Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:9]=2)[CH:4]=[N:3]1>O1CCOCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)Cc1ccc2cn[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Hydrochloric acid (10 mL, 4 M in 1.4 dioxane) was added to tert-butyl 1H-indazol-6-ylacetate (Preparation 181, 1.00 g, 4.3 mmol) in 1,4 dioxane (5 mL) at 0° C. and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated in vacuo and the residue was triturated with dry ether to afford the title compound as a white solid in 100% yield, 800 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[C:13]([O:15][Si](C(C)C)(C(C)C)C(C)C)[CH:12]=[C:11]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][N:30]4[Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)=[O:8])[CH:2]=1.[CH3:45][Mg]Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[Na+].O>[OH:8][C:7]([C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[CH:29][NH:30]3)[CH:10]=1)([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:45]
Reactant: C[Mg]Cl
Reactant: CC(C)[Si](Oc1cc(C(=O)c2cccnc2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1cccnc1)c1cc(O)cc(-c2cccc3[nH]ccc23)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To pyridin-3-yl-[3-(1-triisopropylsilanyl-1H-indol-4-yl)-5-triisopropylsilanyloxy-phenyl]-methanone (64 mg, 0.102 mmol) in 2 mL of THF was added 2 mL of MeMgCl (1 M in THF) at 0° C. After 30 min TLC indicated the completion of the reaction. Brine was then added to quench the reaction. The aqueous phase was then extracted with EtOAc. The combined organic phases were dried and concentrated to afford the crude product. The residue was again dissolved in 2 mL of THF and followed by addition of 1 mL of TBAF (3M in THF) at 0° C. After 30 min the solvent of the reaction was removed under reduced pressure. The residue was dissolved in EtOAc and the organic phase washed with water and brine, dried and concentrated to afford the crude product. The crude product was then purified by prep. TLC to afford 3-(1-hydroxy-1-pyridin-3-yl-ethyl)-5-(1H-indol-4-yl)-phenol (13 mg, 39% over two steps). 1H NMR (400 MHz, CD3OD): δ 8.66 (d, 1H, J=1.6 Hz), 8.36 (d, 1H, J=4.0 Hz), 7.93 (d, 1H, J=6.4 Hz), 7.36 (dd, 1H, J=8.0, 4.8 Hz), 7.33 (d, 1H, J=8.0 Hz), 7.21 (d, 1H, J=2.8 Hz), 7.20-7.19 (m, 1H), 7.11 (t, 1H, J=8.0 Hz), 7.01 (d, 1H, J=7.2 Hz), 6.99-6.98 (m, 1H), 6.99 (t, 1H, J=1.6 Hz), 6.46 (d, 1H, J=3.6 Hz), 1.98 (s, 3H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[C:34]3[CH2:36][NH:37][CH2:38][CH2:39][C:33]3=[N:32][C:31]=2[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:26][CH2:25]1.N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[C:34]3[CH2:36][N:37]([C:5](=[O:7])[CH3:6])[CH2:38][CH2:39][C:33]3=[N:32][C:31]=2[NH:40][CH:41]([CH3:42])[CH3:43])[CH2:26][CH2:25]1.[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2nc(NC(C)C)c(N3CCC(C(F)c4ccc(F)cc4F)CC3)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (7 μL, 0.075 mmol) was added to a solution of 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (20.1 mg, 0.038 mmol) and pyridine (9 μL, 0.113 mmol) in DCM (380 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (20.1 mg, 93%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (dd, J=6.4, 1.9 Hz, 6H), 1.46 (br s, 1H), 1.56-1.77 (m, 2H), 2.00 (d, J=12.9 Hz, 1H), 2.04-2.15 (m, 1H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.76 (qd, J=12.8, 2.4 Hz, 3H), 2.87 (t, J=5.9 Hz, 1H), 3.40-3.56 (m, 2H), 3.78-3.83 (m, 1.1H), 3.83-3.89 (m, 0.9H), 4.09-4.17 (m, 1H), 4.52 (s, 2H), 5.53 (dd, J=46.7, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH:16](=[O:20])[CH:17]([CH3:19])[CH3:18].Cl>O1CCCC1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOc1ccc(Br)cc1
Reactant: CC(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)C(C)C)cc1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 100.4 %

Procedure:
A solution of p-bromophenetole (2.01 g, 0.01 mol) in tetrahydrofuran is cooled to −65° C., treated dropwise with a 2.5 M solution of n-butyllithium in hexane (4 mL), stirred for 20 minutes at −55 to −65° C., treated dropwise with a solution of isobutyraldehyde (0.91 mL, 0.01 mol) in tetrahydrofuran, stirred overnight at room temperature, diluted with an ice-water mixture, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a tan oil (1.95 g) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([CH:14]=[O:15])[N:7]=1>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([CH2:14][OH:15])[N:7]=1
Reactant: COC(=O)/C=C/c1nc(C=O)ccc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1nc(CO)ccc1OC
Yield: 98.2 %

Procedure:
Under the conditions of example 1 C, a solution of 11 g of 3-(6-formyl-3-methoxy-2-pyridyl)-(2E)-2-propenoic acid methyl ester in 140 ml of tetrahydrofuran and 40 ml of methanol in the presence of 1.2 g of 10% palladium catalyst is hydrogenated on activated carbon and worked up. 11 g of 3-(6-hydroxymethyl-3-methoxy-2-pyridyl)-propionic acid methyl ester is obtained as oily crude product, which is reacted under the conditions of example 16 E with 78 g of manganese dioxide for 21/2 hours and is worked up. 8.92 g of 3-(6-formyl-3-methoxy-2-pyridyl)-propionic acid methyl ester of melting point 95°-97° C. is obtained.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C@H:23]3[CH2:25][C@H:24]3[CH2:26][CH2:27][O:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[C:31]([F:44])[CH:30]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C@H:23]3[CH2:25][C@H:24]3[CH2:26][CH2:27][O:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([CH2:36][C:37]([OH:39])=[O:38])=[C:31]([F:44])[CH:30]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)[CH3:9]
Reactant: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC(C)(C)C)c(F)c3)CC2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A solution of 4 M HCl in dioxane (16.2 mL, 64.7 mmol) was added to a solution of tert-butyl 2-(4-(2-((1S,2R)-2-(1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethoxy)-2,6-difluorophenyl)acetate (3.35 g, 6.47 mmol) in DCM (16 mL). This mixture was stirred at 35° C. for 4 hrs. The mixture was concentrated under reduced pressure to afford the title compound. LC/MS (m/z): 462 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1COCC1>[Cl:21][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(OCCN2CCCCC2)cc1
Solvent: C1CCOC1
Product: ClCCc1ccc(OCCN2CCCCC2)cc1
Yield: 91.9 %

Procedure:
2-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-ethanol (4.23 g, 16.98 mmol) was dissolved in 200 ml of THF. HCl gas was bubbled through the solution at 0° C. for 5 minutes. Still at 0° C. the thionyl chloride (2.48 ml, 33.9 mmol) was added dropwise. The reaction mixture was heated at reflux for 2 hours before it was concentrated. 1-{2-[4-(Chloro-ethyl)-phenoxy]-ethyl}-piperidine (4.74 g, 15.6 mmol) was isolated as a brown semisolid; Yield 92%; MS: 268.3 (M+H)+
Reaction SMILES: Cl[Si](C)(C)C.C(O[C@H:10]1[N:13]([Si](C)(C)C)[C:12](=[O:18])[C@@H:11]1[C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])(=O)C.C[Si](C)(C)[O:31][C:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH:33]=1>ClCCl>[Si:22]([O:21][C@@H:19]([C@@H:11]1[C@@H:10]([C@@H:37]2[CH2:36][CH2:35][CH:34]=[CH:33][C:32]2=[O:31])[NH:13][C:12]1=[O:18])[CH3:20])([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: C[Si](C)(C)OC1=CCCC=C1
Reactant: CC(=O)O[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H]1CCC=CC1=O
Reaction time: 5 h
Yield: 14.8 %

Procedure:
To stannous chloride (379 mg) was added a dichloromethane solution (10 ml) of chlorotrimethylsilane (217 mg) followed by addition of a dichloromethane solution (10 ml) of (3R,4R)-4-acetoxy-3-[(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-1-trimethylsilylazetidin-2-one (7.19 g). To this suspension was added a dichloromethane solution (10 ml) of 2-[(trimethylsilyl)oxy]-1,3-cyclohexadiene (4.05 g) dropwise at room temperature over a period of 1 hour. The mixture was stirred at 25° C. for 2 hours, at the end of which time a dichloromethane solution (10 ml) of 2-[(trimethylsilyl)oxy]-1,3-cyclohexadiene (5.38 g) was added dropwise over a period of 1 hour. The mixture was further stirred for 5 hours and then allowed to stand at 0° C. overnight. The solvent was then distilled off under reduced pressure. To the residue were added ether (100 ml) and aqueous sodium hydrogen carbonate solution (30 ml) and the mixture was stirred for 10 minutes. The insolubles were filtered off and the aqueous layer was extracted with ether. The ether layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was dissolved in THF-water (17:2, 95 ml). To this solution was added pyridinium p-toluenesulfonate (610 mg) and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and ether (150 ml) was added to the residue. The organic layer was washed successively with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (packing: silica gel 300 g; ether-hexane 5:1) to give (3S,4R)-3-[(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[(R)-2-oxo-3-cyclohexen-1-yl]azetiidin-2-one (R-compound; 1.01 g) and (3S,4R)-3-[(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[(S)-2-oxo-3-cyclohexen-1-yl]azetidin-2-one (S-compound; 0.96 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:20]=1[CH2:21]Br>>[CH3:18][C:19]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1ccc(C)c(CBr)c1
Product: Cc1ccc(C)c(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dimethylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CCN2CCC(CO)C2)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CCN2CCC(COS(=O)(=O)c3ccc(C)cc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 g (0.005 mol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-hydroxymethyl-pyrrolidine are dissolved in 10 ml of pyridine, 1.05 g (0 0055 mol) of p-toluenesulphonic acid chloride are added and the mixture is stirred for 6 hours at ambient temperature. The excess pyridine is then distilled off in vacuo, the residue obtained is dissolved in methylene chloride and the organic phase is extracted with ice water. After the organic phase has been dried over magnesium sulphate it is concentrated by evaporation in vacuo. Yield: 1.4 g (66.7% of theory), Rf value: 0.40 (aluminium oxide, neutral, eluant: 2% ethanol in methylene chloride).
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[S:13](N3C=CC=C3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1.[K].S(Cl)([Cl:29])(=O)=O>>[Cl:29][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:21]=[CH:22][C:23]2[O:24][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(c1ccsc1CCc1ccc2c(c1)OCO2)n1cccc1
Agent: [K]
Product: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Yield: 42 %

Procedure:
3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene was prepared in the same manner as described in the Example 64E using N-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole by conducting basic hydrolysis (iso-propanol and potassium hydroxide) of the sulfonamide to the potassium salt of sulfonic acid (93%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 42% yield.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+].[I-:16].[K+]>Cl.O.S(=O)(=O)(O)O>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([I:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [I-]
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(Cl)cccc1I
Yield: 61 %

Procedure:
To the cold solution of 2-amino-6-chlorobenzoic acid (2.0 g, 11.6 mmol) in conc. HCl (10 mL) was added aq. solution of sodium nitrite (0.8 g, 11.6 mmol) at 0° C. followed by addition of solution of potassium iodide (2.88 g, 17.4 mmol) in water and conc. sulphuric acid (1 mL). The reaction mixture was refluxed for 2 h. The reaction mass was washed with sodium metabisulphate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.08 (t, J=7.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 8.37 (br s, 1H); MS (m/z): 280.59 (M)−.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:46][CH3:47])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:31][C:32]([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=2)=[O:33])[CH:23]=1)=O)(C)(C)C>>[CH2:46]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:31][C:32]([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=2)=[O:33])[CH:23]=1)[CH3:47]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Trifluoroacetic acid (7.9 mL) was added to the obtained 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid (0.79 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a 30% aqueous solution of ethanol was added to the obtained residue. After adjusting the pH to 5.0 with a 4.0 mol/L aqueous solution of sodium hydroxide, the solid substance was collected by filtration to obtain 0.61 g of 4-(2-(ethylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a yellow solid.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([CH:12]2[C:16](=O)[CH2:15][N:14]([CH3:18])[C:13]2=[O:19])[CH:11]=1.O.Cl>ClC1C=CC=CC=1Cl.CCCCCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16]3[CH2:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[C:10]=2[CH:11]=1
Reactant: CN1CC(=O)C(c2cc(Cl)ccc2Oc2ccccc2)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: Clc1ccccc1Cl
Solvent: O
Solvent: CCCCCC
Product: CN1CC2=C(C1=O)c1cc(Cl)ccc1Oc1ccccc12
Temperature: 85 °C
Reaction time: 9 h

Procedure:
Anhydrous aluminium bromide (2.5 g) was added to a reaction mixture containing 3-(5-chloro-2-phenoxyphenyl)-1-methylpyrrolidine-2,4-dione (1 g) in 1,2-dichlorobenzene (4 mL) at ambient temperature. The reaction mixture was stirred at about 85° C. for about 9 hours, then cooled to ambient temperature. A mixture of water and concentrated hydrochloric acid (50 mL:5 mL) was added slowly. The contents were stirred for about 30 minutes. Hexane (10 mL) was added. The contents were stirred for about 1 hour, filtered, washed with hexane (10 mL) and dried in air at about 30° C. for about 15 hours to obtain 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo [2,3:6,7]oxepino[4,5-c]pyrrol-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][N:35]=1>ClCCl.C1(C)C=CC=CC=1>[Cl:33][C:34]1[N:35]=[CH:36][C:37]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])=[CH:38][CH:39]=1
Reactant: O=C=Nc1ccc(Cl)nc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)nc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 2-chloro-5-isocyanato-pyridine (1.28 mL, 0.26 mmol) in toluene (from Example 66a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (6-chloro-pyridin-3-yl)-amide as a white solid. (Yield 32 mg, 28.3%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12](=[C:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:11])[CH3:10].[NH4+].[Cl-]>CCOCC.[Cu]I>[C:9]([CH:12]([C:17]([CH3:19])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:11])[CH3:10]
Reactant: COC(=O)C(C(C)=O)=C(C)C
Reactant: Br[Mg]c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C(C(C)=O)C(C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 146 mg (0.8 mmol) of anhydrous CuI (I) in 5 mL of anhydrous ether are added, at 0° C., under a stream of argon, 3.6 mL (10.9 mmol) of a 3M solution of phenyl magnesium bromide in Et2O. After stirring for 30 minutes at 0° C., 1 g (6.4 mmol) of methyl 2-acetyl-3-methylbut-2-enoate is added in a single portion. The mixture is allowed to warm to room temperature and stirring is continued for 18 hours. The reaction mixture is then treated with 100 mL of saturated NH4Cl solution, the phases are separated by settling, and the organic phase is again treated with 100 mL of saturated NH4Cl solution. The aqueous phases are extracted with 4×100 mL of DCM. The organic phases are combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. After purification by chromatography on silica gel, eluting with a 95/5 cyclohexane/EtOAc mixture, 1 g of methyl 2-acetyl-3-methyl-3-phenylbutanoate is obtained in the form of a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].CC1C=CC(S(O[CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)(=O)=O)=CC=1.Cl>CN(C=O)C>[CH3:22][O:21][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:37][CH2:36]1)[N:9]=[CH:8][N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:6]2=[O:20]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6.12 g, 20 mmol) potassium carbonate (5.52 g, 40 mmol) in DMF (60 ml) was stirred at ambient temperature for 30 minutes. 4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (8.86 g, 24 mmol), (prepared as described for the starting material in Example 10), was added and the mixture was stirred at 100° C. for 2 hours. After cooling, the mixture was poured onto water/ice (400 ml, 1/1) containing 2M hydrochloric acid (10 ml). The precipitate was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide. The solid was triturated in a mixture of ether/pentane (1/1), collected by filtration and dried to give 6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 78.5%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:20]([C:21]([OH:23])=O)=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[CH3:33][O:34][C:35](=[O:41])[C@@H:36]([NH2:40])[CH2:37][O:38][CH3:39].[K+].[Br-]>>[CH3:33][O:34][C:35](=[O:41])[C@@H:36]([NH:40][C:21]([C:20]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:31]=[CH:30][C:5]=4[N:6]=3)=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23])[CH2:37][O:38][CH3:39]
Reactant: O=C(O)c1c(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)noc1-c1ccccc1
Reactant: COC[C@H](N)C(=O)OC
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC[C@H](NC(=O)c1c(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)noc1-c1ccccc1)C(=O)OC
Yield: 69 %

Procedure:
The title compound was prepared from 3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-5-phenyl-isoxazole-4-carboxylic acid and (S)-2-amino-3-methoxy-propionic acid methyl ester hydrochloride as set forth in Example 5 and was obtained in 69% yield. Mass (ES+): 547 (M++1); IR (KBr): 3342, 3270, 1718, 1648, 1605, 1542; 1H NMR (DMSO-d6) δ: 3.23 (s, 3H), 3.61-3.68 (br, 5H), 4.79 (m, 1H), 7.16 (m, 1H), 7.53-7.58 (m, 4H), 7.80-7.87 (m, 7H), 9.53 (d, 1H), 10.73 (s, 1H, NH).