Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>O1CCCC1>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([S:16][C:17]([CH3:21])([CH3:22])[C:18]([OH:20])=[O:19])[S:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)Cc1csc(SC(C)(C)C(=O)O)n1
Solvent: C1CCOC1
Product: CCCCCCCNCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 2-({4-[2-(heptylamino)-2-oxoethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid resin (5.2 g) synthesized in Example 461-5 in tetrahydrofuran (20 mL) was added 1 mol/L borane-tetrahydrofuran complex (18 ml), and the mixture was stirred at room temperature for 30 min, and at 50° C. for 16.5 hr. The resin was collected by filtration from the mixture, washed three times each with tetrahydrofuran and methanol, and vacuum dried to give the title pale-yellow resin (4.0 g).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]C)=[O:4].[Cl:7][C:8]1[C:9]([F:33])=[N:10][C:11](NCC(OC)=O)=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1>>[Cl:7][C:8]1[C:9]([F:33])=[N:10][C:11]([S:1][CH2:2][C:3]([OH:5])=[O:4])=[C:12]([Cl:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1
Reactant: COC(=O)CS
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(SCC(=O)O)c2Cl)ccc1O

Procedure:
By use of methyl mercaptoacetate in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)cn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-benzyloxy-pyridin-2-yl)-methanol described in Preparation Example 183 (2.00 g, 9.29 mmol) in tetrahydrofuran (40 mL) were added phthalimide (1.50 g, 10.2 mmol), triphenylphosphine (2.92 g, 11.1 mmol) and diethyl azodicarboxylate (5.08 mL, 11.1 mmol, 40% toluene solution) at 0° C., and the solution was stirred at room temperature for 2 hours. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1), and the title compound (4.1 g, quantitatively) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([O:17]C(=O)C)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1.C[O-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([OH:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:21])[CH:11]=2)[CH:6]=1
Reactant: C=Cc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1c(CC(=O)OC)cc2ccc(F)cc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of (4-acetoxy-6-fluoro-3-vinyl-naphthalen-2-yl)acetic acid methyl ester (38 mg, 0.126 mmol), sodium methoxide (10.1 mg, 0.189 mmol), and methanol (4 mL) was stirred at room temperature for 2 hours. After the reaction mixture was acidified with concentrated hydrochloric acid to pH 5, a precipitate formed, which was collected by filtration, and dissolved in ethyl acetate (20 mL). The organic solution was dried over sodium sulfate, and concentrated in vacuo to afford the crude product (6-fluoro-4-hydroxy-3-vinyl-naphthalen-2-yl)-acetic acid methyl ester (32 mg, 97.7%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([OH:10])=O)[NH:5][N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[NH:11][C:8](=[O:10])[C:7]([C:4]1[NH:5][N:6]=[C:2]([CH3:1])[CH:3]=1)=[C:19]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: Cc1cc(CC(=O)O)[nH]n1
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)[nH]n1
Yield: 23 %

Procedure:
Synthesized from 5-methyl-2H-pyrazol-3-yl-acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 23%.
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[CH:13]=1.[OH2:27].[OH-].[K+].Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O.C(OCC)(=O)C>[Cl:11][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:14]([F:26])[CH:13]=3)[N:5]=[CH:4][C:3]=2[C:2]=1[OH:27]
Reactant: O
Reactant: Fc1cc(-n2ncc3c(Br)c(Cl)ccc32)ccc1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Oc1c(Cl)ccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of 4-bromo-5-chloro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole (D23) (0.32 g, 0.74 mmol) in 1,4-dioxane (5 mL)/water (5 mL) was stirred and treated with potassium hydroxide (0.17 g, 3.03 mmol), Pd2 dba3 (0.014 g, 0.015 mmol) and 2-di-tertbutylphosphino-2′,4′,6′-triisopropylbiphenyl (0.019 g, 0.045 mmol) and the mixture was heated to 90° C. under argon. After 3 hrs, the mixture was cooled and water/ethyl acetate were added followed by 2N HCl (1.3 mL) and the product was extracted into ethyl acetate. The combined extracts were washed with brine, dried, concentrated and chromatographed (silica, ethyl acetate/hexane) to give the title compound (D24) (0.195 g)
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:24]C1C=C(B(O)O)C=CC=1)(=[O:23])[CH3:22]>>[O:20]=[C:19]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:2]=[C:3]([NH:24][C:21](=[O:23])[CH3:22])[CH:4]=[CH:5][CH:6]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17][NH:18]1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: CC(=O)Nc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-acetamidophenylboronic acid (304 mg, 1.70 mmol) were coupled to yield N-[3-(6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-acetamide, 10 mg (3%) as a clear solid: m.p. 300.5-302.0° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.09 (s, 3H), 3.05 (m, 2H), 3.36 (m, 2H), 7.21 (app t, J=7.8 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.57 (m, 2H), 7.68 (d, J=7.5 Hz, 1H), 7.92 (br s, 1H), 8.08 (br t, 1H), 10.10 (br s, 1H), 11.56 (br s, 1H). MS (FAB, MH+) 320. Anal. (C19H17N3O2) C, H, N.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.BrCCCCl.[OH-].[K+]>CO>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Agent: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a mixture of p-hydroxyacetophenone (50.7 g, 0.37 mol) and 1-bromo-3-chloropropane (160 ml, 1.5 mol) in methanol (250 ml) was added portionwise potassium hydroxide (63 g, 1.12 mol). The mixture was stirred at reflux for 24 hours, cooled to room temperature, filtered through Celite and evaporated in vacuo. The residual semi-solid was diluted with diethyl ether (500 ml) and washed with H2O (2×300 ml). The ether solution was dried over MgSO4, filtered and evaporated in vacuo to give p-chloroproxy acetophenone as a liquid in 68% yield (53.38 g). 1H NMR (CDCl3): δ 7.98-7.89 (d, J=8.9 Hz, 2H), 7.02-6.92 (d, J=8.9 Hz, 2H), 4.16 (t, J=5.9 Hz, 2H), 3.75 (t, J=6.4 Hz, 2H), 2.52 (s, 3H), 2.34-2.16 (m, 2H).
Reaction SMILES: [S:1](=NC1C=CC=CC=1)=O.[NH2:10][CH:11]([CH:15]1[CH2:20][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[N:17][CH2:16]1)[C:12]([NH2:14])=[O:13]>N1C=CC=CC=1>[C:22]1([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:19]2[CH2:20][CH:15]([C:11]3[C:12]([OH:13])=[N:14][S:1][N:10]=3)[CH2:16][N:17]=[CH:18]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)C(N)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: O=S=Nc1ccccc1
Solvent: c1ccncc1
Product: Oc1nsnc1C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 60 %

Procedure:
N-Thionylaniline (2.6 mL, 23.2 mmol) is added to amino(1-triphenylmethyl-1,4,5,6-tetrahydropyrimidin-5-yl)acetamide (1.64 g, 4.1 mmol) suspended in pyridine (25 ml). After heating at 90° C. for 48 hours the pyridine is evaporated, and the black residue partitioned between chloroform and water. The aqueous layer is lowered to pH 5 (HCl) and chromatographed (Dowex-50W, 0.5N ammonium hydroxide) to yield the product as a brown solid 1.05 g (61%) that can be further purified by chromatography (silica, methanol) and converted to a white crystalline hydrochloride salt, ms m/z=426.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:23]1[CH2:26][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24]1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:25]2[CH2:26][O:23][CH2:24]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)cc1Cc1ccc(OC2COC2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a solution of crude 4-(5-bromo-2-chlorobenzyl)phenol (3.0 g, 10 mmol) and cesium carbonate (4.9 g, 15 mmol) in N,N-dimethylformamide (77.5 mL) at room temperature was added a solution of toluene-4-sulfonic acid oxetan-3-yl ester (3.5 g, 15 mmol) in N,N-dimethylformamide (8 mL). The mixture was heated to 65° C. for 22 hours whereupon an additional aliquot of cesium carbonate (3.3 g, 10 mmol) was added. The reaction mixture was stirred for a further 12 hours at 120° C., cooled to room temperature whereupon water and ethyl acetate were added and the mixture was carefully acidified with 1N aqueous hydrochloric acid solution. The organic layer was separated, washed with brine (3 times), and concentrated in vacuo. Purification via Biotage MPLC (silica gel, eluting with a gradient of 0 to 25% ethyl acetate in heptane) afforded 3-(4-(5-bromo-2-chlorobenzyl)phenoxy)oxetane (2.5 g, 70% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[O:9]=[C:10]1[C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]2)[CH2:12][CH2:11]1>>[C:21]([O:20][C:18]([N:15]1[CH2:16][C@@H:17]2[C:10]([OH:9])([C:2]3[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=3)[CH2:11][CH2:12][C@@H:13]2[CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCC(O)(c3ccc(Cl)nc3)[C@H]2C1
Yield: 50.7 %

Procedure:
5-Bromo-2-chloropyridine (1.82 g, 9.46 mmol) and the product from Example 44A (1.64 g, 7.28 mmol) were processed as described in Example 1E to afford the title compound (1.25 g, 51%). MS (DCI/NH3) m/z 339, 341 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12]CC)=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:15][CH2:16][C@@H:17]([N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1)[CH3:18]>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([C@@H:17]([CH3:18])[CH2:16][NH:15][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CCOC(=O)c1coc(C(C)(C)O)n1
Product: C[C@@H](CNC(=O)c1coc(C(C)(C)O)n1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (0.75 mmol, 150 mg) and (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.75 mmol, 209 mg). Yield 87 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.45 (d, 3H), 1.49 (s, 6H), 3.55-3.61 (m, 1H), 3.66-3.73 (m, 1H), 4.69-4.74 (m, 1H), 5.66 (s, 1H), 7.03 (d, 1H), 7.88-7.93 (m, 2H), 8.0 (s, 1H), 8.19 (t, 1H), 8.51 (s, 1H). LC-MS: [M+1]=432.31.
Reaction SMILES: C(O)[C@@H]([C@H]([C@@H](CO)O)O)O.[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH:15]=O.S(=O)(=O)(O)O.[CH3:26][C:27]1[CH:28]=[C:29]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH:30]=[C:31]([OH:40])[C@@H:32]([C@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33]>>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH:15]=[C:38]([OH:39])[C@@H:36]([OH:37])[C@H:34]([OH:35])[C@@H:32]([OH:33])[C:31](=[CH:30][C:29]1[CH:41]=[CH:42][C:43]([CH3:44])=[C:27]([CH3:26])[CH:28]=1)[OH:40]
Reactant: Cc1ccc(C=C(O)[C@H](O)[C@@H](O)[C@H](O)CO)cc1C
Reactant: Cc1ccc(C=O)cc1C
Agent: O=S(=O)(O)O
Agent: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Product: Cc1ccc(C=C(O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc2ccc(C)c(C)c2)cc1C
Temperature: 21 °C
Reaction time: 6 h
Yield: 0.5 %

Procedure:
A 500 ml four-necked flask was charged with a 70 wt % aqueous solution of 120 g (0.55 mole) of D-xylitol, 73.7 g (0.55 mole) of 3,4-dimethylbenzaldehyde and 12 g of 50 wt % sulfuric acid. The air inside the system was replaced with nitrogen gas. The contents of the flask were stirred at a temperature of 21° C. for 6 hours. The obtained reaction mixture was analyzed by GC. It was found that mono(3,4-dimethylbenzylidene)-D-xylitol was produced in a yield of 70% and 0.5% or less of bis(3,4-dimethylbenzylidene)-D-xylitol was also produced. After standing 24 hours, the reaction mixture was neutralized for 2 hours using 8.6 g of potassium hydroxide, and filtered to obtain cake. The cake was dispersed in 150 ml of toluene and was filtered again. After drying at 100° C. under a pressure ranging from normal pressure to 5 mmHg for 7 hours, 44.5 g of 2,4-O-(3,4-dimethylbenzylidene)-D-xylitol was obtained with a purity of 99.2% as measured by GC (yield 30.1%). The product had a melting point of 179.5 to 180.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][C:14]=3[O:15][C:4]=2[CH:3]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[C:23]1([S:29]([C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][C:14]=4[O:15][C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2oc3cc(Br)ccc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCCc2oc3cc(S(=O)(=O)c4ccccc4)ccc3c2C1
Yield: 34 %

Procedure:
The product of step E was coupled with sodium benzenesulfinate following the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 70:30 hexanes/ethyl acetate) provided tert-butyl 8-(phenylsulfonyl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (106 mg, 34%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.04-7.87 (m, 3H), 7.83-7.72 (m, 1H), 7.60-7.41 (m, 4H), 4.64-4.61 (m, 2H), 3.67 (br s, 2H), 3.03 (t, J=6.3 Hz, 2H), 1.99 (br s, 2H), 1.53-1.25 (m, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH3:28])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+]>O.CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH3:28])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Lipase from Rhizopus delemar (300 mg, ex. Biocatalysts Ltd.) was stirred in deionised water (125 ml) and the pH of the mixture adjusted to 7.0. To this mixture, at ambient temperature (23° C.), was added a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoate (690 mg) (enantiomer ratio 8:92 as prepared in example 1) in acetone (5 ml). The resulting reaction mixture was stirred at ambient temperature and pH 7.0 was maintained by autotitration with 0.1M sodium hydroxide solution until hydrolysis was complete. 0.1M Sodium hydroxide solution was added to bring the reaction mixture to pH 9.5 after which it was washed with dichloromethane. The aqueous phase was acidified with hydrochloric acid to pH1 and the acid extracted into dichloromethane, washed, dried (magnesium sulphate), and evaporated. The resulting solid was triturated with hexane to yield 490 mg of (+)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid as a white solid; m.p. 121°-123° C.; enantiomer ratio 92.8 (by HPLC assay); [a]D25 +13°, MeOH, c 0.5. Enantiomer ratios of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid were determined by HPLC on a chiral AGP column eluting with 4.8% acetonitrile in 0.01M sodium dihyrogen phosphate solution at pH 7.0 and detecting products by UV monitoring at 245 nm. Enantiomer ratios are quoted in the order of elution.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]1[CH2:11][CH:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][CH:10]1[CH2:9][CH:8]([CH2:7][OH:6])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(OC2CCCCO2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1CC(OC2CCCCO2)C1
Yield: 83.7 %

Procedure:
tert-Butyl dimethyl-[3-(tetrahydropyran-2-yloxy)-cyclobutylmethoxy]-silane (1.62 g) was dissolved in tetrahydrofuran (11 mL) and treated with a solution of 1.0M tetrabutylammonium fluoride in tetrahydrofuran (8.08 mL) for 2 hours. The reaction mixture was diluted with dichloromethane and the mixture was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 2:3 by volume) to give the title compound (0.84 g). 1H NMR (300 MHz, CHCl3-d): δ 4.62-4.54 (m, 1H), 4.29-4.20 (m, 1H), 3.88 (d, 1H), 3.68-3.60 (m, 2H), 3.53-3.42 (m, 1H), 2.30-2.20 (m, 2H), 2.19-2.08 (m, 2H), 1.86-1.72 (m, 3H), 1.58-1.47 (m, 4H), 1.34 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([C:15]2[N:23](S(C3C=CC=CC=3)(=O)=O)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([C:15]2[NH:23][C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
A solution of 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.2 g, 4.9 mmol) in ethanol (58.5 mL) and tetrahydrofuran (117 mL) was treated with an aqueous sodium hydroxide solution (10%, 22 mL). The reaction was stirred at 70° C. for 18 h. After cooling to 25° C., the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×150 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (50 g, ethyl acetate/petroleum ether 1:15) afforded 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 86%) as a yellow oil: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.59 (s, 1H), 8.16 (d, 1H, J=4.5 Hz), 7.92 (d, 1H, J=7.5 Hz), 7.19 (t, 1H, J=7.8 Hz), 7.04 (q, 1H), 6.82 (t, 2H, J=2.1 Hz), 6.72 (s, 1H), 6.36 (d, 1H, J=1.8 Hz), 6.15 (d, 1H, J=9.9 Hz), 3.95 (q, 2H, J=13.8 Hz), 2.61-2.49 (m, 1H), 1.26 (t, 3H, J=6.9 Hz), 1.03 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:6][CH2:7][CH2:8][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:10]/[CH:11]=[CH:12]/[CH2:13][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:4].[CH2:47](Br)[CH2:48][CH2:49][CH3:50]>CN(C=O)C>[CH2:47]([N:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:16][CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]/[CH:12]=[CH:11]/[CH2:10][N:9]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:8][CH2:7][CH2:6][N:5]([CH2:3][CH3:4])[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:48][CH2:49][CH3:50]
Reactant: CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.059 g (1.47 mmol) of sodium hydride dispersion (approx. 60%) is added, with stirring, to a solution of 0.46 g (0.73 retool) of (E)-1-ethyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 5a) in 6 ml of DMF. The mixture is stirred for 5 min. at room temperature; 0.159 ml (1.47 mmol) of butyl bromide is added, and the reaction mixture is stirred for a further 15 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a) yields the title compound, Rf value=0.56 (silica gel/ethyl acetate:hexane (1:1)).