Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=O.Cl.[NH2:25][OH:26].N1C=CC=CC=1.Cl>C(O)C>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=[N:25][OH:26]
Reactant: NO
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=O)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=NO)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.8 %

Procedure:
A stirred mixture of 4-methyl-3-oxo-5α-4-azaandrostan-17-carboxaldehyde (0.952 g, 3.0 mM), hydroxylamine hydrochloride (1.10 g, 15.8 mM), anhydrous pyridine (6 mL) and anhydrous ethanol (12 mL) was refluxed gently under a nitrogen atmosphere for 6.3 hours. After cooling, the ice-cooled mixture was diluted, with stirring, with a slight excess of chilled dilute hydrochloric acid (ca. 0.3N), the suspension aged for ca. 20 minutes, filtered, washed with water and dried to give (38) 0.855 g. MS M+ calcd for C20H32N2O2 332.48, observed m/e 332.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[OH-].[Na+].C1C(=O)[N:31](OC(CI)=O)[C:29](=[O:30])[CH2:28]1.Cl>CO.O.C(Cl)(Cl)Cl.CO.C(O)(=O)C>[NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1.[I:7][NH:31][C:29](=[O:30])[CH3:28]
Reactant: O=C(CI)ON1C(=O)CCC1=O
Agent: Cl
Agent: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NI

Procedure:
78 mg (0.1 mmole) of L-thyroxine was dissolved in 1.0 ml of methanol on addition of 34 mls (0.2 mmole) of 6N NaOH and sonication in a bath sonicator. 48 mg of iodoacetic acid N-hydroxysuccinimide ester was added and the mixture vortexed. 8.5 mls of 6N NaOH was added and the mixture vortexed. TLC (chloroform:methanol:acetic acid 50:6:2 on silica gel) indicated complete reaction. 50 mls of 6N HCl was added and then 4 mls of water and formed a precipitate. The precipitate was collected by centrifugation and washed with 1 ml of methanol and 4 mls of water. After centrifugation the pellet was dried under vacuum to 82 mg of an off-white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9]([S:25][CH3:26])=[N:8][C:7]=2[N:27]=1.Cl.N1C=CC=CC=1.Cl>CN(C)C=O>[CH3:26][S:25][C:9]1[N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:27][C:7]=2[N:8]=1
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(SC)nc2n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
7-Methoxy-2-(methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (1.55 g) and pyridine hydrochloride (3.1 g) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred at 120° C. for 2 hr, and allowed to be cooled. The reaction mixture was poured into 0.5M hydrochloric acid (22 ml), and the white precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (30 ml). The solution was diluted with ethyl acetate (60 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (1.33 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[N:18]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Yield: 94.3 %

Procedure:
A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (1.02 g, 4.44 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.76 g, 3.42 mmol) and triethylamine (1.42 ml, 10.3 mmol) in tetrahydrofuran (20 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing diethyl ether to give the title compound (1.22 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:55])[NH:11][C:12]1[CH:53]=[CH:52][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]([CH3:51])[C:28]([CH2:31][N:32]([CH2:47][CH2:48][O:49][CH3:50])[C:33](=[O:46])[C@@H:34]([NH:38]C(=O)OC(C)(C)C)[CH:35]([CH3:37])[CH3:36])=[CH:29][N:30]=4)[S:25][C:18]=23)=[C:14]([F:54])[CH:13]=1.Cl.O1CCOCC1>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([N:32]([CH2:31][C:28]1[N:27]([CH3:51])[C:26]([C:24]2[S:25][C:18]3[C:19](=[N:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:52]=[CH:53][C:12]([NH:11][C:10]([NH:9][C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[O:55])=[CH:13][C:14]=3[F:54])[CH:23]=2)=[N:30][CH:29]=1)[CH2:47][CH2:48][O:49][CH3:50])=[O:46]
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a suspension of the compound 352 (200 mg, 0.256 mmol) in DCM (10 ml) was added HCl in dioxane (0.7 ml, 10.95 eq, 2.80 mmol, 4M in dioxane) and the reaction mixture was stirred at RT for 3 hours. The mixture wad diluted with water and solid NaHCO3 was added. The reaction mixture was extracted with EtOAc then the organic phase was collected, dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (eluent 30% MeOH in EtOAc) afforded the desired compound 353 as pale yellow powder (155 mg, 89% yield). 1H NMR (d6-DMSO) 9.36 (s, 1H), 8.60 (s, 1H), 8.49 (m, 1H), 8.01 (m, 1H), 7.87 (s, 1H), 7.71 (m, 1H), 7.41 (t, J=8.99 Hz, 1H), 7.31 (m, 1H), 7.20 (m, 1H), 7.02 (m, 1H), 6.98 (s, 1H), 6.65 (d, J=5.09 Hz, 1H), 4.83 (d, J=15.65 Hz, 1H), 4.48 (d, J=15.65 Hz, 1H), 3.81 (s, 1H), 3.80 (s, 2H), 3.40 (m, 1H), 3.39-3.295 (m, 6H), 1.71 (m, 2H), 0.81 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[C:11]([Cl:24])=[CH:10][C:9]=2[F:25])[C:6](=[O:26])[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[N:3]=1.[C:31]1(=[N:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[Cl:24][C:11]1[C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])=[CH:13][C:8]([N:7]2[C:6](=[O:26])[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[N:3]=[C:2]2[O:37][N:36]=[C:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:9]([F:25])[CH:10]=1
Reactant: ON=C1CCCC1
Reactant: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(C(F)(F)F)nc(ON=C2CCCC2)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Yield: 84.7 %

Procedure:
A mixture of 2-chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(1.28 g, 0.0027 mol), cyclopentanone oxime(027 g, 0.0027 mol), potassium carbonate(0.38 g, 0.027 mol) and tetrahydrofuran(11 ml) was heated under reflux for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.C[Al](C)C.C[O:19][C:20]([C:22]1[N:23]=[C:24]([CH2:68][CH2:69][CH3:70])[N:25]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:34][CH:33]=2)[C:26]=1[C:27]([O:29][CH3:30])=[O:28])=O>CCOCC.C1(C)C=CC=CC=1>[CH3:30][O:29][C:27]([C:26]1[N:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:36][CH:37]=2)[C:24]([CH2:68][CH2:69][CH3:70])=[N:23][C:22]=1[C:20]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[O:19])=[O:28]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCc1nc(C(=O)N2CCN(c3ccccn3)CC2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 0.72 g (4.4 mmol) of 1-(2-pyridyl)piperazine in 10 mL of anhydrous CH2C12 under N2 was added 4.4 mL (4.4 mmol) of a 1 N solution of HCl in ether. After 15 min., the suspension was cooled to 10° C. and treated with 2.2 mL (4.4 mmol) of 2.0 M Me3Al in toluene. Slow gas evolution was noted. After 30 min., a solution of 2.81 g (4.00 mmol) of 4,5-bis(methoxycarbonyl)-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole in 12 mL of CH2C12 was added. The reaction mixture was allowed to warm to room temperature and stir for 2 h, then partitioned between EtOAc and H2O. The water layer was washed with EtOAc and the combined organic extracts were washed with water and brine, then dried over MgSO4. After removal of solvents at reduced pressure, the residual tan foam (4.08 g) was purified using flash chromatography (eluent: 50/50 EtOAc-hexane to 1% MeOH-EtOAc) to give 2.36 g (71%)of the title compound as a white foam. 1H NMR (300 MHz, CDCl3): δ0.88 (t, J=7.5 Hz, 3H, CH3); 1.70 (sextet, J=7.5 Hz, 2H, CH2); 2.52 (t, J=7.5 Hz, 2H, CH2); 3.45 (m, 2H, piperazine); 3.54 (m, 2H, piperazine); 3.63 (m, 2H, piperazine); 3.71 (s, 3H, CO2CH3); 3.93 (m, 2H, piperazine); 5.46 (s, 2H, benzyl); 6.67 (m, 2H, aromatic); 6.82 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 6.94 (d, J=7.5 Hz, 6H, trityl); 7.11 (d, J=8.0 Hz, 2H, p-disubstituted aromatic); 7.2-7.4 (m, 10H, aromatic); 7.4-7.5 (m, 3H, aromatic); 7.91 (dd, J=7.0, 6.0 Hz, 1H, tetrazolyl-phenyl); 8.19 (approx. dd, J=5.5, 2.0 Hz, 1H, pyridyl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:17][CH2:16][CH:14]2[CH2:13][O:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COCC2CO2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
p-Methoxybenzyl chloride (2.326 g, 14.85 mmol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil, 0.594 g, 14.85 mmol) in DMF (25 mL) at 0° C. and the mixture stirred for 25 mins. Glycidol (1 g, 13.50 mmol) was then added dropwise over 25 mins, the mixture was allowed to warm to room temperature and stirred for 3 days. The mixture was diluted with EtOAc (50 ml) and washed with saturated NH4Cl (aq) (30 ml), saturated NaHCO3 (aq) (50 ml) and brine (100 ml). The organic phase was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-10% EtOAc/hexane, afforded the title compound.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:14])=[C:10](OC)[CH:11]=1.[OH2:15]>C(Cl)Cl>[Cl:14][C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[C:7]([OH:15])[CH:8]=1
Reactant: O
Reactant: COc1cc(Br)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Cl)ccc1Br
Reaction time: 0.17 h

Procedure:
9 ml of boron tribromide is added dropwise to a solution containing 20 g of 5-bromo 2-chloro anisole in 200 ml of methylene chloride. Agitation is carried out for 10 minutes at 0° C., then for 24 hours at 20° C. and the reaction medium is poured into a water and ice mixture. The resultant suspension is agitated for 30 minutes, extraction is carried out with methylene chloride, followed by saturation with sodium chloride and extraction twice with methylene chloride. The organic phases are collected, dried over magnesium sulphate, evaporated under reduced pressure and 18.5 g of 5-chloro 2-bromophenol is obtained. M.p.=56° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH:8]([NH:12]C(N)=O)[C:9]([OH:11])=[O:10].[OH-].[Na+].OP(O)(O)=O>O>[NH2:12][C@@H:8]([CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[C:9]([OH:11])=[O:10]
Reactant: NC(=O)NC(CC1CCCC1=O)C(=O)O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC1CCCC1=O)C(=O)O
Temperature: 38 °C
Reaction time: 16 h

Procedure:
3-(2-oxocyclopentyl)-2-ureidopropanoic acid (10.0 g, 46.7 mmol) was suspended in water (80 mL) and the pH was adjusted to 8.0 with 10.8 N NaOH aq. Then, MnCl2 solution (5 mL, 100 mmol/L) was added and the solution was flushed with N2 for 15 min. Then 40 g of wet cell slurry obtained according to ‘Expression of Hyu genes in Escherichia coli RV308’ (see above) was added. The reaction was stirred at 38° C. for 16 h, after which time TLC indicated complete conversion to product. During this period, the pH was kept constant at 8.0 by addition of 5N H3PO4 aq. The reaction mixture was then centrifuged (12.000 rpm) and the clear liquid was separated from the remaining cell mass. The pH of the liquid was adjusted to ca. 1.0 with 37% HCl aq., which caused proteins to precipitate. This mixture was centrifuged for a second time (12.000 rpm) and the clear solution was collected. After charcoal treatment (0.5 g active carbon) and microfiltration (0.45μ), the solution was loaded on an ion-exchange resin (Amberlyst 15, 80 mL/144 meq.). Elution was initially done with water to neutral pH to remove impurities. Then, the amino acid was eluted with 2N NH3 aq. and water to neutral pH. These aqueous fractions were combined, the pH was brought to ca. 7 with 37% HCl aq. and water was removed in vacuo at 50° C., affording a light brown solid. The product amino acid has the S configuration at C2 with >99% ee (the other chiral center C4 is scrambled).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](O)([CH2:12][CH3:13])[CH2:10][CH3:11].P(=O)(O)(O)O>C1C=CC=CC=1>[CH3:8][C:9]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: Oc1ccccc1
Reactant: CCC(C)(O)CC
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CCC(C)(CC)c1ccc(O)cc1
Yield: 91 %

Procedure:
A mixture of phenol (396 g, 4.2 mol), 3-methyl-3-pentanol (230 g. 2.25 mol), 85% phosphoric acid (50 g, 0.43 mol) and benzene (1.5 liters) was refluxed and the azeotroped water was collected in a Dean Stark trap (53 ml). The reaction mixture was cooled and transferred to a separatory funnel. A small bottom layer was separated and the top (organic) layer was washed with 500 ml portions of water until the pH of the washes was 7 (neutral). The solvent was removed on a rotary evaporator. Distillation of the residual oil under vacuum gave the desired 4-(3-methylpent-3-yl)phenol: 365 g, 91% yield; bp 112° C. (1.0 mm); mol wt. 178 (ms); nmr, 0.68 (6H, t, J=8 2-methyls), 1.26 (3H, s, methyl), 1.4-2.0 (4H, m, --CH2 --), 6.28 (1H, s, hydroxyl), 6.8-7.3 (4H, m, aromatics); ir, 3260, 2980, 2940, 2890, 1615, 1600, 1515, 1466, 1380, 1250, 1190, 1120, 830 cm-1.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]2)[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.C(OC(=O)C(C(OCC)=O)C(C1C=CC(OC)=C(OC)C=1)C(OCC)OCC)C>>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)[CH:15]=1)[CH2:5][C:4]([OH:38])=[O:3])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OCC2(c3ccccc3)CC2)c1)C(OCC)OCC
Agent: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Product: CCOC(OCC)C(CC(=O)O)c1ccc(OC)c(OCC2(c3ccccc3)CC2)c1
Yield: 65.1 %

Procedure:
Using the same procedure as in Example 1(3), 4,4-diethoxy-2-ethoxycarbonyl-3-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]butyric acid ethyl ester, instead of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester, was used to obtain a yellow solid of the above-described compound via 4,4-diethoxy-3-[4-methoxy-3-[(1-phenylcyclopropyl)methyloxy]phenyl]butyric acid (yield 65.1%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([C:7]1[N:11]([CH3:12])[C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]=1[OH:24])=[O:6].[H-].[Na+].O>CN(C=O)C>[CH2:22]([O:21][C:19]([C:9]1[C:8]2[O:24][CH2:2][C:3]3[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=3[C:5](=[O:6])[C:7]=2[N:11]([CH3:12])[C:10]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20])[CH3:23]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccccc2CCl)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2c(n1C)C(=O)c1ccccc1CO2
Reaction time: 1 h
Yield: 88.9 %

Procedure:
Ethyl 5-[o-(chloromethyl)benzoyl]-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (525 mg, 1.29 mmol) is suspended in 5 ml dry DMF under nitrogen followed by subsequent addition of sodium hydride (68 mg, 1.42 mmol, 50% dispersion in oil). Gas is evolved and the reaction turns dark brown. The mixture is stirred for one hour, then the solution is poured into water (50 ml). Upon agitation, a solid separates which is filtered and dried. The crude material is recrystallized from ethanol to give 426 mg (90%) of ethyl 5,10-dihydro-3-ethoxycarbonyl-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:4]([CH3:16])[N:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CN(C)C=O>O>[CH3:14][CH:13]([CH3:15])[CH2:12][NH:11][C:6]1[CH:5]=[C:4]([CH3:16])[N:3]2[N:17]=[N:18][N:19]=[C:2]2[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NCC(C)C)c([N+](=O)[O-])c2nnnn12
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (10.0 g, 41.0 mmol), sodium azide (2.67 g, 41.0 mmol), and anhydrous N,N-dimethylformamide (200 mL) was heated at 60° C. After 5 hours, the dark green solution was allowed to cool to room temperature, poured slowly into water (2 L), and stirred for fifteen minutes. A green precipitate formed, which was filtered and washed with water to yield 9.37 g of N-(2-methylpropyl)-5-methyl-8-nitrotetraazolo[1,5-α]pyridin-7-amine as a light green solid, m.p. 185-187° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:11][CH:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:15][C:16]2[C:17]([NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccccc2Nc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of lithium aluminum hydride (1.0 g) in THF (40 ml) cooled to 5° C. was added a solution of 4-methoxy-N-(2-phenylamino-phenyl)-benzamide (5.0 g) in THF (30 ml) over a 45 minute period. After complete addition, the reaction mixture was heated to reflux for 1.5 hrs. The solution was cooled to room temperature and excess lithium aluminum hydride was quenched with ethanol until hydrogen evolution ceased. Saturated agueous sodium hydrogen carbonate (100 ml) was added and the resultant solution extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried with sodium sulfate and filtered through a pad of silica. The silica pad was washed with ethyl acetate (500 ml) and the organic fractions were combined. The filtrate was concentrated in vacuo to a brown oil which solidified on standing to give the title compound. (4.78 g). 1H (300 MHz, CDCl3): d 3.79 (s, 3H), 4.27 (s, 2H), 4.52 (br s, 1H), 5.08 (s, 1H), 6.67-6.74 (m,4H), 6.79-6.86 (m, 3H), 7.04-7.24 (m, 6H); TLC (EtOAc/Hex (1:4)): Rf =0.57
Reaction SMILES: C(C1C(OC)=CC([CH2:11][C:12]([OH:14])=[O:13])=C(F)C=1)#N.C(OC(C)(C)C)(=O)CC(OC(C)(C)C)=O.[F:31][C:32]1[CH:39]=[C:38](F)[C:37]([O:41][CH3:42])=[CH:36][C:33]=1[C:34]#[N:35]>>[C:34]([C:33]1[C:32]([F:31])=[CH:39][C:38]([CH2:11][C:12]([OH:14])=[O:13])=[C:37]([O:41][CH3:42])[CH:36]=1)#[N:35]
Reactant: COc1cc(C#N)c(F)cc1F
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Agent: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Product: COc1cc(C#N)c(F)cc1CC(=O)O

Procedure:
(4-Cyano-5-fluoro-2-methoxyphenyl)acetic acid was prepared in a similar fashion to the previously described synthesis of (4-cyano-2-fluoro-5-methoxyphenyl)acetic acid starting from di-tert-butyl malonate and 2,4-difluoro-5-methoxybenzonitrile. LC-MS (IE, m/z): 208 [M−1]+.
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:66]([NH:76][C:77](=[O:95])[CH2:78][N:79]2[C:87]3[C:86]([F:89])([F:88])[CH2:85][CH2:84][C:83]([F:91])([F:90])[C:82]=3[C:81]([CH:92]([F:94])[F:93])=[N:80]2)[CH2:67][C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[C:70]([F:75])[CH:69]=2)=[N:52][C:53]([N:56]2[CH2:65][CH2:64][C:59]3([O:63][CH2:62][CH2:61][O:60]3)[CH2:58][CH2:57]2)=[N:54][CH:55]=1>>[F:94][CH:92]([F:93])[C:81]1[C:82]2[C:83]([F:91])([F:90])[CH2:84][CH2:85][C:86]([F:88])([F:89])[C:87]=2[N:79]([CH2:78][C:77]([NH:76][C@H:66]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([N:56]3[CH2:57][CH2:58][C:59]4([O:63][CH2:62][CH2:61][O:60]4)[CH2:64][CH2:65]3)[N:52]=2)[CH2:67][C:68]2[CH:69]=[C:70]([F:75])[CH:71]=[C:72]([F:74])[CH:73]=2)=[O:95])[N:80]=1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(N2CCC3(CC2)OCCO3)ncc1Br
Product: NC(=O)c1cc(-c2cnc(N3CCC4(CC3)OCCO4)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (19B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 19A. MS (m/z) 798.63 [M+H]+.