:7].C(N(C(C)C)CC)(C)C.Cl[C:53](OC1C=CC=CC=1)=[O:54].O>O1CCCC1>[F:42][CH:2]([F:1])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:36][CH2:37]2)[CH:11]=[CH:10][C:5]=1[C:6]1[NH:7][C:53](=[O:54])[O:9][N:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CN3CCC(C(F)(F)F)CC3)cc2OC(F)F)no1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 475 mg of 2-difluoromethoxy-N-hydroxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzamidine in 7.8 mL of tetrahydrofuran at 0° C. was added 1.8 mL of diisopropylethylamine followed by 0.1 mL of phenyl chloroformate. The resulting mixture was stirred for 5 minutes at 0° C. then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved 7.8 mL of tetrahydrofuran and 0.33 mL of diisopropylethylamine. The resulting solution was heated in a sealed tube to 150° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (diisopropyl ether 100 followed by a gradient from dichloromethane 100 to dichloromethane 90/methanol 10) followed by another column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/tetrahydrofuran 10) to give 70 mg of 3-{2-difluoromethoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]([CH2:27][C:28]1[O:44][C:31]([CH2:32][S:33][CH2:34][CH2:35][NH:36][CH:37](SC)[CH2:38][N+:39]([O-:41])=[O:40])=[CH:30][CH:29]=1)[CH3:26]>>[CH3:26][N:25]([CH2:27][C:28]1[O:44][C:31]([CH2:32][S:33][CH2:34][CH2:35][NH:36][C:37]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH3:21])=[CH:38][N+:39]([O-:41])=[O:40])=[CH:30][CH:29]=1)[CH3:24]
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: CSC(C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCN(C)CCN(Cc2ccc(F)cc2)c2ccccn2)o1

Procedure:
Preparation is effected analogously to Example 22, using 0.54 g (1.7 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of 1-[2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethyl]amino-1-methylthio-2-nitroethane as starting materials. Working up by chromatography analogously to Example 22 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=600 ([M+H]+, 12), 109 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 63° C. (ethanol/ether).
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C([O-])(=O)C.[Na+].O.[PH2]([O-])=O.[Na+]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1Nc2ccc3ccccc3c2CCC1(Cl)Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=[PH2][O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccc3ccccc3c2CCC1Cl
Temperature: 56 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
A solution of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho- [2,1-b]azepine (28.0 g, 100 mmol) in glacial acetic acid (250 ml) was placed under an atmosphere of nitrogen. Sodium acetate (22.6 g, 275 mmol), sodium hypophosphite hydrate (24.6 g, 280 mmol) and palladium on carbon (10%, 1.5 g) were added. The reaction mixture was stirred at 56° C. for 20 h under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and then filtered. The solid was boiled with THF (3×700 ml) and filtered while still warm. The combined THF phases were evaporated in vacuo to give 19.1 g of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho-[2,1-b]azepine.
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH:23]([CH3:25])[CH3:24])[CH2:8][C@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN1CCCN(C)C1=O>[N:26]([CH2:6][C@H:7]([CH:23]([CH3:25])[CH3:24])[CH2:8][C@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)[C@@H](COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CC(C)[C@@H](CN=[N+]=[N-])C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The mixture of 3.47 g of tert-butyl 4(S)-(2(S)-methanesulphonyloxymethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxyiate and 3.57 g of sodium azide in 50 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is stirred at 50° C. over 3 hours. The reaction mixture is cooled, poured onto water and extracted with diethyl ether (3×). The combined organic phases are washed successively with water (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.63 (1:1 EtOAc-heptane); Rt=5.86 (gradient I).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([Br:24])[CH:7]=[C:8]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:9]=2[CH2:11]O)[NH:4][N:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:40])([F:39])[CH2:37][NH2:38].C(O)(=O)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:38]([CH2:37][C:36]([F:40])([F:39])[F:35])[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:8]=3[CH:7]=[C:6]([Br:24])[C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1CO)C(=O)OC
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
(S)-Dimethyl 2-((3,7-dibromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (460 mg, 0.991 mmol) was dissolved in thionyl chloride (2.0 M. in dichloromethane) (496 μl, 0.992 mmol). Reaction stirred at room temperature for 4 hours. Mixture was concentrated by roto-vap. Residue was dissolved in ethyl acetate. Material was washed twice with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Residue (415 mg, 0.860 mmol) was dissolved in acetonitrile (15 mL). Potassium carbonate (165 mg, 1.194 mmol) was added to the mixture followed by 2,2,2-trifluoroethylamine (350 μl, 4.40 mmol). Mixture was warmed to reflux and held with stirring for 30 minutes. Mixture was cooled to room temperature. Mixture was filtered over celite. Filtrate was concentrated by roto-vap. Residue was dissolved in toluene (17 mL). Acetic acid (200 μl, 3.49 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 16 hours. Mixture was cooled to room temperature and then diluted with ethyl acetate. Mixture was washed with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as white solid in 45% yield. MS (M−H)−=512.1, 510.1, 514.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=N)[CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2].CC[O:33]C(C)=O>O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCOC(=N)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 100 °C

Procedure:
400 mg (0.89 mmol) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyrimidic acid ethyl ester were suspended in 10 ml water and heated to 100° C. for 2.5 h. EtOAc was added, and the inorganic phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated to give 355 mg (89%) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyric acid ethyl ester as yellow oil, MS: 452 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>C(O)C.[Pd]>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:14])=[N:6][CH:7]=1
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cnc1N
Reaction time: 5 h

Procedure:
Add 10% Pd/C (0.5 g) to a solution of 3 nitro-5-(trifluoromethyl) pyridin-2-amine (1.0 g, 4.83 mmol) in ethanol (10 mL). Hydrogenate the mixture at a pressure of 50 psi for 5 hours. Filter the mixture through celite, evaporate to dryness under reduced pressure to obtain 5-trifluoromethyl-pyridine-2,3 diamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[S:15])[NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:15][CH:20]=[C:18]([CH2:17][Cl:16])[N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)C1

Procedure:
To a solution of 3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.06 g, 4.60 mmol) in acetone (25 mL) was added 1,3-dichloroacetone (0.76 g, 5.98 mmol), MgSO4 (0.83 g, 6.1 mmol) and MgCO3 (3.87 g, 4.6 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (20 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1>O1CCOCC1>[O:20]=[C:14]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10](=[O:11])(=[O:12])[NH2:13])=[CH:8][CH:9]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(CCNC(=O)CCC(=O)O)cc1
Yield: 92000 %

Procedure:
4-(2-aminoethyl)benzene sulfonamide (1 g, 5.0 mmol) and succinic anhydride (500 mg, 5.0 mmol) were combined in a round bottom flask containing dioxane (100 mL) and the slurry was heated to a reflux overnight. The white solid was filtered and washed with cold dioxane to yield the desired product (1.4 g, 4.6 mol, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.71 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.38 (s, 1H), 3.26 (m, 2H), 2.75 (t, J=7.1 Hz, 2H), 2.5 (m, 2H), 2.3 (t, J=7.1 Hz, 2H); (M+H)+ (301).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:30][C@@H:8]3[C@H:9](O)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:51]>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:30][C@@H:8]3[C@@H:9]([Cl:51])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 24 g of 3β-acetoxy-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstan-7β-ol in 48 ml of pyridine and 48 ml of carbon tetrachloride was combined with 28 g of triphenylphosphine and stirred for 1.5 hours at room temperature. The reaction mixture was diluted with methylene chloride, washed with water, dried, and evaporated. The residue was chromatographed on silica gel, thus producing 21.5 g of 3β-acetoxy-7α-chloro-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstane, mp 169°-170° C. (diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N+:4]([O-])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl-].[NH4+].C(O)(=O)C>O.[Zn]>[Cl:1][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: [O-][n+]1nc(Cl)nc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc2nc(Cl)nnc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 21,8 g (0.1 mole) of 3,7-dichlorobenzo-1,2,4-triazine 1-oxide, 7.5 g of zinc dust and 5.5 g of ammonium chloride in 400 ml of water was stirred vigorously at room temperature for 24 hours. 50 ml of glacial acetic acid were then added, the mixture was stirred for a further hour and the insoluble constituents were then filtered off. The latter were extracted twice with methylene chloride. The combined methylene chloride solutions were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from wash benzine. 7.5 g, that is to say 37% of theory, of 3,7-dichloro-benzo-1,2,4-triazine with a melting point of 113°-115° C were obtained. ##STR36## (Preparation according to process variant (a))
Reaction SMILES: [Br-].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>C1COCC1>[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:48][CH:47]=1
Reactant: c1ccc(OCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C=CCCCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
To a suspension of 6-phenoxyhexyltriphenylphosphonium bromide (6.1) (4.60 g, 8.86 mmol) in dry THF (80 mL) at 0° C., under an argon atmosphere was added potassium bis(trimethylsilyl)amide (1.76 g, 8.86 mmol). The resulting slurry was stirred for 5 min at the same temperature and then a solution of 4-methoxybenzaldehyde (0.61 g, 4.46 mmol) in dry THF (10 mL) was added. The reaction mixture was stirred for an additional 10 min and quenched with saturated aqueous NH4Cl (20 mL). The resulting mixture was warmed to room temperature, diluted with Et2O (100 mL), the organic phase was separated and the aqueous phase extracted with Et2O. The combined organic layer was washed with brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The residue obtained was purified through a short column of silica gel, eluting with 5% Et2O-hexane, to give the product 7.1 (1.21 g, 92% yield, predominantly cis, cis:trans=96:4) as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21]S(C)(=O)=O)[CH:18]=[CH:17][C:16]=2[F:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[F:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2F)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2F)C(=O)C1

Procedure:
A solution of product from Step C (3.88 g, 9.65 mmol), potassium t-butoxide (2.16 g, 19.3 mmol) in ethanol (100 mL) and H2O (5 mL) was heated at reflux for 3 hours. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and sat. NH4Cl. The organic layer was washed with H2O, and brine and then dried over magnesium sulfate and concentrated in vacuo to give title product which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][OH:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CCCCCC.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH:15]=[O:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CCO)C(C)(C)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(=CC=O)C(C)(C)C1
Reaction time: 10 h
Yield: 71.1 %

Procedure:
Manganese dioxide (10 g) was added to a solution of 4-(2-hydroxyethylidene)-3,3-dimethylpiperidine-1-carboxylic acid t-butyl ester (0.9 g, 3.5 mmol) in a mixture of hexane (30 mL)-chloroform (10 mL) and stirred for 10 hours. After the reaction was completed, insoluble materials were filtered off through Celite, and the filtrate was concentrated under a reduced pressure to obtain 0.63 g (yield 70.8%) of 3,3-dimethyl-4-(2-oxoethylidene)piperidine-1-carboxylic acid t-butyl ester (VII-141, 142). Its physical property is shown below.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[O:12]([C:8](=[N:9][C:10]#[N:11])[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCNCC1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Product: N#CN=C(Oc1ccccc1)N1CCCCC1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a stirred solution of 6 g of diphenyl cyanocarbonimidate in 50 ml of dichloromethane at room temperature were added portionwise 2.1 g of piperidine. Stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated and the residue was crystallized from 2,2'-oxybispropane. The crystals were filtered off and dried, yielding 4.6 g (80.7%) of [phenoxy(1-piperidinyl)methylene]cyanamide; mp. 85.7° C. (interm. 32).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4=[CH:45][CH:46]=[CH:47][CH2:48][CH:43]4[NH:42][CH2:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4=[CH:45][CH:46]=[CH:47][CH2:48][CH:43]4[NH:42][CH2:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.