Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[C:21]([OH:27])=[CH:20][C:19]=1[OH:28]>C(#N)C>[C:24]([C:22]1[C:21]([O:27][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][C:19]([O:28][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]([CH:23]=1)[C:17]([O:16][CH3:15])=[O:29])(=[O:26])[CH3:25]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C(C)=O)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)=O)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a stirred solution of benzyl bromide (16.14 L, 136 mol) and anhydrous potassium carbonate (20.25 Kg, 147.6 mol) in acetonitrile (184.5 L) was added methyl 5-acetyl-2,4-dihydroxybenzoate (14 Kg, 66.6 mol, step 2) in 6 portions over 5 h. The mixture was stirred and held at reflux for 20 hours, cooled to room temperature the mixture was poured onto water (682 L) and stirred vigorously for 2 hours. The solids were collected by centrifugation and dried under reduced pressure to constant mass in a vacuum oven at 60° C. overnight to afford methyl 5-acetyl-2,4-bis-benzyloxybenzoate (23.5 Kg, 97.3%) as a cream solid mp 114-115° C.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]>C(Cl)Cl.B(Br)(Br)Br>[OH:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])cc1O
Yield: 75.9 %

Procedure:
Prepared as described in the Demethylation section above using 2-methoxy-4-nitrobenzaldehyde (1.0 g, 5.52 mmol) in dry DCM (25 ml) and BBr3 in DCM (1.0 M, 16 ml, 16 mmol) to give the title compound (0.70 g, 78%) as tan plates after recrystallisation from EtOH.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O-].[Na+].CI.O>CO>[C:1]([C:5]1[CH:10]=[C:9]([N:11]([CH3:27])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CI
Product: Cc1ccc(S(=O)(=O)N(C)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 5.1 %

Procedure:
To a solution of 3.75 grams (0.01 mole) of the product of Example 1, 2,6-di-tert-butyl-4(p-toluenesulfonamido)phenol, and 0.54 grams (0.01 mole) of sodium methylate in 50 ml of methanol was added 1.42 grams (0.01 mole) of methyl iodide. The reaction mixture was heated with stirring for 72 hours in a pressure tube at 100° C. The reaction mixture was then cooled, poured into 150 ml of water and extracted with heptane. The heptane layer was separated and allowed to stand after cooling. Crystals formed which were isolated by filtration, washed and dried to weigh 0.5 gram and melted at 123°-142° C. Recrystallization from heptane gave 0.2 gram of crystals melting at 130°-142° C. Proton NMR spectra confirmed the expected, desired structure. (Compound 6)
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.Cl.[CH3:12][O:13][NH2:14].CO.C[O-].[Na+]>CN(C)C=O>[CH3:12][O:13][NH:14][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CON
Reactant: O=C(O)Cn1nnnc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CONC(=O)Cn1nnnc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-acetic acid (9.6 g) in N,N-dimethylformamide (60 ml) is added N,N'-carbonyldiimidazole (11.6 g), and the mixture is stirred at 0° C. for 1 hour. To this mixture is added a solution of methoxyamine hydrochloride (11.6 g) in a mixture of N,N-dimethylformamide (45 ml) and 4.6 N-sodium methoxide methanol solution (28.5 ml) and the whole mixture is stirred under ice cooling for 1 hour. The reaction mixture is poured onto ice water and extracted with a mixture of ethyl acetate and methyl ethyl ketone (2:1). The extract solution is washed with water, dried and concentrated in vacuum. The residue is crystallized from a mixture of acetone and ether to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (7.73 g). mp. 175°-176° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20](C)[C:21](OCC(Cl)(Cl)Cl)=O)#[N:2]>[Zn].C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][NH:20][CH3:21])#[N:2]
Reactant: CN(CCC=C1c2ccccc2CCn2cc(C#N)cc21)C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CNCCC=C1c2ccccc2CCn2cc(C#N)cc21
Yield: 95.3 %

Procedure:
2-Cyano-6,11-dihydro-11-(N-2,2,2-trichloroethoxycarbonyl-3-methylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzazepine (4.0 g., 8.7 mmole) and zinc dust (8 g.) in 25 ml. acetic acid was stirred at room temperature for 18 hours. The solid was filtered off and washed with acetic acid. The filtrate was taken to dryness. The residue was dissolved in dilute hydrochloric acid and extracted with ethyl acetate. The aqueous phase was then made basic, extracted with methylene chloride; the organic layer was washed with water, dried over sodium sulfate and concentrated to yield 2-cyano-6,11-dihydro-11-(methylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzazepine (2.3 g., 95%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](O)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:11])=[CH2:10])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(O)c1ccc(F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C=C(C)c1ccc(F)c(F)c1
Temperature: 60 °C

Procedure:
To a solution of 2-(3,4-difluorophenyl)propan-2-ol (1.0 g, 5.8 mmol) in 40 mL benzene was added 0.1 g of p-toluenesulfonic acid and the solution was heated to 60° C. TLC analysis showed disappearance of the starting material. After cooling, the solution was extracted with EtOAc, washed with saturated NaHCO3, dried over Na2SO4, filtered and the solvent was removed in vacuo. 1,2-difluoro-4-isopropenyl-benzene was obtained as a yellow oil (0.82 g, 92% yield).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=1[CH3:34]>>[CH3:34][C:28]1[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:21]1[N:20]=[C:19]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(O)ccc1N
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Cc1cc(O)ccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 49.7 %

Procedure:
Using procedure of example 1, compound 1f (4.0 g) was reacted with 4-amino-3-methylphenol (2.66 g) to provide 1.7 g (50%) of compound 79. 1H NMR (400 MHz, DMSO) δ 12.20 (s, 1 H), 9.18 (s, 1 H), 8.45 (s, 1 H), 8.35 (d, 1 H), 8.22 (d, 1 H), 8.18 (d, 1 H), 7.15 (m, 1 H), 7.00 (m, 1 H), 6.65 (d, 1 H), 6.60 (dd, 1 H), 2.15 (s, 3 H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][N:30]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>C(O)C>[NH2:30][CH2:29][C@H:27]1[CH2:26][C@H:25]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9]2)[CH2:28]1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4.15 g (7.83 mmol) of trans-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dione in 100 ml of dry ethanol are added dropwise at RT and under argon 5.87 g (5.7 ml; 117.5 mmol) of hydrazine monohydrate. After 20 min all the starting material is dissolved, and the reaction is complete after 20 h stirring at RT. The colorless precipitate is filtered off, and washed with ethanol. The filtrate is evaporated to dryness and the crude compound is purified by chromatography on silica gel (dichloromethane:methanol:NH4OHaqu.=90:10:1) to provide trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=7.50 min (Grad 1); ES-MS: m/eo=400; 1H-NMR (CDCl3): 8.30/s (1H); 7.3-7.5/m (6H); 7.20/s (1H); 7.05-7.15/2 peaks (2H); 6.99/m (1H); 5.41/m (1H); 5.14/s (2H); 5.04/broad s (2H); 2.98/d (2H); 2.54-2.69/m (2H); 2.35-2.54/m (3H); 1.73/broad s (2H).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[S:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=1[CH3:11])=[O:3]
Reactant: CC(=O)c1sc(=O)n(C)c1C
Reactant: COC(OC)N(C)C
Product: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Temperature: 100 °C
Yield: 44.5 %

Procedure:
5-Acetyl-3,4-dimethyl-3H-thiazol-2-one (4.64 g, 27.10 mmol) and dimethylformamide dimethyl acetal (8.4 mL, 59.62 mmol) were mixed in a dry, argon-flushed flask, and heated at 100° C. for 3 h. The mixture was cooled, producing some precipitation, which was enhanced by the addition of an equal volume of Et2O. The resulting orange solid was filtered and washed with Et2O to give 2.73 g of 5-(3-dimethylamino-acryloyl)-3,4-dimethyl-3H-thiazol-2-one. 1H-NMR (d6-DMSO): δ: 2.52 (s, 3H), 2.82 (bs, 3H), 3.11 (bs, 3H), 3.22 (s, 3H), 5.10 (d, 1H, J=12.2 Hz), 7.61 (d, 1H, J=11.7 Hz). IR (ATR): 1669 and 1630 cm−1 (CO str).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Si:29](Cl)([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31]>CN(C=O)C>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([O:17][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC[Si](Cl)(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of 10 g (38.6 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 100 mL of DMF was treated with 6.3 mL (42.4 mmol) of DBU and then dropwise with 6.5 mL (38.6 mmol) of TESCl. After stirring the mixture at RT overnight the solvent was partially evaporated i.v. Distribution of the crude mixture between a diluted aqueous solution of NaOH and Et2O and drying of the combined organic phases over Na2SO4 gave 13 g (90%) of 4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenylamine as a colorless oil, MS: 374 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:25][O:26]C(C)(C)C)[CH2:10][C:11]1([OH:24])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C>[CH2:1]([O:8][CH:9]([CH2:25][OH:26])[CH2:10][C:11]1([OH:24])[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OCC(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(O)(CC(CO)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
2.36 g of tert-butyl 4-[2-(benzyloxy)-3-(tert-butoxy)propyl]-4-hydroxy-1-piperidinecarboxylate was dissolved in 40 ml acetonitrile, 426 mg of cerium ammonium nitrate was added thereto, and the mixture was stirred at room temperature overnight. Silica gel was added to the reaction solution, and then it was evaporated It was purified by adsorptive silica gel charged in a non-adsorptive silica gel column with hexane-ethyl acetate to give 547 mg of tert-butyl 4-[2-(benzyloxy)-3-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:25]1[N:26]=[C:27]([NH:42][CH2:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=3)[NH:30][C:29]=2[N:41]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:24]([C:25]1[N:26]=[C:27]([NH:42][CH2:43][CH2:44][CH2:45][N:46]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]2)[C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=3)[NH:30][C:29]=2[N:41]=1)(=[O:23])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(C(O)c3ccccc3)nc(NCCCN3CCCCC3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(C(=O)c3ccccc3)nc(NCCCN3CCCCC3)c12
Reaction time: 1 h
Yield: 79 %

Procedure:
Dess-Martin periodinane reagent (22.67 mg, 0.053 mmol) was added to a mixture of methyl 2-(hydroxy(phenyl)methyl)-4-((3-(piperidin-1-yl)propyl)amino)-9H-pyrimido[4,5-b]indole-7-carboxylate (compound of Example 22) and TFA (15.7 mg, 0.027 mmol) in DCM (1000 μL, 15.54 mmol) to give a light orange solution. After 1 h, the solvent was evaporated and the residue was purified by flash chromatography to afford Example 23: methyl 2-benzoyl-4-((3-(piperidin-1-yl)propyl)amino)-9H-pyrimido[4,5-b]indole-7-carboxylate (10 mg, 79% yield) as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.36 (m, 2H) 1.36-1.48 (m, 4H) 1.74-1.88 (m, 2H) 2.14-2.44 (m, 6H) 3.52-3.68 (m, 2H) 3.91 (s, 3H) 7.54 (t, J=7.8 Hz, 2H) 7.69 (t, J=7.4 Hz, 1H) 7.76 (t, J=5.1 Hz, 1H) 7.90 (dd, J=8.2, 1.4 Hz, 1H) 7.94 (d, J=7.0 Hz, 2H) 8.10 (d, J=1.4 Hz, 1H) 8.52 (d, J=8.2 Hz, 1H) 12.43 (s, 1H); HRMS m/z 472.2342 (M+H)+; HPLC 97.1% @ 220 nm and 98.9% @ 254 nm, RT=1.86 minutes.
Reaction SMILES: Cl[Si:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[CH2:17]([Mg]Cl)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([Si:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[CH:18]=[CH2:17]
Reactant: C=CC[Mg]Cl
Reactant: COc1ccc([Si](Cl)(C(C)C)C(C)C)cc1
Solvent: C1CCOC1
Product: C=CC[Si](c1ccc(OC)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To the crude chloro(4-methoxyphenyl)diisopropylsilane (54.8 g, 214 mmol, 1.0 equiv.) was added THF (335 mL) via cannula under positive argon pressure. The solution was chilled to 0° C. and treated with allylmagnesiumchloride (128 mL, 256 mmol, 2.0 M in THF, 1.2 equiv.). After 3 h at 0° C., the solution was allowed to warm to 23° C. with stirring overnight. The mixture was treated with NH4Clsat'd (50 mL) and the aqueous layer extracted with ether (3×500 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, concentrated in vacuo. The crude material was purified by silica gel chromatography (3-5% EtOAc/hexanes) to yield 52.86 g (94%) of a slightly cloudy, viscous oil. This reagent distills at 130° C. at 500 mtorr as a colorless oil. TLC Rf=0.40 (9:1 Hexanes/EtOAc). IR (film) 2942, 2865, 1630, 1595, 1504, 1463, 1277 cm−1. 1H NMR (500 MHz, CDCl3) δ7.32 (d, 2H, J=6.84, C3-H,C7-H), 6.18 (d, 2H, J=6.84, C4-H, C6-H), 5.82 (q, 1H, J=8.5, 8.5, C15-H), 4.88 (d, 1H, J=17.05, C16-Hb), 4.76 (d, 1H, J=9.77, C16-Ha), 1.82 (d, 2H, J=7.32, C14-H), 1.17 (q, 2H, J=7.3, C8-H, C11-H), 0.94 (d, 6H, J=7.3, C9-H, C10-H), 0.90 (d, 6H, J=7.3, C12-H, C13-H). 13C NMR (125 MHz, CDCl3) δ160.51, 136.48, 135.70, 125.78, 113.78, 113.62, 55.09, 19.34, 18.22, 18.17, 17.68, 11.30. Anal. Calcd for C16H26OSi: C, 73.22; H, 9.98; Si, 10.70.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14](C1C=CC=CC=1)[C:15](=[O:17])[O-])(=[O:13])=[O:12])[CH:2]=[CH2:3].[NH2:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1>O1CCOCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1)=[O:17])(=[O:12])=[O:13])[CH:2]=[CH2:3]
Reactant: COc1nc(C)nc(N)n1
Reactant: C=CCOc1ccccc1S(=O)(=O)N(C(=O)[O-])c1ccccc1
Solvent: C1COCCO1
Product: C=CCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 20 °C
Yield: 52.8 %

Procedure:
A mixture of 3.33 g of N-(2-allyloxyphenylsulfonyl)phenylcarbamate and 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 30 ml of absolute dioxane is heated to reflux for 1/2 hour, then cooled to 20° C., filtered, evaporated to dryness, and the residue is crystallised from ether. Recrystallisation from ethyl acetate/petroleum ether (1:1) yields 2 g of N-(2-allyloxyphenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea with a melting point of 146°-147° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[C:3]#[N:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>>[NH2:4][CH2:3][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:1]
Reactant: N#CC(O)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a well stirred solution of hydroxy-(3,4-difluorophenyl)-acetonitrile (3.34 g, 20 mmol), was added a 1.0 M solution of LiAlH4 in ether (40 mL, 40 mmol) dropwise at 0° C. The resulting yellow solution was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and then carefully quenched sequentially with 1.5 mL of water, 1.5 mL of 3N NaOH followed by 4.5 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et2O and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO4, filtered and the solvent was removed in vacuo. 2-amino-1-(3,4-difluorophenyl)-ethanol was obtained as a yellow glassy syrup (3.3 g, 99%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:23][C:24](O)=[O:25])[CH3:22])[C@@H:17]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)Cl>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:23][C:24]([Cl:44])=[O:25])[CH3:22])[C@@H:17]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)Cl)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The residue from Step B was taken up in methylene chloride and a trace of DMF was added followed by 0.21 mL of oxalyl chloride. The reaction was stirred at room temperature for 1 h and then evaporated and used in Step D.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(C1C=CC=CC=1)(=O)C.[CH3:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([OH:34])=[CH:31][C:32]=1[OH:33])=[O:26]>>[CH3:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:34][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:31][C:32]=1[OH:33])=[O:26]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)c1ccccc1
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O

Procedure:
The reaction of (1) above is repeated using 1.1 molar equivalents of benzyl chloride, 1.0 molar equivalent of K2CO3, and substituting for the above acetophenone, 2,4-dihydroxyacetophenone ##STR19##
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)CCCCOc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)OC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccc(OCCCCC(=O)OC)cc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 61 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.66 g (1.4 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-5-(5-methoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester (from example 57), 5-(5-methoxy-5-oxopentyloxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 61% yield (0.5 g) as a colorless solid. This diester (0.85 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 24 hr. Work-up as in example 4 gave a crystalline acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.44 g (93%) of pure 5-(4-carboxybutoxy)-2-[5-[(3,4-dihydro-4-oxo- 8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid. Recrystallization from ethyl acetate gave 0.35 g (74%) of a colorless solid, mp 138°-139° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:12]2[NH:13][C:14]([C:16]([O:18]CC)=[O:17])=[CH:15][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([CH:8]1[C:12]2[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(Cc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)C(Cc1ccccc1)CC2
Yield: 47 %

Procedure:
The title compound was synthesized from ethyl 6-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and NaOH according to General Procedure 7.