Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:11][N:10]([C:12](OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.ClC1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[Cl:31][C:28]1[CH:29]=[N:30][C:12]([N:10]2[CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)([OH:19])[CH2:11]2)=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)cc2)C1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CC(O)(c2ccc(F)cc2)C1
Yield: 60.3 %

Procedure:
The title compound (D81) (0021/074/1) (75.9 mg) was prepared according to the experimental procedure described in Description 80 starting from tert-butyl 3-(4-fluorophenyl)-3-hydroxyazetidine-1-carboxylate (D29) (100 mg, 0.374 mmol) and methyl 2,5-dichloronicotinate (77.32 mg, 0.374 mmol).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 25 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and acetyl chloride give the title compound in 25% yield as a white solid. 1H NMR (CDCl3) δ 2.12 (s, 3H), 2.76-3.61 (br m, 4H), 6.71 (d, 1H), 6.75 (s, 1H), 6.96-7.50 (m, 13H); MS (ES) 340 (M+H). HPLC shows 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20]3([OH:30])[CH2:29][CH2:28][C:23]4(OCC[O:24]4)[CH2:22][CH2:21]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>O1CCCC1.Cl>[OH:30][C:20]1([C:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1
Reactant: Cc1ccc(-c2cc(C3(O)CCC4(CC3)OCCO4)nn2-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C3(O)CCC(=O)CC3)nn2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.6 %

Procedure:
To a solution of 8-(1-(4-chlorophenyl)-5-p-tolyl-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 34) (931 mg, 2.19 mmol) in tetrahydrofuran (5.5 mL), 6 M hydrochloric acid (11 mL) was added, and the obtained solution was stirred at room temperature for 15 hours. The reaction solution was basified by pouring it into saturated aqueous sodium hydrogen carbonate solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (513 mg, 1.35 mmol, 61%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.O.O1CCCC1>[Si:21]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:11])[CH:5]=[CH:6][CH:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxyphenylacetic acid (1.5 g) in dimethylformamide (15 ml), 3.4 g of imidazole and 4.5 g of tert-butyldimethylchlorosilane was added, and the reaction solution was stirred overnight at room temperature. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a brown oil. To a solution of lithium aluminum hydride (748 mg) in tetrahydrofuran (10 ml), a solution of the crude product in tetrahydrofuran (5 ml) was added under ice-cooling, and the reaction solution was stirred at the same temperature for 1 hour. To the reaction solution was added sodium sulfate decahydrate, the mixture was stirred at the same temperature for further 1 hour and then Celite-filtered, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][Li].C.Cl>CCOCC.CCOC(C)=O.C1COCC1>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: [Li]C
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (10.0 g, 48.5 mmol) and THF (100 mL) was cooled to <5° C. (internal temperature) and methyllithium (95 mL of a 1.6M solution in Et2O, 152 mmol) was added, keeping the internal temperature ≦20° C. (slow addition, methane generation). Following methyllithium addition, the solution was warmed to ambient temperature and stirred for 1 h. The solution was then re-cooled to 10° C. and treated carefully with EtOAc (100 mL) and 2N HCl (100 mL). The reaction mixture was further diluted with EtOAc (100 mL) then washed with water (100 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (10.3 g) which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(O)C>[F:23][C:20]([F:21])([F:22])[C:19]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:16]=[N:17][N:18]=1
Reactant: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A solution of 129 g (0.40 mol) of 1-(4-benzyloxyphenyl)-5-trifluoromethyl-1H-tetrazole in 900 mL 1:2 THF/ethanol was hydrogenated at ambient temperature over 6 g 10% Pd/C at 45 psi hydrogen for 12 h. The catalyst was removed by filtration through Celite®, the cake washed with ethanol, and the filtrate concentrated. The product was dissolved in ether, filtered through magnesium sulfate and concentrated. During concentration the product began to crystallize, as the product crystallized the mixture was flushed with hexanes to remove the ether. The resulting slurry was cooled to 0° C., aged 1 hr, filtered, and the cake washed with hexanes. The yield upon drying was 84.8 g (91.5%) of white crystalline 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol: 1H NMR (CDCl3) δ 5.6 (s, 1H), 7.07 (m, 2H), 7.35 (m, 2H). MS (EI) m/z 230. Anal. Calcd for C8H5F3N4O: C, 41.75; H, 2.19; F, 24.76; N, 24.34. Found: C, 41.76; H, 2.23; F, 24.53; N, 24.42. KF <0.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CC([O-])(C)C.[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=C1NCCc2nc(Cl)ccc21
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3nc(Cl)ccc3C2=O)cc1
Temperature: 60 °C

Procedure:
2-chloro-7,8-dihydro-6H-[1,6]naphthyridin-5-one, (1.6 g, 8.77 mmol) was dissolved in DMF (20 mL) and treated with KOtBu (1.3 g, 10.7 mmol), followed by p-methoxybenzyl chloride (1.6 mL, 11.8 mmol). The mixture was heated to 60° C. for 2 h, concentrated and purified by silica chromatography (0 to 100% EtOAc in Hexanes) to give the compound. LC-MS (M+H)=303.2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:9][C:8]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1S(C)(=O)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccccc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 78.6 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (55 mg, 0.053 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (63 mg, 0.106 mmol) and cesium carbonate (1.3 g, 3.99 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-phenyl-quinoline (compound of example 2) (1 g, 2.66 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.28 g, 3.19 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate 80:20 to give a yellow solid (800 mg, 78%). MS: m/z=383 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH2:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9](I)[CH:8]=3.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH2:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[CH:8]=3
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(I)ccc12
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(-c3cccnc3)ccc12
Temperature: 105 °C

Procedure:
3-Bromo-7-iodo-9H-carbazole-1-carboxamide (100 mg, 0.241 mmol), pyridin-3-ylboronic acid (35.5 mg, 0.289 mmol), PdCl2(dppf)-CH2Cl2 adduct (39.4 mg, 0.048 mmol), and Na2CO3 (2M) (0.482 mL, 0.964 mmol) were mixed with DME (4 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 105° C. in an oil bath for 5 hrs. The mixture was used as it is. MS (ESI) m/z 365.88 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([OH:39])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([O:39][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (2.04 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (3.00 g, yield 96%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 101-102° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][C@H:25]2[C@H:29]([OH:30])[CH2:28][O:27][CH2:26]2)=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:30][C@@H:29]2[C@H:25]([O:24][C:3]3[C:2]([F:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:4]=3[CH2:5][N:6]([C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH3:17])[CH2:26][O:27][CH2:28]2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@H]1O)C(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
Intermediate 27C (250 mg, 0.595 mmol) was mixed with 4-nitrobenzoic acid (447 mg, 2.68 mmol), PPh3 (741 mg, 2.82 mmol) in THF (1.5 mL) and stirred at rt for 10 min. The reaction was cooled to 0° C., then DIAD (0.589 mL, 2.97 mmol) was added. After stirring at rt for 16 h, the reaction was quenched with H2O and extracted with EtOAc (2×). The organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography to give 27D (268 mg, 0.471 mmol, 79% yield) as a white foam. The relative stereochemistry of hydroxyether is cis however absolute stereochemistry is undetermined MS (ESI) m/z: 570.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:16])[C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:36]=1)#[N:2].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])([O:16][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:12]([F:14])([F:13])[F:15])=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)(c1nc2cc(C#N)ccc2o1)C(F)(F)F
Reactant: COC(=O)CBr
Product: COC(=O)COC(c1nc2cc(C#N)ccc2o1)(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)C(F)(F)F

Procedure:
The title compound was synthesized from tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 128-A) and methyl 2-bromoacetate following Example 109-A. MS (ESI+) m/z 574.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1>CCO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])/[C:8]/2=[CH:20]\[C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)/C(=C/c1ccc(F)cc1)C(=O)N2

Procedure:
To a solution of methyl-2-oxindole-5-carboxylate (4.764 g) in EtOH (100 mL) was added 4-fluoro-benzaldehyde (4.72 mL) in one portion, followed by piperidine (790 μL). The mixture was refluxed for 3 hours and the yellow precipitate was collected by filtration. The yellow product was used for the next step without further purification.
Reaction SMILES: C(OC(=O)[CH2:7][CH2:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[C:10]=1[CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=O)(C)(C)C.[H-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:18][O:17][C:11]1[C:10]2[CH2:19][CH2:20][C:21](=[O:23])[CH2:7][CH2:8][C:9]=2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=1
Reactant: COc1ccc(OC)c(CCC(=O)OC(C)(C)C)c1CCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(OC)c2c1CCC(=O)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
3-[2-(2-tert-butoxycarbonylethyl)-3,6-dimethoxyphenyl]-propionic acid tert-butyl ester (6.33 g) was added dropwise to a refluxed solution of sodium hydride (578 mg) in dry toluene (60 ml) and dry tert-butyl alcohol (0.5 ml), and stirred for 3 hours. After cooling, to the reaction mixture glacial acetic acid was added dropwise followed by addition of ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the residue were added methanol (50 ml) and 6N hydrochloric acid (15 ml), and this mixture was refluxed for 3 hours, poured into ice and extracted with ethyl acetate. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 1,4-dimethoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-one (2.99 g).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:27][N:13]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=1)(=[O:16])=[O:15])[C@H:10]1[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[CH2:8][CH2:9]1
Reactant: COC(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
1.14 g (2.7 mmol) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid methyl ester in 27 mL of THF were treated with 27 mL of 1M LiOH at RT for 1 h. By adding 1M KHSO4 the solution was acidified, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated to give 1.1 g (quantitative) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid as colorless oil, MS: 408 (M−H)−.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([NH:19][NH2:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC2N(O)N=NC=2C=1.[CH3:31][O:32][C:33]1[C:42]2[C:37](=[C:38]([O:43][CH3:44])[CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:45]([N:47]2[CH2:52][CH2:51][C:50]3([CH2:61][C:60](=[O:62])[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:63](O)=[O:64])[CH:58]=4)[O:53]3)[CH2:49][CH2:48]2)=[O:46])[CH:34]=1>C(OCC)(=O)C.CN(C=O)C>[CH3:31][O:32][C:33]1[C:42]2[C:37](=[C:38]([O:43][CH3:44])[CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([C:45]([N:47]2[CH2:52][CH2:51][C:50]3([CH2:61][C:60](=[O:62])[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:63]([NH:20][NH:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:64])[CH:58]=4)[O:53]3)[CH2:49][CH2:48]2)=[O:46])[CH:34]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)O)ccc2O3)nc2c(OC)cccc12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NNC(=O)OC(C)(C)C)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.5 %

Procedure:
50.6 mg of EDCI was added to a mixture of 29.1 mg of Boc-hydrazine, 33.7 mg of HOBT, 105 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(carboxy)spiro[chroman-2,4′-piperidin]-4-one and 2.2 mL of DMF, and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with 15 mL of ethyl acetate, washed with water and aqueous saturated NaHCO3 solution, and dried over sodium sulfate. The residue was purified through silica gel chromatography (2% MeOH/CHCl3) to obtain 119 mg of tert-butyl 2-({1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}carbonyl)hydrazinecarboxylate. 2 mL of 4 N HCl in dioxane was added to 59.1 mg of the product, and stirred at room temperature for 1 hour, and then concentrated. The residue was suspended in 2.5 mL of THF, and 0.049 μL of triethylamine and 24.3 mg of CDI were added thereto at 0° C., and stirred at room temperature for 14 hours. Water was added to the reaction solution, and extracted with chloroform, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified through silica gel thin-layer chromatography (17% MeOH/CHCl3) to obtain the intended compound. 1H-NMR (CDCl3) δ: 8.85 (1H, br s), 8.38 (1H, d, J=2.2 Hz), 7.97 (1H, dd, J=2.2, 8.8 Hz), 7.77 (1H, dd, J=8.5, 1.0 Hz), 7.47 (1H, dd, J=7.8, 8.5 Hz), 7.20 (1H, s), 7.13 (1H, d, J=8.8 Hz), 7.08 (1H, dd, J=1.0, 7.8 Hz), 4.64-4.56 (1H, m), 4.24-4.16 (1H, m), 4.09 (3H, s), 4.03 (3H, s), 3.67-3.58 (1H, m), 3.43-3.34 (1H, m), 2.87 (1H, d, J=16.8 Hz), 2.81 (1H, d, J=16.8 Hz), 2.26-2.18 (1H, m), 2.11-2.04 (1H, m), 2.01-1.87 (2H, m). MS [M+H]+=517.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[CH:36]3[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:30][CH2:29]2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:28]1([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:36]2[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29]1
Reactant: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCC2CCCCC21
Temperature: 25 °C

Procedure:
201 mg (0.69 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-on-dihydrochloride were added to 184 mg (0.69 mmol) (6-chloropyrimidin-4-yl)-(octahydroindol-1-yl)-methanone and 488 μL (2.8 mmol) DIPEA in 3 mL DMF. The reaction mixture was stirred at RT over the weekend and then purified by preparative HPLC-MS. The product fractions were combined and the organic solvent was removed using the rotary evaporator. The aqueous solution was neutralised with aqueous 1N NaOH solution and the precipitate obtained was suction filtered. The precipitate was washed with water and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](OC)[CH:12]=2)[NH:7][CH:6]=1.O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[CH:17][CH:18]=4)[NH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:6]1
Reactant: COc1ccc2[nH]cc(CCCCl)c2c1
Reactant: Oc1ccc2[nH]cc(C3CCNCC3)c2c1
Product: c1ccc2c(CCCN3CCC(c4c[nH]c5ccccc45)CC3)c[nH]c2c1

Procedure:
of 3-(3-chloropropyl)-5-methoxyindole with 4-(5-hydroxyindol-3-yl)piperidine: