Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]CC)=O.[OH-].[Na+]>C(O)C.CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[O:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6](=[O:8])[C:5]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCOc1c(SC)cccc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C1CCOc2c(SC)cccc2C1=O
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 79.3 %

Procedure:
To a solution of ethyl 3-methylthio-2-(3-ethoxycarbonylpropoxy)benzoate (3.83 g) in a mixture of ethanol (34 μl) and N,N-dimethylformamide (40 ml) was added 60% sodium hydroxide (1.03 mg) at 5° C. After the mixture was allowed to stir at room temperature for 15.5 hours, it was poured into ice-water and extracted with ethyl acetate (x 3). The combined extracts were washed with water (x 2) and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (20:1) to give ethyl 9-methylthio-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (2.61 g, colorless crystals).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.Cl[CH2:20][O:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][O:21][CH2:20][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)COCCl
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Product: Cc1c(-c2cccnc2)n(COCC(C)(C)C)c2ccc(C#N)cc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) and 1-chloromethoxy-2,2-dimethyl-propane are processed according to the method described in Example 68 to give 1-(2,2-dimethyl-propoxymethyl)-3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, MeOD) δ ppm 0.84 (s, 9H), 2.33 (s, 3H), 3.04 (s, 2H), 5.48 (s, 2H), 7.59 (dd, J=8.6, 1.5 Hz, 1H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.77 (dd, J=8.6, 0.5 Hz, 1H), 8.07 (dt, J=7.8, 1.9 Hz, 1H), 8.09 (dd, J=1.5, 0.8 Hz, 1H), 8.70 (dd, J=4.9, 1.6 Hz, 1H), 8.75 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 334.1914 [(M+H)+ Calcd for C21H24N3O: 334.1919].
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Br)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Br)cccc2-3)no1
Yield: 94.1 %

Procedure:
1.3 g (3 mmol) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one were stirred at room temperature for 5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.41 g (94%) of (S)-8-bromo-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[CH:9]=[N:10][CH:11]=1.[CH3:14][NH2:15]>CO>[CH3:14][NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: CN
Reactant: COc1cncc(OCCCCl)c1
Solvent: CO
Product: CNCCCOc1cncc(OC)c1
Temperature: 100 °C

Procedure:
Crude 5-(3-chloropropoxy)-3-methoxypyridine (0.75 g, 3.73 mmol) was dissolved in methanol (10.5 mL) and added to a 40 wt % aqueous solution of methylamine (10.6 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation. Saturated NaCl solution (50 mL) was added, and the mixture was basified with 10% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give 0.54 g of a brown oil. The product was purified by column chromatography on silica gel (18 g) eluting with CHCl3—CH3OH (1:1, v/v) to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2, v/v/v) to collect the product. Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3 (25 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to give 0.228 g (31.2%) of a brown oil.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=O)[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[NH2:52][OH:53]>>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])/[C:7](=[N:52]\[OH:53])/[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: NO
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)/C(=N\O)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
reacting the C-9 ketone of erythromycin A with hydroxylamine to form erythromycin oxime;
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22]C2C=CC=CC=2)=[O:20])[C:3]=1[Cl:29].CO.C[O-].[Na+]>O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:29]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Reaction time: 24 h

Procedure:
Benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (3.00 g, 6.83 mmol) was added to CH3OH (35 mL). Sodium methoxide (25 wt % in CH3OH; 1.9 mL, 8.2 mmol) was added to the reaction mixture. and the reaction mixture was allowed to stir for 24 h. Water (50 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove most of the CH3OH. The mixture was extracted with EtOAc (2×40 mL), and the combined organic layers were washed with water (40 mL) and satd sodium chloride (40 mL). Concentration of the volatiles under reduced pressure provided methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate as a pale yellow solid (2.04 g, 88% purity by LC area).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([CH3:28])[CH:16]=1.C(N(CC)CC)C.[CH:36]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O>[CH:36]1([NH:41][C:42]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=5)[N:10]=[CH:9][N:8]=4)=[CH:16][C:17]=3[CH3:28])[CH2:23][CH2:24]2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2c1
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2ncnc(Nc3ccc(OC4CCN(C(=O)NC5CCCC5)CC4)c(C)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a suspension of (6-Methoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (150 mg, 0.251 mmol) in N,N-dimethylformamide (1.5mL) was added triethylamine (143 μL, 1.03 mmol) and cyclopentyl isocyanate (0.343 mmol). The reaction was stirred at room temperature overnight The reaction was then filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 36.3 mg of 4-[4-(6-Methoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-piperidine-1-carboxylic acid cyclopentylamide was isolated. 1H NMR (300 MHz, DMSO d6) δ 9.505 (s, 1H), 8.436 (s, 1H), 7.904 (d, J=0.9 Hz, 1H), 7.707 (d, J=3.0 Hz, 1H), 7.498-7.458 (dd, J=9.0, 3.0 Hz, 1H), 7.571-7.513 (m, 2H), 7.045 (d, J=3.0 Hz, 1H), 6.28 (d, J=2.3 Hz, 1H), 4.564-4.514 (m, 1H), 3.962-3.894 (m, 1H), 3.950 (s, 3H), 3.677-3.599 (m, 2H), 3.246-3.163 (m, 2H), 2.216 (s, 3H), 1.928-1.863 (m, 2H), 1.862-1.751 (m, 2H) 1.671-1.518 (m, 4H), 1.517-1.365 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23]S[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:39][S:40]([O-:42])=O.[K+]>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:40](=[O:42])(=[O:39])[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCSCC3)c2=O)cc1OC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCS(=O)(=O)CC3)c2=O)cc1OC
Yield: 77.7 %

Procedure:
0.55 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-thiopyran-4-yl)-quinazoline-2,4(1H,3H)-dione and 0.196 g of Oxone® in 100 ml of an MeOH/water mixture (10/1) (v/v) is stirred at room temperature overnight. The resulting mixture is evaporated under reduced pressure. Water is added and the resulting mixture is extracted with DCM. The organic phase is dried over Na2SO4. The resulting solution is filtered and the filtrate is then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture from (50/50, v/v) to (0/100, v/v) to give 0.454 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]([O:20][CH3:21])=[C:13]([C:16]([O:18]C)=[O:17])[NH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:6]([O:22][C:11]1[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[C:12]=1[O:20][CH3:21])[C:5]1[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1[nH]cc(C(=O)NCc2ccc(F)cc2)c(=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)ncc(C(=O)NCc2ccc(F)cc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109 %

Procedure:
The compound 28 (900 mg, 2.12 mmol) was dissolved in methanol (8 ml), and a 2N aqueous sodium hydroxide solution (4 ml) was added. The solution was stirred at room temperature for 2 hours, 2 M hydrochloric acid (3 ml) was added, and crystals were collected by filtration. 4-Benzyloxy-5-(4-fluoro-benzylcarbamoyl)-3-methoxy-pyridine-2-carboxylic acid 29 (474 mg, 54%) was obtained as a colorless crystal.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[N:10][CH:11]=1.[N+:14]([CH:17]=[C:18](SC)SC)([O-:16])=[O:15]>CO>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][N:4]2[CH2:3][CH:2]([CH3:13])[NH:1][C:18]2=[CH:17][N+:14]([O-:16])=[O:15])=[CH:11][N:10]=1
Reactant: CC(N)CNCc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CO
Product: CC1CN(Cc2ccc(Cl)nc2)C(=C[N+](=O)[O-])N1
Yield: 73 %

Procedure:
A mixture of 2 g of 2-amino-1-(2-chloro-5-pyridylmethylamino)propane, 1.6 g of 1-nitro-2,2-bis(methylthio)ethylene and 20 ml of methanol was refluxed for 5 hours with stirring. A crystaline product was precipitated after standing at room temperature. The product was filtered with suction, washed with methanol and then dried in vacuum. 1.9 g of 1-(2-chloro-5-pyridylmethyl)-4-methyl-2-(nitromethylene)imidazolidine was obtained in form of light yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:30])[CH2:27][NH:26][C@H:25]([CH2:28][OH:29])[CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([F:30])([F:22])[CH2:24][C@H:25]3[CH2:28][OH:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OC[C@@H]1CC(F)(F)CN1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(F)C[C@H]1CO

Procedure:
The title compound was synthesized in analogy to Example 47b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1 b) and (S)-(4,4-difluoropyrrolidin-2-yl)methanol hydrochloride (CAS 623583-10-8) as starting materials and isolated as colorless oil. MS (EI): m/e=404.5 [MH+].
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]CCCC.CCCCCC.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1COCC1>[CH3:25][N:26]([CH3:30])[C:27]([C:11]1[N:10]([CH3:13])[N:9]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:12]=1)=[O:28]
Reactant: Cc1ccc(C)n1-c1ccn(C)n1
Reactant: CN(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(=O)N(C)C)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (2.0 g, 11.4 mmol) in THF (100 mL) at −78° C., 2.5M nBuLi in Hexane (5.5 mL, 13.7 mmol) is added. After stirring for 1.5 hour dimethylcarbamyl chloride (1.26 mL, 13.7 mmol) is added. After 10 min the ice bath is removed and the reaction allowed to reach room temperature and stir at room temperature for 2 hour before being poured into water, separated, and the water layer extracted with DCM. The organic layers are combined and concentrated. The residue is purified by FCC to give the title compound. MS (ESI) m/z 247.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:9](=[N:11][OH:12])[NH2:10])=[N:7][CH:8]=1.[Br:15][C:16]1[CH:20]=[CH:19][O:18][C:17]=1[C:21](Cl)=O>>[Br:15][C:16]1[CH:20]=[CH:19][O:18][C:17]=1[C:21]1[O:12][N:11]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:8][N:7]=2)[N:10]=1
Reactant: O=C(Cl)c1occc1Br
Reactant: NC(=NO)c1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(-c2noc(-c3occc3Br)n2)nc1

Procedure:
The title compound was prepared from 5-trifluoromethyl-pyridine-2-amidoxime (480 mg, 2.34 mmol) and 3-bromo-furan-2-carbonyl chloride (490 mg, 2.34 mmol) similar to Example 16, and yielded 718 mg (85%) of light yellow solid. 1H NMR (CDCl3): 9.09 (m, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.14 (dd, J=8.10, 2.34 Hz, 1H), 7.70 (d, J=1.92 Hz, 1H), 6.78 (d, J=1.92 Hz, 1H).
Reaction SMILES: [C:1]([CH:5]1[CH2:26][CH2:25][C:8]2([O:12][CH:11]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([CH:5]1[CH2:26][CH2:25][C:8]2([O:12][CH:11]([CH2:13][NH2:14])[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CN1C(=O)c3ccccc3C1=O)O2
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)OCC(CN)O2
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a warm (50° C.) solution of 8-t-butyl-2-(phthalimidomethyl)-1,4-dioxaspiro(4,5)decane (12.5 g, 35 mmol) in ethanol (100 ml) was added hydrazine hydrate (3.6 g, 72 mmol). The reaction mixture was kept at 50° C. for 1 hour. Light petroleum 200 ml was added and insoluble material was filtered off. The solvent was evaporated in vacuo. The residue was dissolved in toluene (100 ml) washed with brine (100 ml) and dried (MgSO4). Evaporation of the solvent yielded the title compound as a yellow oil (7.2 g). GC analysis indicated the compound as existing as a mixture of two diastereoisomers (cis, cis and cis, trans) in a ratio of 48:52. The NMR spectra are in agreement with the assigned structure.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][C@:6]1([OH:34])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C:21]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=4)[CH2:23][C@:7]12[CH3:8])=[C:20]1[C:15](=[CH:16][C:17](=[O:33])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:5]([C@:6]1([OH:34])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C:21]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=4)[CH2:23][C@:7]12[CH3:8])=[C:20]1[C:15](=[CH:16][C:17](=[O:33])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)[C:4]#[CH:3]
Reactant: CC(=O)c1ccc([C@H]2C[C@@]3(C)[C@@H](C=C[C@@]3(O)CC#C[Si](C)(C)C)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CC[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C(C)=O)cc3)C[C@@]21C
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
350 mg of 17-(3-trimethylsilyl-prop-2-inyl)-17β-hydroxy-11β-(4-acetylphenyl)-4,9,15-estratrien-3-one is dissolved in methanol and stirred at 23° C. for 1.5 hours after addition of 387 mg of potassium carbonate. This is poured into water and extracted with acetic ester. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed with a mixture of hexane/acetic ester over silica gel. 205 mg of the title compound is isolated as white foam. Crystallisation from ether yields 176 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][O:19]2)=[CH:5][CH:4]=1
Reactant: C=CCCCc1ccc(OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CCCC2CO2)cc1

Procedure:
5-(4-Methoxyphenyl)pent-1-ene (18.9 g, 0.107 mol) and 3-chloroperoxybenzoic acid (22.3 g of 85%, 0.11 mol) in dichloromethane (250 ml) was stirred at room temperature for 25 minutes. Dichloromethane (150 ml) was added and the resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×300 ml) and dried (MgSO4). The solvent was evaporated off under reduced pressure to yield an oil which was purified by column chromatography (silica gel, chloroform) to yield [3-(4-methoxyphenyl)propyl]oxirane as a colourless oil having the following structural characteristics:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:33](N)[CH2:34][CH3:35].C(OCC)(=O)C>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:33][CH2:34][CH3:35])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1
Reactant: CCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCNC1
Yield: 65 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and propylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as glass (100 mg, 65%); LCMS (method B): RT=3.89 min, M+H+=488.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 84.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2f (300 mg, 0.883 mmol), 6-mercaptopurine monohydrate (165 mg, 0.972 mmol), K2CO3 (134 mg, 0.972 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 341 mg of a pale orange crystalline solid (85%), mp 233.7-234.4° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.58 (br s, 1H); 8.50 (s, 1H); 8.47 (s, 1H); 7.77-7.85 (m, 2H); 7.68 (d, J=8.1 Hz, 2H); 7.65 (d, J=7.7 Hz, 1H); 7.41-7.56 (m, 2H); 4.45 (d, J=1.2 Hz, 2H). 13C NMR (DMSO-d6) ppm:, 158.7, 156.8, 153.8, 151.5, 149.6, 149.5, 143.5, 135.4, 134.1, 133.3, 132.2, 131.6, 131.6, 130.5, 130.2, 128.8, 127.1, 117.6, 32.0. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS.C2H6O.0.3H2: C, 52.14; H, 3.70; Cl, 13.99; N, 16.58; S, 6.33. Found: C, 52.07; H, 3.37; Cl, 13.40; N, 16.65; S, 6.42.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-bromosalicylaldehyde (5.00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) was added octyl bromide (4.52 ml), and the mixture was stirred at room temperature for 1.5 hr, and further at 50° C. for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine 3 times, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (7.72 g) as a white solid.
Reaction SMILES: Br[C:2](=[CH:6]OC)[C:3](=[O:5])[CH3:4].Cl.[C:10]([NH2:13])(=[NH:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[CH3:11][C:10]1[NH:12][CH:6]=[C:2]([C:3](=[O:5])[CH3:4])[N:13]=1
Reactant: CC(=N)N
Reactant: COC=C(Br)C(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1c[nH]c(C)n1
Yield: 230 %

Procedure:
6.3 g (35 mmol) of 3-bromo-4-methoxy-3-buten-2-one, 16.7 g acetamidine hydrochloride (175 mmol) and 29.2 ml triethylamine (210 mmol) were combined in 300 ml tetrahydrofuran and heated at reflux for 6 hours. The solvent was removed in vacuo to a crude orange solid. The crude solid was dissolved in 200 ml ethyl acetate and concentrated to 25 ml by boiling off the solvent. Cooling in ice resulted in crystallization of a yellow solid. This was collected by filtration, washed first with ethyl acetate, then with ether and dried at 25° in vacuo to give 9.995 g (23%) of 1-(2-methyl-4-imidazolyl)ethanone, mp 124°-7°. nmr (DMSO-d6) (δ): 4.61 (s, 1H); 1.41 (s, 3H); 1.39 (s, 3H).