Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][N:7]=1)=[O:2].[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[OH-].[Na+]>>[O:2]1[CH2:19][CH2:20][O:21][CH:1]1[CH:3]1[NH:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1-n1ccnc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1ccc([N+](=O)[O-])cc1N1CCNC1C1OCCO1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Into a round bottom flask equipped with a Dean Stark trap, 2-(2-formyl-imidazol-1-yl)-4-nitro-benzonitrile (10.48 g, 0.04327 mol), 1,2-ethanediol (15.0 mL, 0.269 mol), p-toluenesulfonic acid monohydrate (8.23 g, 0.0433 mol), and benzene (150 mL, 1.7 mol) were added. The reaction was heated to reflux for 6 hours. The reaction was cooled to room temperature. 1N NaOH was added to adjust the pH to 10. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 5% methanol). The collected fractions afforded 2-(2-[1,3]dioxolan-2-yl-imidazolidin-1-yl)-4-nitro-benzonitrile as a yellow solid (8.20 g, 66%). 1H-NMR (DMSO-D6, 400 MHz): δ8.53 (d, 1H), 8.42 (s, 1H), 8.35 (d, 1H), 7.65 (s, 1H), 7.14 (s, 1H), 5.82 (s, 1H), 3.65 (bs, 2H), 3.45 (bs, 2H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]#[CH:14])[C@H:10]([OH:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:1]([NH:8][C@H:9]([C:13]#[CH:14])[C@H:10]([O:12][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne was prepared by the treatment of (2R,3R)-N-Boc-3-amino-pent-4-yn-2-ol (1.10 g, 5.02 mmol) (Example 117A above) with imidazole (680 mg, 10.04 mmol) and tert-butyldimethylsilyl chloride (800 mg, 5.52 mmol) in 35 mL of CH2Cl2. After 24 hrs stirring at room temperature, the mixture was concentrated to a residue which upon silica gel column chromatography with a 0-20% EtOAc in hexanes gradient yielded (2R,3R)-N-Boc-3-amino-2-(-tert-butyldimethylsilyloxy)-pent-4-yne. (Yield 1.30 g, 83%).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].[CH3:11][Si](C=[N+]=[N-])(C)C>CC(C)=O>[CH3:11][O:9][C:8]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=Cc1ccc(C(=O)O)o1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Formyl-2-furancarboxylic acid (5 g, 35.7 mmol) was dissolved in acetone (100 mL), and trimethylsilyl-diazomethane/2M hexane solution (23.2 mL, 46.4 mmol) was slowly added dropwise at room temperature. After stirring at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to give 5-formyl-2-furancarboxylic acid methyl ester as a crude product.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:29][CH3:30])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:27][CH3:28])[C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])[CH:9]=1)#[N:2].C(=O)([O-])[O-:32].[K+].[K+].OO>CS(C)=O>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:29][CH3:30])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:27][CH3:28])[C:22]([CH:24]2[CH2:25][CH2:26]2)=[O:23])[CH:9]=1)(=[O:32])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)C1CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(N)=O)ccc1OC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclopropanecarboxylic acid (5′-cyanomethyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-ethyl-amide (0.064 g, 0.15 mmol) and potassium carbonate (0.064 g, 0.46 mmol) in DMSO (1 mL) at 0° C. was added hydrogen peroxide (30%; 0.44 mL), and the reaction was warmed to room temperature and stirred for 3 hours. The mixture was partitioned between EtOAc and aqueous Na2S2O4, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 435.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:1][C:2]2[C:3]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:22])([CH3:23])[C:4]=3[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)Nc2cccc(F)c2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Reaction time: 8 h
Yield: 71.5 %

Procedure:
5-tert-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (3.0 g, 9.24 mmol) was dissolved in anhydrous THF (50 ml), treated at room temperature with 3-fluorophenyl-isocyanate (1.4 g, 10.21 mmol, 1.1 eq) and stirred overnight. The following day the reaction mixture was evaporated, taken up with DCM and washed with brine. The organic phase was dried over sodium sulfate and evaporated to dryness. Purification by flash chromatography (CH2Cl2/MeOH 90/10) afforded 3.05 g (yield 71%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2].[CH2:27]([O:29]C(C1C=C(C2C=CC(F)=CC=2)N(C2C=CC(OC)=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([O:29][CH3:27])=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccccc2)c1CBr
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(OC)cc2)c1C
Product: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccc(OC)cc2)c1CBr

Procedure:
Prepared in analogy to that of 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 5-(4-fluoro-phenyl)-1-(4-methoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 430 (M−HBr+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:15][NH2:16].O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Br)cc2)=NN1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
4-(4-Bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) was treated with NH2NH2—H2O (Aldrich, 55%, 9.1 mL, 156 mmol) in EtOH (Aldrich, 100 mL) at refluxing for 2 h. It was cooled down to ambient temperature and the white solid was filtered off to give the title compound (24.2 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 2.50-2.76 (m, 2H), 2.85-3.09 (m, 2H), 7.43-7.71 (m, 4H), 8.55 (s, 1H) ppm. MS (DCl/NH3) m/z 253 (M+H)+, 255 (M+H)+, 270 (M+NH4)+, 272 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]([CH:22]([CH3:24])[CH3:23])[C:3]1[C:4]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1.CCN(CC)CC>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][N:2]([CH:22]([CH3:24])[CH3:23])[C:3]1[C:4]([C:17]2[CH:21]=[N:20][N:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(-c3cnn(-c4ccccc4)c3)c(N(C)C(C)C)nc2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 43.3 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate (150 mg, 0.46 mmol) in dioxane (10 mL) was added phenylboronic acid (112 mg, 0.92 mmol), Cu(OAc)2 (123 mg, 0.68 mmol), pyridine (31 mg, 0.39 mmol) and Et3N (310 mg, 2.3 mmol). The resulting solution was stirred for 36 h at room temperature and concentrated under vacuum. The residue was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(1-phenyl-1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a yellow solid (80 mg, 43%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[NH:24][C:23]2[CH:25]=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)[C:22]=2[N:21]=1>CCO>[F:17][C:15]([F:18])([F:16])[C:8]1[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[N:12][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:20]2[NH:21][C:22]3[C:28]([C:29]4[CH:30]=[C:31]([F:37])[C:32]([F:36])=[C:33]([F:35])[CH:34]=4)=[CH:27][C:26]([C:38]([F:41])([F:39])[F:40])=[CH:25][C:23]=3[N:24]=2)[CH2:3][CH2:2]1
Reactant: OCc1cnc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Solvent: CCO
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)CC2)c(C(F)(F)F)c1

Procedure:
A mixture of (6-piperazin-1-yl-5-trifluoromethyl-pyridin-3-yl)-methanol from step (e) above (131 mg, 0.5 mmol) and 2-chloro-6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (175 mg, 0.5 mmol, Example 51b) in EtOH (2 mL) reacted under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 576 (M+1).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([O:9][N+:10]([O-:12])=[O:11])[CH2:7][O:8][C@@H:3]2[C@H:2]1[OH:13].[CH2:14]([O:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:20]2[C:59]([C:63]([O:65][C:66]([CH3:81])([O:68][C:69](OC3C=CC([N+]([O-])=O)=CC=3)=[O:70])[CH3:67])=[O:64])=[CH:60][CH:61]=[CH:62][C:19]=2[N:18]=1)[CH3:15]>CN(C)C1C=CN=CC=1.ClCCl.CO.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH2:14]([O:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:20]2[C:59]([C:63]([O:65][C:66]([O:68][C:69]([O:13][C@H:2]3[CH2:1][O:5][CH:4]4[C@H:6]([O:9][N+:10]([O-:12])=[O:11])[CH2:7][O:8][CH:3]34)=[O:70])([CH3:81])[CH3:67])=[O:64])=[CH:60][CH:61]=[CH:62][C:19]=2[N:18]=1)[CH3:15]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)O[C@H]3COC4C3OC[C@H]4O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Isosorbide-5-mononitrate (0.203 g, 1.06 mmol) was added to a stirred solution of 1-methyl-1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (Intermediate 1, 0.800 g, 0.883 mmol), 4-dimethylaminopyridine (0.162 g, 1.33 mmol) and scandium trifluoromethanesulfonate (0.087 g; 0.177 mmol) in dichloromethane (12 mL). The solution was stirred at room temperature for 24 hours. Then the mixture was diluted with dichloromethane, washed with aqueous sodium dihydrogenphosphate (20 mL) and brine (20 mL); the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 40+M; TLC method: n-hexane/ethyl acetate: 6/4; Rf=0.33) to afford a solid that was dissolved in methanol (8 mL). The mixture was stirred at 40° C. for 5 hours, at 60° C. for 2 hours, and at room temperature for 18 hours. Then the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 25+M; dichloromethane/methanol: 98/2), affording the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, 1H), 7.69-7.58 (m, 2H), 7.48 (d, 1H), 7.31 (d, 1H), 6.88 (t, 1H), 6.80 (d, 2H), 6.76-6.62 (m, 3H), 5.60 (s, 2H), 5.41-5.33 (m, 1H), 5.03 (d, 1H), 4.95 (t, 1H), 4.48 (d, 1H), 4.36-4.15 (m, 2H), 4.10-3.86 (m, 3H), 1.62 (d, 6H) 1.43 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)[CH:19]=2)[CH:3]=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(N)c3)c2)c1
Yield: 75.1 %

Procedure:
A mixture of the above prepared 4-methyl-2′-(3-nitro-phenyl)-6-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (1.12 g, 3.0 mmol) in THF-MeOH 1:1 (100 mL) and 10% palladium on carbon (1 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with MeOH and the filtrate was completely evaporated totally to leave a crude product, which was purified by trituration with diethyl ether to give the title compound as a light brown solid (0.914 g, 88%). MS (ISP) 406.5 [(M+H)+]; mp 87° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].C(OC(=O)COC(C)C)C.C(OC1C=CC(C=O)=CC=1OC)C1C=CC=CC=1.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:59]2[S:60][C:61]([CH3:67])=[C:62]([CH2:64][CH2:65]O)[N:63]=2)[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=1.COC(=O)CC(=O)C(Br)C.COC1C=C(C=C(OC)C=1)C(N)=S.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:3][C:4](=[O:20])[CH:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:65][CH2:64][C:62]2[N:63]=[C:59]([C:53]3[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:51]([O:50][CH3:49])[CH:52]=3)[S:60][C:61]=2[CH3:67])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OC(C)C
Reactant: COc1cc(OC)cc(-c2nc(CCO)c(C)s2)c1
Agent: CCOC(=O)COC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3cc(OC)cc(OC)c3)sc2C)c(OC)c1)OC(C)C

Procedure:
In analogy to the procedure described in example 1 d], [rac]-3-(4-hydroxy-3-methoxy-phenyl)-2-isopropoxy-propionic acid ethyl ester [prepared from isopropoxy-acetic acid ethyl ester (Tetrahedron (1982), 38(17), 2733-9) and 4-benzyloxy-3-methoxy-benzaldehyde in analogy to the procedures described in examples 54 a]to c)] was reacted with 2-[2-(3,5-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 3,5-dimethoxy-thiobenzamide [PCT Int. Appl. (1992), WO 92/09586 A1] in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(3,5-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-isopropoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(3,5-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-isopropoxy-propionic acid as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:18])=[C:13]([CH2:16][OH:17])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:18])=[C:13]([CH:16]=[O:17])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1
Reactant: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(I)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(I)c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To a solution of (1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (5.0 g, 8.45 mmol) in DCM (85 mL) at 0° C. was added PCC (3.64 g, 16.90 mmol) and the mixture was stirred at RT for 4 h. The mixture was adsorbed on silica gel and purified by column chromatography to provide 1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.0 g, 6.19 mmol, 73.2% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.91 (s, 3 H), 5.45 (s, 2 H), 6.56 (d, J=3.71 Hz, 1 H), 6.91-7.19 (m, 3 H), 7.22 (d, J=3.51 Hz, 1 H), m10.40 (s, 1H); LCMS (m/z) ES+=413 (M+1).
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])C=CC=CC=1>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Reaction time: 4 h
Yield: 100.4 %

Procedure:
Methyl 3-(phenylmethyl)oxy-5-[4-(methylsulfonyl)phenoxy]benzoate (3.50 g, 8.50 mmol) was dissolved in THF (60 mL) followed by 10% palladium on carbon (500 mg). The reaction was then placed under a hydrogen atmosphere by an evacuation-backfill technique. The reaction was then stirred vigorously for 4 h followed by filtration and evaporation which afforded the title compound as an colourless oil (2.75 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C@@:18]4([CH3:25])[NH:23][C:22](=O)[CH2:21][O:20][CH2:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C@@:18]4([CH3:25])[NH:23][C:22](=[S:36])[CH2:21][O:20][CH2:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=S)N1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one (76 mg, 0.2 mmol) in dioxane (3 ml) was treated with Lawesson's reagent (53.2 mg, 0.13 mmol). The reaction mixture was stirred at 80° C. for 3 hours. For the workup, the mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 45:55 as the eluent. The (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-thione was obtained as a white solid (58 mg, 73%); (calculated) C19H19ClFN3OS [391.90]; (found) [M+H]+=392, [M+2+H]+=394.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Cl[CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: COc1ccccc1COCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Temperature: 120 °C
Reaction time: 60 h
Yield: 87.5 %

Procedure:
(α) A solution of 5.2 g (17.7 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] and 3.37 ml (3.8 g,17.7 mmol) of 2-methoxybenzyl 3-chloropropyl ether in 18 ml of absolute DMF was treated with 3.7 g (26.9 mmol) of anhydrous potassium carbonate and stirred at 120° C. for 60 h. For the working-up, the reaction mixture was partitioned between 250 ml of water and 250 ml of ethyl acetate. The organic phase was separated and the aqueous phase was extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed twice with 100 ml of water each time and finally the solvent was distilled off under reduced pressure. The crude product was crystallized by treatment with ether. There were obtained 7.3 g (88% of theory) of tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 472 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1(Br)[CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][N:8]2[CH:20]2[CH2:23][CH2:22][CH2:21]2)=[CH:4][C:3]=1[F:13]
Reactant: BrC1CCC1
Reactant: N#Cc1c[nH]c2cc(Br)c(F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cn(C2CCC2)c2cc(Br)c(F)cc12
Temperature: 90 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
To 6-bromo-5-fluoro-1H-indole-3-carbonitrile (49.2 g, 206 mmol) [prepared as in Example 6, Step B] was added cesium carbonate (133 g, 408 mmol), DMF (200 mL), and cyclobutylbromide (30 mL, 311 mmol). This mixture was stirred at 90° C. for three days, cooled to room temperature and poured into ice water. The precipitate was collected, washed with water and dried to give 6-bromo-1-cyclobutyl-5-fluoro-1H-indole-3-carbonitrile as a light grey solid (55 g, 90%).