Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].S(Cl)([Cl:19])=O.O>C(Cl)Cl.N1C=CC=CC=1>[Cl:19][CH2:2][C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C)Oc1cc(C)ccc1CCl

Procedure:
A solution of 2.20 g (0.0098 mole) of methyl 2-(2-hydroxymethyl-5-methylphenoxy)propionate in 10 mL of dry methylene chloride was added to a colorless solution of 1.28 g (0.0108 mole) of thionyl chloride and 5 drops of pyridine in 10 mL of dry methylene chloride during a 10 minute period. This mixture was heated at reflux for one hour and then poured into 50 mL of water. The phases were separated, and the aqueous phase was extracted three times with methylene chloride. These extracts were combined with the organic phase, which was then washed three times with a saturated aqueous solution of sodium bicarbonate and once with a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure, leaving a yellow oil as a residue. This oil was placed on a silica gel column and eluted with methylene chloride. After the product-containing fractions were combined and the solvent evaporated under reduced pressure, 2.06 g of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate was recovered as a colorless oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:15][C:9]2=[C:10]([CH3:14])[S:11][C:12]([CH3:13])=[C:8]2[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:14][C:10]1[S:11][C:12]([CH3:13])=[C:8]2[CH2:7][C:6]([NH:16][C:17]([C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)=[O:18])([C:4]([OH:5])=[O:3])[CH2:15][C:9]=12
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2c(C)sc(C)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1sc(C)c2c1CC(NC(=O)c1cccc3c1CCCC3)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
The mixture of 1,3-dimethyl-5-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (74) (942 mg, 2.37 mmol) and KOH (3 g, 23 mmol) is dissolved in EtOH (20 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (75) as a pale brown solid (832 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[CH2:15][CH2:14]2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl-].[NH4+]>CO.O.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[NH2:27])[CH2:17][CH2:18]2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)ccc(F)c2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)ccc(F)c2n1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 8-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (0.126 g; 1 eq) in methanol (4 mL) was added dropwise to a suspension of iron powder (0.125 g; 7 eq) and ammonium chloride (0.119 g; 7 eq) in water (4 mL). The reactants were heated at reflux for 8 hours, with additional amounts of iron powder (total 0.125 g; 7 eq) and ammonium chloride (0.119 g; 7 eq) added in 3 portions during the reaction. The reaction mixture was cooled to room temperature and filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 mL) and extracted into ethyl acetate (3×5 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound in 77% yield (0.090 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:35][C:12]2=[C:13]3[C:18](=[C:19]4[CH:24]=[C:23](B5OC(C)(C)C(C)(C)O5)[CH:22]=[CH:21][C:20]4=[C:11]2[N:10]=1)[C:17](=[O:34])[NH:16][CH:15]=[CH:14]3.Br[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:23]2[CH:22]=[CH:21][C:20]3=[C:11]4[N:10]=[C:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[NH:35][C:12]4=[C:13]4[C:18]([C:17](=[O:34])[NH:16][CH:15]=[CH:14]4)=[C:19]3[CH:24]=2)=[N:38][CH:39]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc3c(c2)c2c(=O)[nH]ccc2c2[nH]c(-c4c(F)cccc4F)nc32)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4F)nc3c3ccc(-c4ccc(Cl)cn4)cc3c12
Temperature: 90 °C

Procedure:
To a pressure flask with stir bar, the intermediate from Example 10 Step A (75mg, 0.16 mmol), 2-bromo-5-chloropyridine (33.5 mg, 0.17 mmol), and (Ph3P)2PdCl2 (11.1 mg, 0.02 mmol) were added. The flask was purged of air and back-filled with argon (3×). Toluene (0.79 ml) and ethanol (0.79 ml) were bubbled with argon for at least 10 min before addition to the flask. Na2CO3 (0.24 ml, 0.48 mmol) was bubbled with argon, and then added to the flask. The mixture was heated at 90° C. in an oil bath overnight. Water was added to quench the reaction. The water layer was extracted with ethyl acetate 3×. The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude compound was purified by reverse phase HPLC (10-100% acetonitrile in H2O+0.05% TFA) to afford a light yellow solid. 1H NMR (600 MHz, CD3OD) δ 14.00 (m, 1H), 11.40 (m, 1H), 10.97 (s, 1H), 8.73 (s, 1H); 8.53 (d, 1H); 8.29 (s, 1H); 8.05 (s, 2H); 7.56 (m, 3H); 7.25 (d, 2H): [M+H]+ 459.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27](=O)[CH2:28]Cl)[CH3:23]>CCO>[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27]1[N:21]=[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13](=[O:14])[NH:12][CH2:11][C:1]34[CH2:2][CH:3]5[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]5)[CH2:10]3)[CH2:8]4)[N:16]2[CH:28]=1)[CH3:23]
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Temperature: 25 °C

Procedure:
A mixture of N-(1-adamantylmethyl)-6-aminopyridine-2-carboxamide (1.4 g, 4.9 mmol) and 4-chloro-3-oxo-butyric acid ethyl ester (808 mg, 4.9 mmol) in EtOH (20 mL) is heated under reflux for 20 h. After cooling to RT, the solvent is removed in vacuo. The residue is partitioned between EtOAc and saturated aqueous sodium carbonate. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The brown residue is purified by re-crystallization from 2% MeOH in CH2Cl2 to give the title compound. 1H-NMR (δ, ppm, CDCl3 as internal standard): 8.39 (s, 1H), 7.71 (d, 1H), 7.16 (t, 1H), 7.06 (d, 1H), 6.22 (m, 1H), 4.20 (q, 2H), 3.87 (s, 2H), 3.20 (d, 2H), 2.02 (m, 3H), 1.78-1.58 (m, 12H), 1.28 (t, 3H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.N1C=CC=CC=1>COCCO.CCCCCC>[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][CH2:2][N:1]3[C:10]=2[C:9]=1[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=13
Reactant: O=C1CCCCC1Cl
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCCCCC
Solvent: COCCO
Solvent: c1ccncc1
Product: c1cc2c3c(c1)c1c(n3CCC2)CCCC1
Temperature: 120 °C

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (4.0 mL, 32 mmol), 2-chlorocyclohexanone (3.6 mL, 32 mmol) and pyridine (3.0 mL, 38 mmol) in 2-methoxyethanol (80 mL) was heated to 120° C. for 48 h and was then concentrated. The black gummy residue was extracted into ethyl acetate and washed with 2 N HCl. The organic layer was dried (MgSO4) and concentrated. The material was purified by flash column chromatography (elution with 5% ethyl acetate-hexanes) to provide a clear oil which was dissolved in hexane. Upon cooling the solution to −78° C. a precipitate formed. The precipitate was collected to provide 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazole. MS (ES) m/z 212.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11](Cl)[CH:12]=2)[N:7]=1)=O)C.C(Cl)[Cl:29].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.CO>[CH:4]([C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[C:9]([Cl:29])[CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:3]
Reactant: CCOC(=O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: ClCCl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cccc(Cl)c2n1
Yield: 52 %

Procedure:
0.50 g (0.0013 mol) of 2-ethoxycarbonyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in a solvent mixture comprising 20 ml of methylene chloride and 20 ml of tetrahydrofuran. 2.6 ml of a 1.0M solution of diisobutylaluminum hydride in toluene was dropped into the solution prepared above at -78° C. under stirring. The obtained mixture was stirred at -78° C. for several hours, followed by the addition of 20 ml of methanol. The obtained mixture was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate/n-hexane to give 0.23 g of the title compound as a pale-yellow crystal.
Reaction SMILES: O[CH:2]([O:10][PH:11](=[O:22])[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/[O-])=C/C(C)=[O:27].C(OO)(C)(C)C>ClC1C=CC=CC=1>[CH3:21][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:12]([PH:11](=[O:22])[O:10][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:27]
Reactant: Cc1cc(C)c(C[PH](=O)OC(O)Cc2ccccc2)c(C)c1
Reactant: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Clc1ccccc1
Product: Cc1cc(C)c(C(=O)[PH](=O)OCCc2ccccc2)c(C)c1
Reaction time: 20 h
Yield: 55 %

Procedure:
To 26.5 g (0.08 mol) of α-hydroxy-(2,4,6-trimethylbenzyl)-phenylethoxy phosphine oxide and 1 g (38 mmol) of vanadyl(IV) bis-acetylacetonate in 110 g of chlorobenzene there were added 28 g (0.22 mol) of 70 wt % strength aqueous tert-butylhydroperoxide and the mixture was stirred for a period of 20 h. The product was isolated by distillation. Yield: 55%, bp 180° C. (0.1 mbar).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18](=[O:21])[CH2:19]Br>CN(C=O)C>[CH3:16][O:17][C:18](=[O:21])[CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxybenzaldehyde (100 g, 0.818 mol) in dry DMF (1 L) was added potassium carbonate (260 g, 1.88 mol) and KI (10 g) with stirring at rt. The reaction mixture was slowly heated to 40° C. and added methylbromoacetate (104 g, 0.67 mol) with stirring and heated to 70° C. for 4 h. The reaction mixture was cooled to rt, filtered off the solid and filtrate was diluted with water (1.5 L). The aqueous mixture was extracted with EtOAc (3×750 mL), washed with 2.5% aqueous NaOH solution (2×400 mL), water and dried. The solvent was removed under vacuum to give the title compound a slight yellow solid (112 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O>[CH3:30][S:31]([O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:33])=[O:32]
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
4-(3-bromo-4-fluorophenyl)-3-(4-(2-hydroxyethylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (72.2 g, 0.188 mol) was mixed with ethyl acetate (600 mL). Methanesulfonyl chloride (19.2 mL, 0.248 mol) was added followed by triethylamine (34.9 mL, 0.250 mol). The reaction was stirred at room temperature for 5 min. When LCMS indicated completion of reaction (M+H=442), 500 mL of water was added into reaction. The reaction was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate solution was washed with brine (500 mL), dried over sodium sulfate and concentrated to give 85.1 g crude brown solid. 1H NMR verified the structure. Crude yield was 97%. LCMS for C13H11BrFN5O6SNa (M+Na)+: m/z=485.9, 487.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.58 (dd, J=11.2, 5.6 Hz, 2H), 3.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:5][C:6]([OH:24])([CH2:11][C:12]([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13])[C:7]([F:10])([F:9])[F:8].[N+:33]([O-])([OH:35])=[O:34].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:5][C:6]([OH:24])([CH2:11][C:12]([CH3:14])([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([N+:33]([O-:35])=[O:34])[CH:16]=1)[CH3:13])[C:7]([F:9])([F:8])[F:10]
Reactant: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cccc2c1OCC2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cc([N+](=O)[O-])cc2c1OCC2
Reaction time: 0.08 h

Procedure:
To a solution of 42 mg (0.087 mmol) of 2-(3-chloro-2-fluoro-5-trifluoromethylbenzyl)-4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-ol in 2 mL of acetic acid was added a mixture of 15 μL of fuming nitric acid (90%) and 22 μL of sulfuric acid in 250 μL of acetic acid in several portions. The mixture eventually turned from clear to green to deep blue. After 5 minutes, the reaction was cautiously made basic with saturated aqueous sodium bicarbonate and extracted with four 6 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of saturated aqueous sodium bicarbonate, two 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The yellow residue was purified by preparative chromatography (silica gel, EtOAc-hexanes, (2:8)) to afford 34 mg of partially purified product, a second preparative chromatography (silica gel, toluene-hexanes (6:4)) afforded 24 mg of the title compound.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:13][C:14]1[CH:19]=[C:18]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][N:25]3[C:33]([C:36](O)=[O:37])=[CH:34][CH:35]=[C:24]3[CH2:23]2)=[O:21])[CH:17]=[CH:16][C:15]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:48])([F:47])[F:46].[CH3:49][NH:50][CH2:51][C@@H:52]([C@H:54]([C@@H:56]([C@@H:58]([CH2:60][OH:61])[OH:59])[OH:57])[OH:55])[OH:53].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:49][N:50]([CH2:51][C@H:52]([OH:53])[C@@H:54]([OH:55])[C@H:56]([OH:57])[C@H:58]([OH:59])[CH2:60][OH:61])[C:36]([C:33]1[N:25]2[C:24]([CH2:23][N:22]([C:20]([C:18]3[CH:17]=[CH:16][C:15]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]([F:48])([F:46])[F:47])=[C:14]([CH3:13])[CH:19]=3)=[O:21])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26]2)=[CH:35][CH:34]=1)=[O:37]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1.1°-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (1.0 g, 2.04 mmol), and N-methyl-D-glucamine (0.48 g, 2.46 mmol) in N,N-dimethylformamide (8 mL) was added 1-hydroxybenzotriazole (0.30 g, 2.22 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.43 g, 2.24 mmol) followed by N,N-diisopropylethyl amine (0.55 mL, 3.09 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent system of 10% methanol in chloroform provided 1.08 g of title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]2O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]([CH2:12][C:13]([O:15][CH3:21])=[O:14])=[CH:8]2
Reactant: O=C(O)CC1Cc2ccc(Br)cc2C1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1=Cc2cc(Br)ccc2C1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
The product from Example 52B (1.35 g, 5 mmol) in methanol (12 mL) was treated with concentrated sulfuric acid (2 mL) and heated to gentle reflux. After 2 hours, additional sulfuric acid was added (1 mL) and heating was continued for another 2 hours. The mixture was concentrated under vacuum and the residue was diluted with water (15 mL). The mixture was cooled to 10° C., filtered, and the filter cake washed with water (5 mL) and dried to provide the title compound. 1H NMR (CDCl3) δ 3.42 (s, 2H); 3.55 (s, 2H); 3.74 (s, 3H); 6.65 (m, 1H); 7.22-7.31 (m, 2H), 7.44 (m, 1H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1([O:23][CH3:24])[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.[CH:25](=[O:27])[CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:27][CH:25]([C:13]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15][C:11]([O:23][CH3:24])([O:10][CH3:9])[CH2:12]1)[CH3:26]
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)C1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)O)C1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a cooled (−78° C.) solution of LDA (2M in THF/heptane, 39 mL, 78 mmol) in THF (40 mL) was added dropwise over 15 min tert-butyl 3,3-dimethoxycyclopentanecarboxylate (15.0 g, 65.0 mmol) in 100 mL of THF. The resulting mixture was stirred at −78° C. for 40 min, then was treated dropwise with acetaldehyde (7.27 mL, 130 mmol). After stirring for an additional 45 min, the reaction mixture was poured into 500 mL of 10% citric acid solution. The mixture was extracted twice with ether and the combined ethereal layers were washed with brine. The ethereal layer was then dried over anhydrous MgSO4, filtered, and concentrated. TLC analysis indicated that the reaction had not gone to completion and a considerable amount of starting material was still present. Purification/separation by flash chromatography (silica, 30% ethyl acetateihexane) gave the tert-butyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclopentanecarboxylate as an approximately 1:1 ratio of threo and erythro diastereomer pairs and recovered tert-butyl 3,3-dimethoxycyclopentanecarboxylate.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2].C(OP([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCn1cc(C=O)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a mixture of 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.27 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl (2E)-3-{1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoate as colorless crystals (0.51 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[ClH:13].[CH2:14]=O>CO>[ClH:13].[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][Cl:13])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: C=O
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reaction time: 0.12 h

Procedure:
To a solution of (-)-α-amino-4-hydroxybenzeneacetic acid (100 g, 0.6 mole) in a minimum amount of concentrated hydrochloric acid at 35°-40° C. is added 50 ml of aqueous formaldehyde (35-37%) (0.6 mole). The addition of hydrogen chloride gas is begun. After 5-10 minutes, a solid begins to precipitate. Stirring is continued for 30 minutes, and the solid is then collected. The crude product is washed with ether and with acetone. A second crop is obtained from the filtrate after standing at room temperature overnight. Total yield is 102 g (67%) m.p. >300° C., [α]D18 =-134° (c 4.75, CH3OH) NMR (DMSO--D6) ppm (δ) 4.68 (s,2), 4.9 (broad s,1), 6.9-7.6 (superimposed q and s,3).