Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:12][CH2:13][CH:14]([OH:16])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NCC(C)O)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To 30 ml of a solution of 5.00 g of 3,4-dimethylbenzoic acid and 2.75 g of 1-amino-2-propanol in N,N-dimethylformamide, 4.95 g of 1-hydroxybenzotriazole, 6.96 ml of triethylamine and 7.02 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added sequentially, and stirred for 15 hours at room temperature. After addition of water, the reaction solution was extracted with ethyl acetate, washed with 10% hydrochloric acid, ice-cold water and aqueous solution of saturated sodium hydrogen carbonate sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 6.28 g of the objective compound as colorless crystals. M.p. 77–78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([O:33]CC)=[O:32])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:36])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:31]([OH:33])=[O:32])[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][S:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(CCSc4ccccc4)CC3)c2c1
Temperature: 25 °C
Yield: 29.4 %

Procedure:
To 1.5 mL of an ethanol solution containing 90 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(phenylthio)ethyl)piperidine-4-carboxylate, 0.5 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 3 hours and 10 min. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, water was added, and adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to give 25 mg of 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(phenylthio)ethyl)piperidine-4-carboxylic acid as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:35]
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Si]([O:18][C:19]1[CH:54]=[CH:53][C:22]([O:23][CH2:24][C@@H:25]([OH:52])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[CH2:45][CH2:46][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:47]1([CH2:46][CH2:45][C:37]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:52])[CH2:24][O:23][C:22]4[CH:53]=[CH:54][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]=2)[CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(CCC4CCCC4)nc4cccnc43)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(CCC4CCCC4)nc4cccnc43)cc2)cc1
Yield: 77.7 %

Procedure:
(2S)-1-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-3-({4-[2-(2-cyclopentylethyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethyl}amino)-2-propanol (0.209 g, 0.283 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.11 g, 0.22 mmol).
Reaction SMILES: CN(CCC1C=CC=CC=1)[C:3](=O)[CH2:4]N1C2C(=CC(OCC3C=CC=CC=3)=CC=2)C(C=CC(OCC)=O)=C1.[CH3:38][N:39]([CH2:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:40](=[O:66])[CH2:41][N:42]1[C:50]2[C:45](=[C:46]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:47]=[CH:48][CH:49]=2)[C:44]([CH:59]=[CH:60][C:61]([O:63]CC)=[O:62])=[CH:43]1.CN(CCC1C=CC=CC=1)C(=O)CN1C2C(=C(OCC3C=CC=CC=3)C=CC=2)C(C=CC(O)=O)=C1>>[CH3:38][N:39]([CH2:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[C:40](=[O:66])[CH2:41][N:42]1[C:50]2[C:45](=[C:46]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:47]=[CH:48][CH:49]=2)[C:44]([CH:59]=[C:60]([C:61]([OH:63])=[O:62])[CH2:3][CH3:4])=[CH:43]1
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2cccc(OCc3ccccc3)c12
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC(=O)O)c2c(OCc3ccccc3)cccc21
Product: CCC(=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2cccc(OCc3ccccc3)c12)C(=O)O

Procedure:
When N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamide in the procedure of Example 23 is replaced with N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboethoxyvinyl)indol-1-yl]acetamide then the product prepared is N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide as a white powder. (m.p. 170°-174° C.)
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41](O)=[O:42])(=[O:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[C:33]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:42])(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), (S)-acetyl-pyrrolidine-2-carboxylic acid (35 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (64 mg). MS found for C31H34F2N6O3 as (M+H)+ 577.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.13 (with 8.15, 1H, s), 7.36 (with 7.32, 2H, d, J=8.8 Hz), 7.25 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.83 (with 5.79, 1H, s), 4.95 (1H, m), 4.65 (1H, m), 4.56 (with 4.55, 2H, s), 4.20 (1H, m), 3.66 (2H, m), 3.30 (1H, m), 2.92 (1H, m), 2.79 (1H, m), 2.27 (1H, m), 2.12 (with 2.10, 3H, s), 2.07-1.85 (5H, m), 1.68 (2H, m) ppm.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH2:24][CH2:23]1>O1CCCC1.C(OCC)(=O)C>[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])[CH2:24][CH2:23]1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: CN1CCNc2ccccc21
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)C2(C(=O)O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (1 g, 7.69 mmol) in dry tetrahydrofuran (20 mL) at 0° C. under nitrogen, was added triethylamine (1.07 mL, 7.69 mmol) and the mixture was stirred for 30 min. Thionyl chloride (0.56 mL, 7.69 mmol) was added, stirring was continued at 0° C. for 30 min., 1-methyl-1,2,3,4-tetrahydroquinoxaline (310) (1.2 g, 8.46 mmol)[Smith R. F. et al., J. Org. Chem., 24, 1959, 205] was added and the reaction mixture was allowed to warm to room temperature. After stirring for 1 h, ethyl acetate was added and the resulting mixture was extracted twice with a 1N NaOH solution. The combined aqueous layers were acidified to pH 4-5 by addition of a 3N HCl solution and extracted 4 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by Biotage (Si 12M, gradient: MeOH in dichloromethane 0% to 10%) to afford title compound 311 (638 mg, 32% yield). MS (m/z): 259.0 (M−H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:22]Br>[N+](C1C=CC=CC=1)([O-])=O.CO>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[C:8]([Br:22])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cccc2c1C(=O)c1c(O)cccc1C2=O
Reactant: BrBr
Solvent: CO
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)Nc1ccc(Br)c2c1C(=O)c1c(O)cccc1C2=O

Procedure:
55 g of 1-isopropylamino-8-hydroxy-anthraquinone are dissolved in 110 ml of nitrobenzene at 100°, the solution is cooled to 15°-20° whilst stirring, 40 g of bromine are added over the course of approx. 10 minutes, the mixture is stirred overnight until cold and is diluted with 150 ml of methanol whilst cold, the whole is stirred for some time longer and the product is filtered off, washed with methanol and dried. Yield: 53 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:14]([C:24](OCC)=O)=[CH:15][NH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>C1COCC1>[C:7]1([C:13]2[C:14]([CH3:24])=[CH:15][NH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c[nH]c(-c2ccccc2)c1-c1ccccc1
Yield: 53.8 %

Procedure:
To a stirred slurry of 0.76 g (20 m moles) of lithium aluminum hydride in 25 ml. THF was added dropwise a solution of 0.58 g (2 m moles) of ethyl 4,5-diphenylpyrrole-3-carboxylate in 5 ml THF. The mixture was heated at reflux overnight. After cooling, 0.8 ml water, 2.4 ml 15% sodium hydroxide solution and 0.8 ml water were added dropwise. The solids were removed by filtration and the filtrate concentrated by rotary evaporation. The crystalline residue was purified by chromatography on 50 g Silic AR CC-7, eluting with hexane/toluene (90/10) to give 0.25 g of product, m.p. 163°-4°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])[CH3:17]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:7][NH:8][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:18]=1[CH2:16][CH3:17])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1c(OC)cccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1c(OC)cccc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Tert-butylcarbazate (80.0 g, 605 mmol) was stirred in 800 mL methylene chloride and cooled to 0° C. To this was added the potassium carbonate solution (937 g, 847 mmol). 2-Ethyl-3-methoxybenzoyl chloride (132 g, 666 mmol) was dissolved in 400 mL of methylene chloride and added to the reaction mixture dropwise over 15 minutes. The mixture was stirred at 0° C. for 15 min, then at room temperature for 18 hours. The reaction was diluted with more methylene chloride and water. The aqueous phase was separated. The remaining organic phase was washed with 1N HCl, water, saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was triturated with hexane to give a white solid, N′-(2-ethyl-3-methoxy-benzoyl)-hydrazinecarboxylic acid tert-butyl ester (167 g, 567 mmol) in 94% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.4 (br s, 1H), 7.22 (t, 1H), 7.03 (br d, 1H), 6.95 (d, 1H), 6.65 (br, 1H), 3.84 (s, 3H), 2.8 (q, 2H), 1.51 (s, 9H), 1.2 (t, 3H).
Reaction SMILES: N#N.[CH:3]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[C:15](=[O:16])[C:14]4=[CH:17][C:18](Br)=[CH:19][CH:20]=[C:13]4[C:12]3=[O:22])=[CH:10][C:5]=2[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][Si:43]([C:46]#[CH:47])([CH3:45])[CH3:44]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCN(CC)CC>[CH:3]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[C:15](=[O:16])[C:14]4=[CH:17][C:18]([C:47]#[C:46][Si:43]([CH3:45])([CH3:44])[CH3:42])=[CH:19][CH:20]=[C:13]4[C:12]3=[O:22])=[CH:10][C:5]=2[CH:4]=1
Reactant: O=C1c2ccc(Br)cc2C(=O)N1c1ccc2c(c1)C=C2
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)N(c1ccc3c(c1)C=C3)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 ml 3 necked round-bottomed flask, equipped with a thermometer, reflux condensor and N2 -adaptor, were placed N-4-benzocyclobutenyl 4-bromophthalimide (4.00 g, 12.2 mmol), palladium acetate (24 mg), triphenylphosphine (48 mg) and 60 ml of dry NEt3. The resultant reaction mixture was refluxed under N2 for about 15 minutes. Then, it was allowed to cool slowly to room temperature under N2. Trimethylsilylacetylene (2.50g, 25.4 mmol) was introduced into the reaction mixture via the reflux condensor. Immediately, the quantitative amount of white solids precipitated. The reaction mixture was then heated at 100° C. for about 3 hrs and stirred at room temperature overnight under N2. The brown heterogeneous mixture was poured into about 300 ml of H2O and extracted with CH2Cl2 (2×100 ml+2×50 ml). The CH2Cl2 extract was then washed with 200 ml H2O and dried over MgSO 4. Upon removal of the solvent, a mixture of white and brown solids was obtained. The mixture was washed with approximately 250 ml of H2O and air dried for an hour. It was then dissolved in 50 ml CH2Cl2 and the resultant solution was passed through a short column containing 25 g of silica gel saturated with hexane. Elution with 1:1 CH2Cl2 /hexane led to the isolation of microcrystalline tan solid from the first fraction. Yield=4.0 g (95%) mp=192-193° C. Calc. for C21H19NO2Si: 73.01% C; 5.54% H; 4.05% N. Found: 72.95% C; 5.45% H; 4.01% N. Mass Spectroscopy: 345 (M+, 100%). Proton NMR (CDCl3) 0.30 (Singlet, Me3Si--); 3.24 (Singlet, alicyclic protons); 7.10-7.29, 7.92-8.06 (complex, aromatic protons). IR(KBr): 2960 m, 2930 m (aliphatic and alicyclic C--H stretches); 2175 w (C≡C stretch); 1712, 1772 (symmetric and asymmetric stretches of imide group).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH:10]=[CH:11]2)[CH2:3]1.C1(C)C=CC=CC=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH2:5][C:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH:3]=4)[C@@H:8]1[CH2:9][CH:10]=[CH:11]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CC=C3C[C@@H](O)CC[C@]3(C)[C@H]1CC2
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2

Procedure:
250 ml. of a solution of 68 g. of 3β-hydroxy-androsta5,16-diene in 1.25 l. of toluene and 0.5 l. of cyclohexanone was distilled to obtain an anhydrous solution. A solution of 34 g. of aluminum isopropoxide in 170 ml. of dry toluene was added. The mixture was slowly distilled during 30 minutes to remove the acetone formed. After completion of the reaction water was added, and the mixture steam distilled to remove volatile components. the residue was extracted with methyl isobutyl ketone and the extract washed with an aqueous hydrogen chloride solution and water. The solvent was removed by distillation in vacuo and the residue was crystallized from acetone; 38.1 g. of androsta-4,16-dien-3-one were obtained. Recyrstallization from acetone yielded a pure product melting at a 131°-133° C. mol. peak in mass spectrum (m/e): 270. EXAMPLE IV
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[O:6].[CH3:12]CCCC.C(OCC)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:6][CH2:12]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: CCCCC
Reactant: O=Cc1cc(F)c(F)c(F)c1
Solvent: CCOCC
Product: Fc1cc(C2CO2)cc(F)c1F

Procedure:
Following General Procedure EC and using 3,4,5-trifluorobenzaldehyde (Strem), the title compound was isolated after flash chromatography with 10:1 pentane/diethylether.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[OH:6])C.[H-].[Na+].[CH3:17]I.[Cl-].[Na+].Cl>C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH:5]([O:6][CH3:17])[C:4]([OH:3])=[O:14])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(O)c1cccc(Br)c1
Reactant: CI
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(C(=O)O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-Bromomandelic acid ethyl ester (0.5 g, 2.2 mmol) in THF (5 mL) at 0° C. was added sodium hydride (352 mg, 60% in mineral oil, 8.8 mmol) and the resulting mixture was stirred at 0° C. for 15 minutes. Methyl iodide (1.9 g, 13.2 mmol) was added and the resulting mixture was stirred at 0° C. for 10 minutes and warmed to room temperature for 15 minutes. Saturated sodium chloride (10 mL) was added and 1 N hydrochloric acid was added to adjust the pH to 4. The resulting mixture was extracted with ethyl acetate (5 mL×4) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue (0.43 g, 80%) was used in next step without further purification. MS: m/z 245 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:13][CH2:12][C:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]=[C:20]=[O:21].O>CC(C)=O>[CH3:18][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:9][CH2:10][C:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][O:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CC)COC(c2cccc(N)c2)OC1
Reactant: CN=C=O
Solvent: O
Solvent: CC(C)=O
Product: CCC1(CC)COC(c2cccc(NC(=O)NC)c2)OC1

Procedure:
Nine and four tenths grams (9.4 g) of 2-(m-aminophenyl)-5,5-diethyl-1,3-dioxane was reacted with 3 g of methyl isocyanate in 75 ml of acetone. The mixture was refluxed for between one and two hours and poured into water and the product collected by filtration. The yield was 11.7 g of the title compound, m.p. 112°-125° C. Trituration with diethyl ether raised the melting point to 135°-137° C.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8](O)=[O:9])=[CH:5][N:4]=[C:3]([Cl:11])[CH:2]=1.C1N=C[N:14](C(N2C=NC=C2)=O)C=1>C1COCC1>[Cl:11][C:3]1[N:4]=[CH:5][C:6]([CH2:7][C:8]([NH2:14])=[O:9])=[CH:1][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc(Cl)nc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To 10.0 g (58.3 mmol) (2-chloropyridyl)-5-acetic acid in 150 mL THF are added 9.45 g (58.3 mmol) CDI and the mixture is stirred at 45° C. for 1 h. Then 28.0 g (291 mmol) NH4CO3 are added and the mixture is stirred at r.t. over night. The reaction mixture is poured onto water and extracted with EtOAc. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is triturated with TBME and recrystallized from EtOH.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]3[CH2:19][C@@H:14]2[C:15]3([CH3:21])[CH3:20])(=O)=O)=CC=1.[C-:22]#[N:23].[K+]>CS(C)=O.[Cl-].[Na+].O>[CH3:21][C:15]1([CH3:20])[C@H:14]2[CH2:19][C@@H:16]1[CH2:17][CH2:18][C@@H:13]2[CH2:12][C:22]#[N:23]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)[C@H]2CC[C@H](CC#N)[C@@H]1C2
Temperature: 70 °C

Procedure:
To a solution of Example 21A (13.6 g, 44.2 mmol) in DMSO (100 mL) was added potassium cyanide (11.5 g, 177 mmol). The reaction was heated at 70° C. for 48 h. The mixture was diluted with brine and extracted with ether (3×75 mL). The organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on SiO2 (Hexanes/ethyl acetate, gradient 0 to 50%) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([NH2:8])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]#[N:8]
Reactant: COc1cc(C(N)=O)ccc1[N+](=O)[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-methoxy-4-nitrobenzamide (8 g, 41 mmol) in dioxane (300 mL) was added pyridine (32 g, 408 mmol), followed by dropwise addition of trifluoroacetic anhydride (43 g, 204 mmol). The reaction mixture was stirred at room temperature for 5 h. Water was added to quench the reaction. The mixture was concentrated, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, aqueous saturated CuSO4 solution, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrobenzonitrile as a off white solid (6.5 g, 90%)
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:21](=[O:23])[CH3:22])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: CC(=O)Oc1ccc(N2CCNCC2)cc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2ccc(OC(C)=O)cc2)CC1
Yield: 89 %

Procedure:
Phenyl-N-(5,6-dimethyl 2methoxypyridin 3-yl)carbamate and 1-(4-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[F:21])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.N1C2=C(OC3C=CC(N)=CC=3F)N=CC=C2C=C1>>[Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:21])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Agent: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Product: Nc1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Yield: 92 %

Procedure:
Starting from the compound 272 and following the procedure described above for the synthesis of compound 261 (scheme 59, example 218, step 3), title compound 273 was obtained in 92% yield as a light brown solid. MS (m/z): 340.0(M+H).