Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:4]=[CH:3]1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CCCCCCC>CN(C=O)C>[Cl:15][C:3]1[N:2]([CH3:1])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:4]=1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COC(=O)c1ncn(C)c1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)n(C)c1C(=O)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a colorless solution of dimethyl 1-methyl-1H-imidazole-4,5-dicarboxylate (500 mg, 2.42 mmol, Eq: 1.00) in DMF (5.00 mL) was added under a nitrogen atmosphere 1,3-dichloro-5,5-dimethylhydantoin (487 mg, 2.42 mmol, Eq: 1.00). The reaction mixture was heated to 80° C. and stirred for 2 h, cooled down to ambient temperature, poured into saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) to give the product as colorless oil (415 mg, 1.78 mmol, 73.7%). MS: M=233.0 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1)=[C:10]([CH3:27])[CH:9]=2)=[O:5])C.[OH-].[K+]>CO.O.O>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[C:12]([CH3:15])=[C:13]3[C:8](=[CH:9][C:10]=2[CH3:27])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:18][C:19]=1[CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(C)C)c3)c(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2[nH]c(C(=O)O)cc2c(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 5-(4-hydroxy-3-isopropyl-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (60 mg, 0.16 mmol) in methanol/water (1:1, 3.2 mL) at room temperature was added 3N potassium hydroxide (324 μL). After stirring at room temperature for 2 hours, the mixture was diluted with water (10 mL) and washed with ethyl acetate. The aqueous solution was acidified with 1 M hydrochloric acid and then extracted with ethyl acetate (3 times 25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford the title compound (30 mg) as a solid. 1H NMR (400 MHz, CD3OD) δ11.07 (s, 1H), 7.16 (s, 2H), 6.62 (d, 1H), 6.57 (d, 1H), 6.25-6.22 (dd, 1H), 3.24-3.19 (m, 1H), 2.27 (s, 3H), 2.17 (s, 3H), 1.12 (d, 6H). MS (APCI−) Calc: 339.1, Found: 338.2 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11](C(OC(C)(C)C)=O)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:41]([CH3:43])([CH3:42])[C:40](=[O:44])[NH:39][C:38]1=[O:45].[C:46](=[O:49])([O-])[O-:47].[K+].[K+]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[C:1]([O:47][C:46](=[O:49])[C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:35])([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH2:8][CH2:9][N:39]1[C:40](=[O:44])[C:41]([CH3:43])([CH3:42])[N:37]([CH3:36])[C:38]1=[O:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)NC(=O)C1(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](CCI)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(CCC(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of the title F compound, (2R)-[t-butyloxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]-4-iodobutyric acid t-butyl ester (0.6 g, 0.94 mmol) in 10 mL DMF is added 3,4,4-trimethyl-2,5-dioxoimidazoline and potassium carbonate (0.65 g, 4.72 mmol) followed by 2 mg of 18-crown-6. The reaction mixture is stirred at room RT for 3 h, then partitioned between water and EtOAc. The organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 1/19—EtOAc/hexane) affords the title compound as a white foam (0.25 g, 41%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)(=[O:10])[CH3:9]
Reactant: OC1CCCNC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCCC(O)C1
Temperature: 10 °C

Procedure:
3-Hydroxypiperidine (0.4 mole) is dissolved in 150 ml. of methylene chloride. The solution is cooled to 10° C. and acetic anhydride (0.46 mole) is added dropwise, maintaining the temperature under 20° C. The reaction mixture is allowed to come to room temperature, and is then refluxed for 2 hours. The methylene chloride is evaporated off, and the remaining liquid is distilled under high vacuum. A thick yellow oil is collected at 122°-126° C. (0.3 mm Hg).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7]1([CH3:8])[O:14][CH2:13][CH2:12][O:9]1
Reactant: OCCO
Reactant: CON(C)C(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CON(C)C(=O)CCC1(C)OCCO1

Procedure:
To a solution of 4-1 (38 g, 0.239 mol) in 500 mL benzene was added ethylene glycol (17.3 mL, 0.310 mol) and p-toluenesulfonic acid (1 g). The mixture was heated at reflux for 2 h with azeotropic removal of water. After cooling, the solution was washed with 200 mL sat. NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-2 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: C1COCCN1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CN2CCOCC2)c1
Yield: 76.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(morpholinomethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), morpholine (0.046 mL; 0.5 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 0 to 5% methanol in dichloromethane) furnished 0.044 g (76%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O=P(Cl)(Cl)[Cl:23]>N1C=CC=CC=1>[Cl:23][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Solvent: c1ccncc1
Product: ClCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 20) in dry pyridine (10 mL) was added dropwise POCl3 (2.4 g, 14.7 mmol) under N2 atmosphere. The resulting solution was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo. The residue was poured into ice-water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified on silica gel column (0˜20% EtOAc in petroleum ether) affording the title compound (400 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.86 (s, 1H), 7.72 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 3.90-3.86 (m, 1H), 3.81 (t, 2H), 3.77-3.70 (m, 1H), 2.93 (t, 2H), 2.41-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.75-1.71 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 289 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.C([Li])CCC.[O:20]=[C:21]1[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2>C(OCC)C.C1COCC1>[OH:20][C:21]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=2)[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Reactant: Brc1cncc(Oc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cncc(Oc3ccccc3)c1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 3-bromo-5-phenoxypyridine (0.51 g, 2.0 mmol) in dry diethyl ether (15 mL) at −78° C. was added 2.5 M n-butyllithium (0.80 mL, 2.0 mmol). The reaction was stirred for 30 min under nitrogen at −78° C. and then slowly transferred by cannula into a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.20 g, 1.0 mmol) in THF (15 mL) at −78° C. The reaction was stirred 4 h at −78° C. and then warmed to ambient temperature overnight, at which time it was quenched with saturated aqueous ammonium chloride (20 mL). The mixture was then extracted with chloroform (2×10 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Excess pyridine was removed by repeated azeotropic rotary evaporation with toluene, and the residue was chromatographed on a silica gel column (with 5% methanol in chloroform) to yield the desired product (0.31 g, 84%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([CH:26]2[CH2:28][CH2:27]2)[N:22]=1>CN(C)C=O>[CH:26]1([C:23]2[N:22]=[C:21]([CH2:20][O:14][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[O:25][N:24]=2)[CH2:28][CH2:27]1
Reactant: ClCc1nc(C2CC2)no1
Reactant: [H][H]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OCc3nc(C4CC4)no3)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
While cooling, 5.58 g of 4-phenoxyphenol as a solution in 30 ml of absolute dimethylformamide is dripped into 1 g of 80% strength sodium hydride in 25 ml of absolute dimethylformamide. Upon completion of hydrogen evolution, 4.76 g of 5-chloromethyl-3-cyclopropyl-1,2,4-oxadiazole is dripped in and the mixture is stirred for 8 hours at 80° C. After the solvent has been removed, the residue is slurried in 250 ml of water, extracted three times, each time with 100 ml of ether, and the combined ethe phases are dried over sodium sulfate. After removal of the solvent under reduced pressure and recrystallization of the crude product from methanol/water (1:1) there is obtained 8.0 g of 3-cyclopropyl-5-[(4-phenoxyphenoxy)-methyl]-1,2,4-oxadiazole; m.p.: 99° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:10])[NH:6][C:7]=1[CH2:8][CH3:9])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.N1CCOCC1>C(#N)C.CO>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][C:16]([C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)=[O:17])[NH:6][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCc1nc(C)[nH]c1CC
Solvent: CO
Solvent: CC#N
Solvent: C1COCCN1
Product: CCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1CC

Procedure:
The compound is prepared as described in example X (step 4) with 800 mg (5.79 mmol) of 4,5-Diethyl-2-methyl-1H-imidazole (example XXVII, step 1), 2.75 g (17.36 mmol) of 4-fluorobenzoyl chloride and 1.93 g (19.10 mmol) of TEA in 15 ml acetonitrile. The crude intermediate (1.30 g, 2.58 mmol) is dissolved in 10 ml methanol under argon. 1.12 g (12.88 mmol) of morpholine are added dropwise to the solution. The mixture is refluxed for 10 minutes. The solvent is evaporated under argon and the residue is purified over silica (eluent: dichlormethane/methanol 50:1). The solvent is evaporated under vacuum to yield 572 mg (82.6% of th.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[C:6]([CH2:8]O)[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:28])=O.O>O1CCCC1>[Cl:28][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:5]=1[O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCOc1cc(F)cc(CO)c1OCCOC
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COCCOc1cc(F)cc(CCl)c1OCCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.31 g, 1.1 mmol) and pyridine (0.15 mL 1.9 mmol) in tetrahydrofuran (10 mL) at 0° C. was added thionyl chloride (0.093 mL, 1.3 mmol) and the reaction mixture warmed to room temperature and stirred for one hour. Then it was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give 1-(chloromethyl)-5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}benzene (0.33 g, 1.1 mmol, 100% yield), 1H NMR (400 MHz, CDCl3): 6.76-6.26 (m, 2H), 4.69 (s, 2H), 4.22-4.13 (m, 4H), 3.86-3.78 (m, 4H), 3.46 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:6]2=[O:36].[ClH:37].CCOCC>C(Cl)Cl.C(O)(C)C>[ClH:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)[N:9]=[CH:8][N:7]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])[C:6]2=[O:36]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 16 mmol) in methylene chloride (80 ml) containing 5.5M hydrogen chloride in isopropanol (80 ml) was stirred for 1 hour at ambient temperature. Ether was added and the solid was collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (6.9 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=O)([CH3:7])[CH3:6])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 77.9 %

Procedure:
2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) and 6-chlorooxindole (3.6 g, 22 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.85 g, 26 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.[H][H]>O1CCCC1.CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: [H][H]
Reactant: COc1cccc2c1C(=NO)CC2
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c1C(N)CC2
Yield: 97 %

Procedure:
A mixture of 7-methoxy-indan-1-one oxime (CAS 908108-58-7, (E)-oxime 179899-16-2) (22.3 g, 126 mmol)) and Raney-Nickel (11.26 g) in tetrahydrofuran (570 mL) and methanol (570 mL) was hydrogenated at 100 bar hydrogen-pressure at 60° C. for 22 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles were removed in vacuum to give the title compound as a brown oil (19.95 g, 97%, HPLC 0.4 min), MS (ISP) m/e=164.2 [(M+H)+].
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([Cl:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Cl:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:13])[N:18]([OH:19])[C:11](=[O:12])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c(Cl)ccc(c23)C(=O)N1O
Yield: 80.8 %

Procedure:
4-Chloro-1,8-naphthalic anhydride (1.4 g, 6.0 mmol) and hydroxylamine hydrochloride (0.8 g, 11.5 mmol) were reacted in pyridine (50 mL) following the procedure of Example 1 to give 1.2 g of the title compound, mp 234-236° C.;
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([CH3:16])[CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C@@H:19]1[C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][N:21]([C@H:30]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:31]([O:33]CC2C=CC(OC)=CC=2)=[O:32])[CH2:20]1)=O>>[CH3:16][C@@H:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:17][C@@H:19]2[C@@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][N:21]([C@H:30]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:31]([OH:33])=[O:32])[CH2:20]2)[CH2:14][CH2:15]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: C[C@@H](Cc1ccccc1)CC1CCNCC1
Product: C[C@@H](Cc1ccccc1)CC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
The title compound was prepared from 15 mg (0.07 mmol) of 4-(3-phenyl-2-(R)-methylpropyl)piperidine (from EXAMPLE 99, Step C) and 31 mg (0.07 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F. For the title compound: ESI-MS 517 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6](=[O:13])[NH:7][S:8]2(=[O:10])=[O:9])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].[C:23]1([S:29]CCl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:14]([C:4]1[C:3]([CH3:17])=[C:2]([OH:1])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:13])[N:7]([S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:8]2(=[O:10])=[O:9])([CH3:16])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Reactant: ClCSc1ccccc1
Agent: [Cs+]
Solvent: CO
Product: Cc1c(O)cc2c(c1C(C)C)C(=O)N(Sc1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 119.1 %

Procedure:
Five grams (0.0207 mol) of 6-hydroxy-4-isopropylsaccharin was dissolved in 150 ml of methanol and 3.4 g (0.0104 mol) of Cs2CO3 was added. The mixture was stirred for 3-4 hr at RT. The excess methanol was removed under reduced pressure and the residue was dried for 2 hr under high vacuum. The residue was then dissolved in 110 mL of DMF and 0.32 g (0.0209 mol) of chloromethyl phenyl sulfide was added. The stirred mixture was heated at 70°-75° for 12 hr, cooled, treated with ice water and extracted with 600 mL of 4:1 ethyl acetate:ether. The organic layer was washed with water and saturated NaCl and dried. The solvent was removed under reduced pressure. The residue was purified by flash chromatography with 20% ethyl acetate in MDC. There was obtained 4.5 g (60%) of 4-isopropyl-6-hydroxy-2-phenylthio-methylsaccharin, mp 150°-151.5° C. which, on reaction with sulfuryl chloride as described in Preparation 19, yielded 2-chloromethyl-4-isopropyl-6-hydroxysaccharin as before.
Reaction SMILES: [C:1]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[CH2:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1Cc2ccccc2C1
Yield: 69.1 %

Procedure:
Dissolve 2-(carboethoxy)indane (6.49 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidify the aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 2-indancarboxylic acid as a tan solid (3.82 g, 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[C:16]1B(O)O)(OC(C)(C)C)=O>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[NH:15][C:16]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:17]2
Reactant: Brc1cccnc1
Reactant: COc1ccc2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Product: COc1ccc2[nH]c(-c3cccnc3)cc2c1

Procedure:
3-Bromopyridine and N-Boc-5-methoxy-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 5-methoxy-2-pyridin-3-yl-1H-indole. HRMS (ESI) m/z 225.1026 [(M+H)+ Calcd for C14H13N2O: 225.1028]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4](Cl)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][SH:38])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([S:38][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1
Reactant: Fc1ccc(CCS)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-chloro-propionic acid methyl ester (6.56 g, 42 mmol) in anhydrous DMF (200 mL) was added Cs2CO3 (14.34 g, 44 mmol) at 0° C. After stirring for 30 min 2-(4-fluoro-phenyl)-ethanethiol (13.72 g, 40 mmol), dissolved in anhydrous DMF (100 mL), was added dropwise and the resulting organe mixture was stirred for 18 h without removing the cooling bath. The mixture was diluted with Et2O and extracted with three times with H2O. The organic phase was concentrated under reduced pressure and the residue was dissolved in Et2O again and repeatedly extracted with H2O. After drying the seperated organic layer over MgSO4, the solvent was removed under reduced pressure to afford the crude product as an orange oil which was purified by chromatography using n-heptane/EtOAc 20:1 as the eluent. The desired product was obtained as an oil (4.93 g, 25.4%). 1H NMR (400 MHz, CDCl3): δ 7.16 (d, 2H), 7.06-6.99 (m, 4H), 6.88 (t, 2H), 4.62 (s, 2H), 3.58 (s, 3H), 3.41 (dd, 1H), 3.10 (dd, 1H), 2.82 (dd, 1H), 2.74-2.76 (m, 4H), 0.85 (s, 9H), 0.00 (s, 6H).