Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=O)[N:9]=2)=[N:3]1.[NH2:16][C@@H:17]([CH3:34])[CH2:18][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.CN(C=O)C>O.CCOC(C)=O>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:10]3[N:9]=[C:8]([C:4]4[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=4)[O:12][N:11]=3)=[O:15])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1cc(-c2nc(C(=O)O)no2)nn1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc(C(=O)N[C@@H](C)Cn3ccc(-c4cc(F)c(C#N)c(Cl)c4)n3)no2)nn1C
Yield: 0.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.614 mmol, 0.336 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (1.345 mmol, 0.375 g) using DMF (10 ml) as the solvent. The reaction mixture was diluted with water and EtOAc, the phases were separated and the organic phase was washed with 2 M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.003 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.29 (d, 3H), 2.34 (s, 3H), 4.24 (s, 3H), 4.30 (dd, 1H), 4.49 (dd, 1H), 4.61-4.72 (m, 1H), 6.65 (d, 1H), 6.88 (s, 1H), 7.53 (d, 1H), 7.61 (dd, 1H), 7.78-7.82 (m, 1H), 8.01 (d, 1H).
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[N+](=[C:7]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:2]([C:1]1[O:18][C:13]([C:14]([F:15])([F:16])[F:17])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]=1)[CH3:3]
Reactant: CCC#N
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)C(F)(F)F
Agent: [Rh+3]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1nc(CC)oc1C(F)(F)F
Temperature: 80 °C
Reaction time: 120 h
Yield: 43 %

Procedure:
To a mixture of rhodium acetate (100 mg) and propionitrile (15 mL) was added ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate (4.20 g, 20.0 mmol) over 12 hr, and the mixture was stirred at 80° C. for 5 days. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate=90/10→0/100) to give the title compound (2.03 g, 43%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[F:18][C:13]([F:17])([CH:14]([F:16])[F:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester (2.6 g) in THF (20 ml) and water (15 ml) was added lithium hydoxide solution (1 M, 19.4 ml) and the reaction mixture was stirred at 22° C. for 30 min. The reaction mixture was neutralised by addition of aqueous HCl (1 N, 19.4 ml), the organic solvent was evaporated, the suspension obtained still containing water was filtered and the residue was dried to give 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid (2.3 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([O:45][CH3:46])[CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([O:45][CH3:46])[CH:40]=2)=[CH:9][CH:10]=1
Reactant: COc1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)ccn1
Temperature: 85 °C
Yield: 88.8 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 250 mg) and 4-bromo-2-methoxypyridine (91 mg) in acetonitrile (8 mL) were treated with aqueous sodium carbonate solution (2M, 0.5 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was evaporated onto silica and purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (214 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(Cn2ncc3c([N+](=O)[O-])cccc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cccc2c1cnn2CC1CCCNC1
Reaction time: 2 h
Yield: 126.9 %

Procedure:
A solution of tert-butyl 3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.118 g, 0.327 mmol) in DCM (1.6 mL) was treated with trifluoroacetic acid (0.4 mL) at ambient temperature and stirring continued for 2 hours. The solvent was concentrated and the resulting gum was dried under high vacuum to afford 4-nitro-1-(piperidin-3-ylmethyl)-1H-indazole (0.108 g, 92% yield) as a brown oil.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].O>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:2]([O:9][CH3:10])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C(O)CCCCCCCCCCCCCCBr
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)C(CCCCCCCCCCCCCCC(=O)O)C(=O)OC
Temperature: 50 °C

Procedure:
Sodium (1.11 g, 48.2 mmol) was dissolved in dry methanol (30 ml) and heated to 50° C. Dimethyl malonate (5.87 ml, 51.4 mmol) was added over 15 min. The mixture was heated to reflux and a suspension of 15-bromopentadecanoic acid (5 g, 15.6 mmol) in dry methanol (50 ml) was added over 45 min. The resulting mixture was refluxed for another 30 min. After cooling to RT, water was added and the mixture was concentrated. Water was added to the residue an made alkaline with 1 N NaOH and extracted with ether (1×50 ml). The aqueous layer was acidified with 1N HCl and extracted with ether (3×30 ml). The combined organic layers was dried (Na2SO4) and concentrated to give the title compound in 98% (5.7 g) yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33]O)[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1.CCN(CC)CC.CS([O-])=O.[Na+]>C(Cl)Cl.CO>[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][S:2]([CH3:1])(=[O:4])=[O:3])[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc2c(F)c(Oc3ccnc(CO)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc2c(F)c(Oc3ccnc(CS(C)(=O)=O)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.046 mL, 0.586 mmol) is added to a solution of 4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (180 mg, 0.391 mmol) and Et3N (0.109 mL, 0.782 mmol) in CH2Cl2 (5 mL) at 0° C. After 10 min, methanol is added, followed by sodium methanesulfinate (798 mg, 7.82 mmol). The resulting mixture is warmed to and stirred at 23° C. for 14 h. The mixture is concentrated and the residue is taken up in DMF (5 mL). The resulting mixture is stirred at 23° C. for 24 h, then partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer is extracted with EtOAc (2×40 mL). The combined organic layers are washed with brine (20 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give 4-fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 474.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1 H) 8.76 (d, J=5.81 Hz, 1 H) 8.12 (s, 1 H) 7.91 (d, J=8.34 Hz, 1 H) 7.64-7.69 (m, 1 H) 7.53 (d, J=8.84 Hz, 2 H) 7.18-7.25 (m, 2 H) 6.63 (s, 1 H) 4.55 (s, 2 H) 2.97 (s, 3 H) 2.59 (s, 3 H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[OH-:25].[Na+:26].ClC=C(Cl)Cl>O1CCCC1>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[O:24])=[N:4][CH:3]=1.[OH2:25].[Na+:26]
Reactant: [OH-]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Solvent: ClC=C(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Product: O
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
Omeprazole (1300 g; 3.77 mol) was added under vigorous mechanical stirring to a mixture of tetrahydrofurane (13 L) and 50% aqueous NaOH (296 g, 3.7 mol) and stirring was continued for 45 min. Trichloroethylene (5.7 L) was added and stirring was continued over night at room temperature. The mixture was cooled to +5° C. and then stirred for 3 h. The precipitate was filtered off and the filter cake was washed with trichloroethylene (5 L) and dried under reduced pressure at 50° C. giving omeprazole sodium salt (1314 g, 95%), m.p. 208-210 ° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[N:14]([CH3:25])[CH:15]([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[N:14]([CH3:25])[CH:15]([CH3:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N(C)C(C)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N(C)C(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methyl-(1-methyl-3-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[C:7]1([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26]([CH:28]4[CH2:29][CH2:30]4)=[O:27])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: ClCCCCSc1ccccc1
Product: O=C(Nc1cccc(C2CCN(CCCCSc3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using [(4-chlorobutyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 409.5 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:39][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccc5ccccc45)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3cccc4ccccc34)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C

Procedure:
Under nitrogen, 2-methyl-2-(4- {2-[5-methyl-2-(4-naphthalen-1-ylphenyl)oxazol-4-yl]ethoxy}-phenoxy) propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 hand concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield of a white solid. Rf=0.25 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.96 (d, 2H), 7.78-7.70 (m, 3H), 7.41-7.29 (m, 6H), 6.78-6.60 (m, 4H), 4.04 (t, 2H), 2.84 (t, 2H), 2.22 (s, 3H), 1.37 (s, 6H); MS (EI) 508.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH2:41]O)([CH3:35])([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH2:41][O:12][C:3]1[C:4]([F:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[F:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1F
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of 2,6-difluoro-3-nitrophenol (170 mg, 0.971 mmol) and triphenylphosphine (383 mg, 1.46 mmol) in THF (8 mL) was added a solution of (3-hydroxypropyl)carbamic acid tert-butyl ester (204 mg, 1.165 mmol) in THF (1 mL). The mixture was cooled in an ice bath and a solution of diethyl azodicarboxylate (255 mg, 1.46 mmol) in THF (1 mL) was added. The reaction was stirred at RT for 30 min, then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 25-40% EtOAc in cyclohexane) affording the title compound as a colourless gum (296 mg, 92%). 1H NMR (CDCl3, 300 MHz): 7.81 (1H, ddd, J=9.4, 7.8, 5.3 Hz), 7.04 (1H, dt, J=9.4, 2.2 Hz), 4.77 (1H, bs), 4.27 (2H, t, J=6.0 Hz), 3.37 (2H, q, J=6.4 Hz), 2.00 (2H, quintet, J=6.3 Hz), 1.45 (9H, s)
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.CCOC(C)=O>C(Cl)(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]([I:29])=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Yield: 90.3 %

Procedure:
From (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl] pyridine (made as described in International Patent Specification No. WO 94/14742) (1.82 g, 4.88 mmol) in CHCl3 (50 ml)m, silver triflate (1.26 g, 4.88 mmol) and iodine (1.24 g, 4.88 mmol). Chromatography (SiO2 ;EtOAc) afforded the title compound (2.2 g) as a colourless gum. (Found C, 59.23; H, 5.32; N, 2.67. C23H26NO2 l requires C, 60.13; H, 5.25; N, 2.81) δH (CDCl3) 1.5-1.9 (8H, m,CH2)4), 3.25 (1H, d, J 5 Hz, CH2 pyridine), 3.27 (1H, d, J 5 Hz, CH2 pyridine), 3.74 (3H, s, OCH3), 4.6-4.7 (1H, m, OCH), 4.64 (1H, t, J 8 Hz, CH phenyl), 6.74 (1H, s, C6H2), 7.01 (2H, d, J 5 Hz, H3, H5 pyridine), 7.24 (1H, s, C6 H2), 7.25-7.4 (5H, m, C6H5), and 8.39 (2H, d, J 5 Hz, H2, H6 pyridine). m/z 500 (M+, 100%), 406 (25) and 212 (14).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH2:18](I)[CH3:19]>>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH2:18]([N:4]1[C:5]2[C:10](=[C:9]([O:11][CH3:12])[CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1)[CH3:19]
Reactant: CCI
Agent: COc1cc2ccccc2c2c1C(C)(C)CN2
Product: CCN1CC(C)(C)c2c(OC)cc3ccccc3c21

Procedure:
The 4-methoxybenzoindoline 25 was synthesized as described above in Example 6. Compound 25 was alkylated by the general amino group alkylation procedure described in Example 3 employing ethyl iodide as the alkylating agent to give the N-ethyl-3,3-dimethyl-4-methoxybenzoindoline intermediate 28 (1HNMR: CD3Cl d 7.90 (d, 1 H, J=8.7 Hz), 7.68 (d, 1 H, J=8.1 Hz), 7.32 (bt, 1 H, J=7.5 Hz), 7.22 (bt, 1 H, J=6.9 Hz), 6.69 (s, 1 H), 3.83 (s, 3 H), 3.52 (q, 2 H J=7.5 Hz), 3.38 (s, 2 H), 1.46 (s, 6 H), 1.27 (t, 3 H, J=7.5 Hz). Subsequent methoxy group deprotection of compound 28 by the general boron tribromide procedure described in Example 1 yielded the N-ethyl-3,3-dimethyl-4-hydroxy-benzoindoline 29.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[O:25])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g) in tetrahydrofuran (10 mL)-ethanol (5 mL) was gradually added sodium borohydride (0.040 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol as colorless crystals (0.47 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 113-114° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][C:44]1[CH:45]=[C:46]([CH:51]=[C:52]([NH:54][C:55]2[N:60]=[C:59]([O:61][CH2:62][C:63]#[CH:64])[C:58]([Br:65])=[CH:57][N:56]=2)[CH:53]=1)[C:47]([O:49][CH3:50])=[O:48]>CN(C=O)C.C(OCC)(=O)C>[Br:65][C:58]1[C:59]([O:61][CH2:62][C:63]#[CH:64])=[N:60][C:55]([NH:54][C:52]2[CH:53]=[C:44]([NH:43][C:17](=[O:19])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:45]=[C:46]([CH:51]=2)[C:47]([O:49][CH3:50])=[O:48])=[N:56][CH:57]=1
Reactant: C#CCOc1nc(Nc2cc(N)cc(C(=O)OC)c2)ncc1Br
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1nc(Nc2cc(NC(=O)[C@@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc(C(=O)OC)c2)ncc1Br
Yield: 83.4 %

Procedure:
N-BOC-D-phenylalanine (3.3 g), 1-hydroxy-1H-benzotriazole hydrate(1.9 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimid hydrochloride (2.37 g) were stirred in DMF (30 ml) for 30 minutes Then methyl 3-amino-5-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]benzoate (3.88 g) were added and the mixture stirred over night. Then ethyl acetate (500 ml) was added and the reaction mixture washed subsequently with hydrochloric acid (0.1 n), saturated NaHCO3-solution, water and brine. After drying (Na2SO4) the organic phase was evaporated and the residue subjected to column chromatography (ethyl acetate/dichloromethane) to yield 5.36 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])CCC.CCCCCC.O>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[CH:2][CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COc2ccccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (3.3 g, 14.53 mmol) in tetrahydrofuran (30 mL) was added dropwise, at −78° C., under an atmosphere of argon, a solution of n-butyllithium in hexane (8.8 mL, 22 mmol). The mixture was stirred at −78° C. for 5 minutes, then water was added and the mixture was warmed up to room temperature and stirred for 30 minutes. The layers were separated. The aqueous layer was extracted twice with ethyl acetate and the organic combined extract was washed with water, brine, dried (MgSO4), and filtered. The solvent was evaporated to afford 2.13 g of 3,3-dimethyl-2,3-dihydro-benzofuran. 99% yield. 1H-NMR (300 MHz, CDCl3): 1.35 (s, 6H), 4.23 (s, 2H), 6.79 (d, J=7.6 Hz, 1H), 6.88 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.6 Hz, 2H).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.[CH3:11][NH2:12]>O>[CH3:1][NH:2][C:4]1([C:11]#[N:12])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CN
Reactant: [C-]#N
Reactant: O=C1CCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CNC1(C#N)CCCC1
Reaction time: 18 h

Procedure:
A solution of 6.5 of potassium cyanide in 13 ml of water was added at 15°-20° C. to a solution of 8.5 g of cyclopentanone and 7 g of methylamine hydrochloride in 7.5 ml of water and returned to room temperature; the mixture was stirred for 18 hours and extracted with methylene chloride. The organic phase was washed with aqueous sodium chloride, dried, and evaporated to dryness, and the residue was distilled to obtain 4.1 g of the expected product with a boiling point of 60° C.±0.3° C. at 7 mm of Hg.