Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]1[C:10](C)=[CH:9][C:8]([O:12]C(=O)C)=[CH:7][N:6]=1)(=O)C.[ClH:16].C[C:18](CC)=[O:19]>>[ClH:16].[OH:12][C:8]1[CH:9]=[CH:10][C:5]([CH2:18][OH:19])=[N:6][CH:7]=1
Reactant: CC(=O)Oc1cnc(OC(C)=O)c(C)c1
Reactant: CCC(C)=O
Agent: Cl
Product: OCc1ccc(O)cn1

Procedure:
220.0 g of the above ester is added to 2,200 ml of 6N-hydrochloric acid and the resulting solution is refluxed for 18 hours. Then, the solution is evaporated to leave an oily viscous residue. This residue is digested with ethyl methyl ketone to yield 5-hydroxy-2-pyridinemethanol hydrochloride melting at 122°-123°. (The corresponding free base is prepared by adding a saturated solution of potassium carbonate to the hydrochloride, extracting the resulting suspension with chloroform, drying the chloroform extract over sodium sulfate, filtering and evaporating the filtrate to yield the free base.)
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C-]#N.[K+].[CH2:21]([OH:24])[CH:22]=[CH2:23]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:24][CH2:21][CH:22]=[CH2:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: C=CCO
Agent: [C-]#N
Agent: [K+]
Product: C=CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.99 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile, 0.59 g of potassium cyanide and 20 ml of allyl alcohol is stirred at room temperature for 20 hours and thereafter the allyl alcohol is distilled off. The residue is poured onto ice/water and extracted with methylene chloride, and the combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated. After flash chromatography on silica gel (eluent: ethyl acetate) there is obtained pure allyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23](Br)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([C:47]([F:50])([F:49])[F:48])[N:33]=1.CC([O-])=O.[K+]>O1CCOCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23]([C:36]2[CH:35]=[C:34]([C:47]([F:48])([F:49])[F:50])[N:33]=[C:32]([F:31])[CH:37]=2)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)nc(C(F)(F)F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ccnc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2cc(F)nc(C(F)(F)F)c2)n2ccnc12
Temperature: 85 °C
Yield: 151.4 %

Procedure:
(5-Bromoimidazo[1,2-a]pyrazin-8-yl)-(4-morpholin-4-ylphenyl)carbamic acid tert-butyl ester (50 mg, 0.11 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (126 mg, 0.21 mmol), KOAc (31 mg, 0.32 mmol) and Pd(dppf)Cl2DCM (4.3 mg, 0.0053 mmol) are stirred under N2 in dioxane (0.3 mL) and heated at 85° C. for 2.5 h. The mixture is cooled and partitioned between NaHCO3 (5% aq., 5 mL) and EtOAc (15 mL). The layers are separated and the aqueous phase extracted with further EtOAc (2×10 mL). The combined organic extracts are washed with brine (10 mL), dried over Na2SO4 and evaporated under reduced pressure to afford the title compound as a brown oil (93 mg) which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([CH3:28])[C:17]2=[O:29])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([CH3:28])[C:17]2=[O:29])[CH2:12][CH2:13]1
Reactant: COc1ccc2nc(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nc(C)c(=O)n(CCN3CCC(N)CC3)c2c1
Yield: 98.8 %

Procedure:
tert-Butyl{1-[2-(7-methoxy-3-methyl-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 160, 100 mg, 0.24 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 75 mg (99% yield) of the crude product as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:30]=[CH:29][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=[O:13])=[CH:10][N:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:27][N:26]([CH3:28])[CH:23]1[CH2:24][CH2:25][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:29]=[CH:30][C:8]([O:38][C:35]4[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=4)=[N:9][CH:10]=3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: Oc1ccc(F)cc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)nc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)C1
Temperature: 140 °C

Procedure:
49 mg of potassium carbonate were added to a solution of 0.041 g of 6-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide and 4-fluorophenol (30 mg) in 0.8 ml of DMF, and the reaction was heated at 140° C. in a microwave apparatus for 90 minutes. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:15]([CH:17]=O)=[CH:16][C:9]=23)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[N:4]1)[CH3:2].[N:37]1([CH2:43][CH2:44][OH:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:15]([C:17]4[CH:9]=[CH:8][C:6]([CH2:7][N:40]5[CH2:41][CH2:42][N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39]5)=[CH:5][CH:28]=4)=[CH:16][C:9]=23)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: OCCN1CCNCC1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(CN4CCN(CCO)CC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described in Intermediate 101 using 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde and 2-(1-piperazinyl)ethanol provided the title compound. ESMS (M+H)+: 692.4.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][N:19]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[C:20]([NH:21]C(=O)C)=[C:10]3[C:9]2=[O:39])=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>>[NH2:21][C:20]1[N:19]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:27][CH:26]=2)[N:18]=[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[NH:8][C:9](=[O:39])[C:10]=12
Reactant: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCN5CCCCC5)cc4)nc3c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1ccc(CCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 43.6 %

Procedure:
A mixture of N-{5-(4-methoxybenzyl)-4-oxo-2-[4-(2-piperidin-1-ylethyl)phenyl]-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-3-yl}acetamide (0.13 g), trifluoroacetic acid (2.5 ml), anisole (1 ml) and trifluoromethanesulfonic acid (0.5 ml) was stirred at room temperature for 26 hours. Ice and 2N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with propylaminated silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate to obtain the target compound (0.04 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[CH3:12]OC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:49][CH2:50][O:51][C:52]([CH3:54])=[O:53]>C1COCC1.O>[N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:12]=[CH:54][C:52]([O:51][CH2:50][CH3:49])=[O:53]
Reactant: CCOC(C)=O
Reactant: Clc1ccc2ncccc2n1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc2ncccc2n1
Temperature: 100 °C
Yield: 90 %

Procedure:
2-chloro-1,5-naphthyridine (101 mg, 0.614 mmol), boronate ester R1 (195 mg, 0.920 mmol), S-Phos (25.2 mg, 0.061 mmol), K3PO4 (391 mg, 1.841 mmol) and PdOAc2 (6.89 mg, 0.031 mmol) were combined in a 5-mL microwave vial in THF (2.5 mL) and water (500 μl). The reaction mixture was heated at 100° C. for 15 min. The reaction mixture was diluted with EtOAc (20 mL), washed with sat. aq. NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (10 to 100% EtOAc in hexanes) to afford the title compound as a pale orange solid (118 mg, 90%). 1H NMR (500 MHz, DMSO): δ 9.02 (dd, J=4.1, 1.6 Hz, 1 H), 8.48 (d, J=8.8 Hz, 1 H), 8.48-8.42 (m, 1 H), 8.25 (d, J=8.7 Hz, 1 H), 7.84-7.79 (m, 2 H), 7.13 (d, J=16.0 Hz, 1 H), 4.25 (q, J=7.1 Hz, 2 H), 1.30 (t, J=7.1 Hz, 3 H) ppm; LRMS m/z (M+H) 229.2 found, 229.1 required.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][CH2:10][C:11]([NH:13][C@H:14]([C:19]([NH:21][C@@H:22]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:23]([OH:38])[C:24]([N:26]2[CH2:37][CH2:36][CH2:35][C@H:27]2[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17])=[O:12])[CH2:5][CH2:4]1.[CH2:46]([O:53][C:54](Cl)=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:46]([O:53][C:54]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][CH2:10][C:11]([NH:13][C@H:14]([C:19]([NH:21][C@@H:22]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]([OH:38])[C:24]([N:26]2[CH2:37][CH2:36][CH2:35][C@H:27]2[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17])=[O:12])[CH2:5][CH2:4]1)=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COC1CCC(N)CC1
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COC1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 47.9 %

Procedure:
Following a procedure similar to that described in Example 30, but using 40 mg (61.2 μmol) of 1-{(2S,3S)-3-[N2 -(4-aminocyclohexyloxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 58) and 0.01 ml (67.3 μmol) of benzyloxycarbonyl chloride, 22 mg of the title compound were obtained as a colorless powder, melting at 109°-114° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:28])[C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[CH:16][C:15]=2[O:22][C@@H:23]([CH3:27])[C:24]#[C:25][CH3:26])[C@H:8]([O:29][CH3:30])[CH2:7]1)=O)C.[OH-].[K+].O>CC(O)C>[CH3:30][O:29][C@H:8]1[C@@H:9]([NH:12][C:13](=[O:28])[C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[CH:16][C:15]=2[O:22][C@@H:23]([CH3:27])[C:24]#[C:25][CH3:26])[CH2:10][CH2:11][NH:6][CH2:7]1
Reactant: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(C(=O)OCC)C[C@H]1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Yield: 16.3 %

Procedure:
2.50 g of the cis-N-(1-ethoxycarbonyl-3-methoxy-4-piperidinyl)-4-amino-5-chloro-2-((S)-1-methyl-2-butynyl)oxybenzamide prepared in the Example 7 and 4.5 g of potassium hydroxide were dissolved in 2-propanol. The obtained solution was refluxed for 1.5 hours and cooled, followed by the addition thereto of water. The resulting mixture was extracted with 10% 2-propanol/chloroform thrice. The combined organic phases were dried over magnesium sulfate and freed from the solvent. The residue was purified by silica gel column chromatography (5 to 12% methanol/dichloromethane) to give 0.34 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12]2)=[C:5]([CH3:18])[C:4]=1[CH3:19].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([CH3:18])[C:4]=1[CH3:19])[NH:9][CH2:10][C:11]1([CH2:12][CH2:13][CH2:14]1)[C:15]2=[O:17]
Reactant: COc1ccc(NCC2(C(=O)O)CCC2)c(C)c1C
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: COc1cc2c(c(C)c1C)NCC1(CCC1)C2=O
Temperature: 116 °C

Procedure:
A solution of 1-((4-methoxy-2,3-dimethylphenylamino)methyl)cyclobutanecarboxylic acid (19 g in toluene (100 mL) was added into phosphoric acid (25 mL). The mixture was heated up in a 116° C. bath and stirred for an hour. The mixture was then cooled down, quenched with ice, and extracted with ethylacetate. The organic phase was then dried and evaporated to dryness. The crude product was passed through a column (Hexane: EtOAc; 10:4) to give 6′-methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (15 g) as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ=7.26 (s, 1H), 4.11 (s, 1H), 3.79 (s, 3H), 3.54 (s, 2H), 2.59-2.29 (m, 2H), 2.38 (3H), 2.34 (3H), 2.06-1.82 (4H) ppm. 13C-NMR (75 MHz, CDCl3) δ=196.22, 150.49, 144.93, 133.95, 122.36, 115.05, 104.75, 55.77, 51.45, 46.5, 25.95, 15.06, 12.98, 12.77 ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C(#N)C>[N:1]1([CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: O=S(=O)(O)CCCN1CCc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of dihydroindole (4.76 g, 40 mmole) and 1,3-propane sultone (4.88 g, 40 mmole) in 50 ml reagent grade acetonitrile was heated under a nitrogen atmosphere and refluxed overnight. After cooling to room temperature, then to ice bath temperature, the resulting white solid was filtered and washed with cold acetonitrile. The yield was 8.1 g (84%), and the product had a melting point of greater then 200° C. Nuclear magnetic resonance (NMR) and elemental analysis showed the product to be consistent with the assigned structure. NMR (D2O): 7.45 (s, 4H), 2.8-4.0 (m, 8H), 2.2 (t, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH2:4][CH3:5])[CH3:3].[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:7]([O:6][C:2]([CH2:4][CH3:5])([CH3:3])[CH3:1])(=[O:9])[CH3:8]
Reactant: CCC(C)(C)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
To a solution of 2-methylbutan-2-ol (10 g, 113 mmol) in DCM (100 mL) was added DMAP (0.693 g, 5.67 mmol) and TEA (17.39 mL, 125 mmol). Mixture was then cooled to 0° C. and acetic anhydride (15.56 mL, 125 mmol) was added and the mixture was stirred at room temp for 24 h. The mixture was then washed with sat.NaHCO3 (100 mL), 1N HCl (100 mL), 10% NaOH (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to afford dark oil which was dilstilled by short path distillation (product distilled at 90-95° C.) to afford tert-pentyl acetate (8 g, 61.5 mmol, 54.2% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.98 (s, 3H), 1.78 (q, J=7.5 Hz, 2H), 1.43 (s, 6H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39]>CN(C=O)C.O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:36][C@H:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][OH:39])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: N[C@@H](CO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCCc1ccccc1)N[C@@H](CO)c1ccccc1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 5-phenylpentanoic acid (1.25 g) and hydroxybenzotriazole (1.18 g) in N,N′-dimethylformamide (25 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.74 g) at 0° C. and the mixture was stirred for 1 hour. To the mixture was added (2R)-2-amino-2-phenylethanol (960 mg) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water (150 ml) and then extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid, 2N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystal was washed with diethy ether to give the title compound (1.09 g) having the following physical data.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([NH:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: NC1CCCCC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCCCC3)c2)cc1
Yield: 99.6 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.4 mmol) and cyclohexylamine (0.14 g, 1.4 mmol) were used to afford 0.61 g of the required product. Percentage purity (LCMS): 78.1%, (M+1)=437.0+1.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH:13]=[CH:14][CH2:15][CH3:16])[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:21]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH3:21])[C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH:13]=[CH:14][CH2:15][CH3:16])[C:6]=2[N:7]=1
Reactant: CCC=CCn1c(=O)sc2c(=O)[nH]c(N)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC=CCn1c(=O)sc2c(=O)n(C)c(N)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-amino-3-(pent-2-ene-1-yl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (350 mg, 1.35 mmol), NaH (80% dispersion in mineral oil, 42 mg, 1.4 mmol) and anhydrous DMF (15 mL) was protected from moisture and stirred at ambient temperature for 0.25 h. Iodomethane (0.1 mL, 1.61 mmol) was added and the mixture was stirred for an additional 1 h. The mixture was evaporated in vacuum and then H2O (20 mL) was added. The mixture was stirred for 15 min and then the solid was collected by filtration. The solid was suspended in MeOH (25 mL) and silica gel (5 g) was added. The mixture was evaporated and the dry powder was placed on top of a silica gel column (5.5×20 cm). The column was flash eluted with progressively increasing concentrations of MeOH in CH2Cl2 (%MeOH, vol in L): (0, 1); (1, 1); (2, 1); (3, 1). Eluate containing the homogeneous product was evaporated and the solid was dried in vacuum at 80° C. for 16 h; 240 mg (0.901 mmol, 66%), mp 184-187° C. Ir (KBr): ν3420, 3330 and 3210 (NH2), 1715 (C=O), and 1675 (C=N) cm-1. Uv, λmax (nm), (ε×10-3): pH 1, 300 (9.37), 252 (8.02), 222 (30.9); MeOH, 302 (9.07), 252 (8.35), 222 (31.3); pH 11, 300 (9.41), 252 (8.08), 226 (21.0). 1H nmr (DMSO-d6): δ0.954 (t, 3H, CH3), 2.15-2.22 (m, 2H, CH3CH2), 3.29 (s, 3H, CH3), 4.38 (d, 2H, NCH2), 5.34-5.40 (m, 1H, CHCH) 5.53-5.59 (m, 1H, CHCH), and 7.51 (br s, 2H, NH2). Anal. Calc'd for C11H14N4O2S (266.32): C, 49.61; H, 5.30; N, 21.04. Found: C, 49.93; H, 5.17; N, 20.77.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[S-:11][C:12]#[N:13].[K+].C(Cl)(=O)C1C=CC=CC=1>CC(C)=O>[CH2:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:12]([NH2:13])=[S:11])=[CH:7][CH:6]=1)[CH3:10]
Reactant: N#C[S-]
Reactant: CCOc1ccc(N)cn1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CCOc1ccc(NC(N)=S)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 12 g of 3-amino-6-ethoxypyridine in 30 ml of acetone was admixed with a solution of 7.6 g of potassium thiocyanate in 60 ml of acetone, and under stirring, 15.4 g of benzoyl chloride was added dropwise. The mixture was then boiled for 10 minutes. The reaction mixture was poured into ice-water and the resulting crystals (m.p. 130°-133° C.) were recovered by filtration and boiled with 50 ml of 10% sodium hydroxide for 15 minutes. After cooling, crystals (m.p. 142°-146° C.) of 6-ethoxy-3-pyridylthiourea were obtained. These crystals were dissolved in 150 ml of hot 10% potassium hydroxide, and after addition of 37 g of lead acetate, the mixture was stirred at 80° C. for 20 minutes. The precipitated lead sulfide was filtered off and the filtrate was neutralized to give 5 g of 6-ethoxy-3-pyridylcyanamide as colorless needles melting 102°-104° C.
Reaction SMILES: N1([CH:6]2[C@@:23]3([CH3:24])[C:10](=[CH:11][CH2:12][C@@H:13]4[C@@H:22]3[CH2:21][CH2:20][C@@:18]3([CH3:19])[C@H:14]4[CH2:15][CH2:16][C:17]3=[O:25])[CH:9]=[C:8](N3CCCC3)[CH2:7]2)CCCC1.[CH2:31]=[O:32].S(=O)(=O)(O)[OH:34]>ClCCl>[OH:32][CH2:31][CH:11]1[C:10]2[C@:23]([CH3:24])([CH:6]=[CH:7][C:8](=[O:34])[CH:9]=2)[C@@H:22]2[C@H:13]([C@H:14]3[C@@:18]([CH2:20][CH2:21]2)([CH3:19])[C:17](=[O:25])[CH2:16][CH2:15]3)[CH2:12]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(N5CCCC5)CC(N5CCCC5)[C@@]43C)[C@@H]1CCC2=O
Reactant: C=O
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1C(CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
The resulting 1,3-dipyrrolidinoandrosta-3,5-diene-17one is then mixed in amount of 1 equivalent with 2.6 equivalents formalin (formaldehyde) in 10 ml dichloromethane/g at room temperature. The reaction mixture is then acidified to a pH of about 2 with 2% sulfuric acid solution. Accordingly, an organic layer is formed, which is washed with 2% sulfuric acid and 1:1 water/brine. Solvent exchange into toluene (approximately 10 ml/g) is then carried out wherein the product crystallizes as toluene exchange transpires. Said product is collected washed and dried to provide 6-hydroxymethyl-androsta-1,4-diene-3,17 dione. One of ordinary skill in the art can further modify the stereochemistry at position 6, if so desired, by employing known techniques in the art.