Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:70])[C@@H:40]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@H:9]1[C@@H:13]([OH:14])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:70])[C@@H:40]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 24.6 %

Procedure:
A solution of tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (63 mg, 0.062 mmol, obtained from Example 10) in anhydrous tetrahydrofuran (1 ml) was cooled at 0° C. under nitrogen. Tetrabutylammonium fluoride (0.186 mL, 0.186 mmol; 1 M solution in tetrahydrofuran, Aldrich) was added and the resulting mixture was warmed to room temperature and stirred for 2.75 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-(hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (12 mg, 25%) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:19][C:20]([OH:22])=[O:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N1C=CN=C1)(N1[CH:29]=[CH:28]N=C1)=O.C(O)C>O1CCCC1>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:29]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 0.75 h
Yield: 134 %

Procedure:
A solution of 0.53 g (1.6 mmol) {methyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic acid in 8 mL anhydrous tetrahydrofuran was treated with 0.32 g (2.0 mmol) 1,1′-carbonyl-diimidazole. After stirring for 45 minutes, 1 mL of ethanol was added. The resulting mixture was then permitted to stir overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed twice with saturated sodium bicarbonate, twice with water, dried over sodium sulfate and concentrated in vacuo. After drying via high vacuum overnight, 0.76 g of the title compound was isolated as a red solid; 1H NMR (CDCl3) δ 1.23-1.29 (m, 3H), 2.59 (t, J=6.15 Hz, 4H), 2.87 (s, 1H), 3.76 (t, J=6.09 Hz, 4H), 3.96 (s, 2H), 4.11-4.18 (m, 2H), 6.89-6.96 (m, 2H), 7.67-7.75 (m, 2H); MS (ES) m/z 355.3 (MH+); HRMS for C16H22N2O5S: 355.1332.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[NH:8][CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20].[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=2[O:13][CH3:14])[C:5](=[O:20])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)cc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 50 °C
Yield: 80.5 %

Procedure:
A mixture of ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (1.00 g, 3.53 mmol), iodomehtane (0.450 mL, 7.23 mmol) and K2CO3 (976 mg, 7.06 mmol) in DMF (15 mL) was heated at 50° C. for 1 h. The mixture was concentrated in vacuo and dried under high vacuum. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with water and then dried to yield ethyl 1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (845 mg, 81%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:22][C:21]=1[F:30]>>[F:30][C:21]1[CH:22]=[C:23]([C:26]([OH:29])([CH3:27])[CH3:28])[CH:24]=[CH:25][C:20]=1[CH2:19][NH:18][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1
Reactant: CC(C)(O)c1ccc(CN)c(F)c1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1

Procedure:
Prepared from 2-(4-Fluoro-phenoxy)-nicotinic acid and 2-(4-Aminomethyl-3-fluoro-phenyl)-propan-2-ol.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][CH:16]([CH3:18])[CH3:17].Cl>CO>[C:11]([C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][N:15]2[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CC(OC)OC)c(NC(C)C)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2ccn(C(C)C)c2c1
Yield: 97.3 %

Procedure:
4-Carbomethoxy-2-(N-2-propylamino)phenylacetaldehyde dimethylacetal (3.7 g, 13.15 mmole) was refluxed with 100 mL of 1N hydrochloric acid in methanol for 1 h. The solution was concentrated and the residue dissolved in 50 mL of ethyl acetate, washed with saturated sodium bicarbonate solution, dried organic layer over magnesium sulfate and evaporated to give 2.78 g of 6-carbomethoxy-1-(2-propyl)indole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C)C=O.[Cu]I>[N:41]1([C:2]2[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:12][CH:11]=3)[CH:7]=2)[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: Cc1ccc(Br)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 110 °C
Yield: 16 %

Procedure:
A mixture of N-(5-bromo-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (198 mg, 0.39 mmol), prepared as described in Example 14, copper (I) iodide (90 mg, 0.47 mmol), 1S,2S—N1,N2-dimethylcyclohexane-1,2-diamine (25 mg, 0.17 mmol), cesium carbonate (270 mg, 0.83 mmol) and imidazole (40 mg, 0.59 mmol) in dimethylformamide (400 μL) were combined in a sealed tube under an atmosphere of nitrogen and heated to 110° C. overnight. Upon cooling to rt, the reaction mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. Insoluble material was filtered and the two layers of filtrate were separated. The aqueous phase was further extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase HPLC to give N-[5-(1H-imidazol-1-yl)-2-methylphenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (31 mg, 16%). 1H NMR (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 9.88 (s, 1H), 8.26 (s, 1H), 8.20 (d, 2H), 8.02 (d, 2H), 7.90-7.70 (m, 8H), 7.65 (m, 2H), 7.45 (m, 3H), 7.12 (s, 1H), 2.30 (s, 3H). MS (EI) for C31H24N6O: 497.2 (MH+).
Reaction SMILES: CO.[BH4-].[Na+].[Cl:5][C:6]1[C:15]([N+:16]([O-])=O)=[C:14]([NH:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.O>O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:16][C:15]1[C:6]([Cl:5])=[N:7][C:8]2[C:13]([C:14]=1[NH:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH2:23]1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of 6.56 g of nickel chloride hexahydrate and 22.3 ml of methanol in 100 ml of tetrahydrofuran, 2.09 g of sodium borohydride was added portionwise under ice-cooling, and then a suspension of 31.9 g of 2-chloro-3-nitro-4-[2-(N-triphenylmethyl-4-piperidyl)ethylamino]quinoline in 300 ml of tetrahydrofuran was added to the mixture. Successively, 8.35 g of sodium borohydride divided in four portions was added portionwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 50 ml of water and an insoluble matter was filtered off, and then the extract was concentrated. The residue was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting pale green liquid was solidified with a mixture of ethyl acetate and diisopropyl ether, and the solid was washed successively with isopropanol and diisopropyl ether to give 20.1 g of pale green crystals. Recrystallization from isopropanol gave pale green crystals having the melting point of from 116 to 121° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[C:12]([CH2:14][CH3:15])[C:10]([NH2:11])=[C:9]([CH2:16][CH3:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[Ca+2].[C:24](Cl)(Cl)=[S:25]>C(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[C:9]([CH2:16][CH3:17])[C:10]([N:11]=[C:24]=[S:25])=[C:12]([CH2:14][CH3:15])[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C2CCCCC2)cc(CC)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C2CCCCC2)cc(CC)c1N=C=S

Procedure:
231 g of 4-cyclohexyl-2,6-diethyl-aniline in 300 ml of methylene chloride are added dropwise at 10°-15° C. to a suspension of 600 ml of methylene chloride, 500 ml of water, 200 g of calcium carbonate and 140 g of thiophosgene. The mixture is then heated to the boil, until the evolution of gas has ended. The batch, when cold, is filtered to remove solids, and the methylene chloride layer is dried over calcium chloride and fractionated; boiling point 175°-179° C./1.5 mm Hg; yield 251 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[C:7]([O:10][CH3:11])[CH:6]=[C:5]([C@@H:12]2[C:25]3[C:20](=[CH:21][C:22]4[O:28][CH2:27][O:26][C:23]=4[CH:24]=3)[C@@H:19]([O:29][C@@H:30]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:33]([OH:38])[C@H:32]([OH:39])[C@H:31]3[OH:40])[C@H:14]3[CH2:15][O:16][C:17](=[O:18])[C@H:13]23)[CH:4]=1.[N+](C)([O-])=O.CO[CH:47](OC)[CH3:48].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl.CO>[CH3:47][C@H:48]1[O:38][C@H:33]2[C@H:32]([OH:39])[C@@H:31]([OH:40])[C@H:30]([O:29][C@H:19]3[C@H:14]4[CH2:15][O:16][C:17](=[O:18])[C@@H:13]4[C@H:12]([C:5]4[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:25]4[CH:24]=[C:23]5[O:26][CH2:27][O:28][C:22]5=[CH:21][C:20]3=4)[O:35][C@@H:34]2[CH2:36][O:37]1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Reactant: COC(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g. of dry 4'-demethylepipodophyllotoxin-beta-D-glucoside was suspended in 30 ml. of nitromethane, and 6 ml. of acetaldehyde-dimethylacetal and 150 mg. of p-toluene-sulphonic acid was added. The mixture was stirred at room temperature in an atmosphere of nitrogen and in the absence of moisture for one hour. After this time, the initial suspension had turned into a clear solution, and no starting material could be detected in the thin layer chromatogram (silica gel plates, eluant: chloroform+6% of methanol). Working up was effected by diluting with 400 ml. of chloroform and shaking out three times with 25 ml. each of water. The crude material obtained after concentrating the dried organic phase by evaporation was subsequently chromatographed on 100 g. of silica gel "Merck" (grain size 0.05 to 0.2 mm.), whereby chloroform containing 6% of methanol was continuously used as eluant. 4'-demethylepipodophyllotoxin-beta-D-ethylidene-glucoside, which is uniform according to thin layer chromatography, was obtained. After recrystallization from methanol colorless crystals having a M.P. of 236°-251° C., [α ]D22 =-110.5° (c.=0.588 in chloroform), were obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([O:33]CC)=[O:32])=[CH:27][CH:26]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:9][C:8]=1[C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:3])[CH3:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:9][C:8]=1[C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCNc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCCO)cc1C(C)(C)C
Yield: 76.2 %

Procedure:
In a manner similar to that of Example 3, by reacting 270 mg of ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate with 0.8 mL and then 0.4 mL of aqueous 1N sodium hydroxide solution in a mixture of 8 mL of tetrahydrofuran and 2 mL of water. 195 mg of 4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained in the form of a white solid (yield=95%, m.p.=75° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[Cl:12][CH2:13][CH2:14][C:15]([N:17]1[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2)=O>O1CCCC1>[Cl:12][CH2:13][CH2:14][CH2:15][N:17]1[CH2:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH2:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2
Reactant: O=C(CCCl)N1Cc2ccccc2Cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: ClCCCN1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 1.0M tetrahydrofuran solution of lithium aluminum hydride (9.8 ml) was introduced under a nitrogen atmosphere to a dry 100 ml three-necked roundbottom flask using a syringe. Concentrated sulphuric acid (0.264 ml) was cautiously added under cooling on an ice bath, and the resulting solution was stirred at room temperature for 1.5 hour. The above amide was dissolved in dry tetrahydrofuran (9.8 ml) and slowly added. The reaction mixture was stirred overnight. The reaction was quenched by addition of water (0.4 ml), 4N sodium hydroxide (0.4 ml) and water (1.2 ml), successively. The resulting mixture was filtered (hyflo) and the filtercake was washed with diethyl ether and ethyl acetate. The solvent was evaporated affording 5-(3-chloropropyl)-6,11-dihydro-5H-dibenzo[b,e]azepine, which was used for further reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[C:18](=[O:44])[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][C:33](OCC2C=CC=CC=2)=O)[C@@H:26]([OH:30])[C:27]#[C:28][CH3:29])[C:21]1=[O:43])([CH3:4])([CH3:3])[CH3:2].[CH3:46][C:47]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:48]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][C:9]=1[C:18](=[O:44])[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C@@H:25]([CH2:31][NH:32][CH2:33][C:48]2[CH:51]=[CH:52][C:53]([CH3:55])=[CH:54][C:47]=2[CH3:46])[C@@H:26]([OH:30])[CH2:27][CH2:28][CH3:29])[C:21]1=[O:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound (2-{(3S)-1-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (87 mg, 0.14 mmol) was dissolved in MeOH (4 mL). The resultant solution was charged with 5% Pd/C, Degussa style (10 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was redissolved in MeOH (4 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.015 mL, 0.11 mmol) and sodium cyanoborohydride (10 mg), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by reverse-phase HPLC afforded the title compound as a white powder after lyopholization (15 mg). MS found: (M+H)+=621.5.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([CH2:13][CH2:12]3)[CH2:10][CH:9]2[C:16]([NH:18][C@H:19]([C:21]2[CH:40]=[CH:39][C:24]([C:25]([O:27]CC3C=CC(C(F)(F)F)=CC=3)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])=[CH:5][CH:4]=1.O[Li].O>>[F:43][C:2]([F:1])([F:44])[C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([CH2:12][CH2:13]3)[CH2:10][CH:9]2[C:16]([NH:18][C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:39][CH:40]=2)[CH3:20])=[O:17])=[CH:5][CH:4]=1
Reactant: C[C@H](NC(=O)C1CC2(CCN1Cc1ccc(C(F)(F)F)cc1)CC2)c1ccc(C(=O)OCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)C1CC2(CCN1Cc1ccc(C(F)(F)F)cc1)CC2)c1ccc(C(=O)O)cc1
Yield: 57.3 %

Procedure:
The title compound (E10) (6.4 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from starting from 4-(trifluoromethyl)benzyl 4-((1S)-1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D129) (15 mg). (LiOH H2O: 4 eq; Reaction time: 18 hrs)
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:100])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][C:87]=3[F:92])[CH:69]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])[CH:71]=2)[C:54]=1[CH2:93][CH2:94][C:95]([O:97]CC)=[O:96])C.[OH-].[Na+]>C1COCC1.CCO>[C:95]([CH2:94][CH2:93][C:54]1[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][C:87]=3[F:92])[CH:69]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:83])[F:84])[CH:71]=2)=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:100])=[O:47])([OH:97])=[O:96]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3F)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3F)c2)c1CCC(=O)O
Yield: 90.9 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-2′-fluoro-bi phenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (100 mg, 0.128 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-2′-fluoro-bi phenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (84 mg, 91%) as a white amorphous solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[CH2:31][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[C:13]([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[O:12])=[CH:14]1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Reactant: ClCc1cccc(Cl)c1
Product: O=C(c1ccc2c(c1)OCCO2)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Yield: 24.4 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one 70 mg (0.228 mmol) and 71.1 mg (0.296 mmol) 1-Chloro-3-chloromethyl-benzene, to give 24 mg of desired compound. LCMS (M+H)+: 432.
Reaction SMILES: C[O:2][C:3](=[O:16])[C@@H:4]([OH:15])[CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[OH-].[Li+:19].O>CO>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][C@H:4]([OH:15])[C:3]([O-:16])=[O:2])=[O:9])([CH3:14])([CH3:12])[CH3:13].[Li+:19]
Reactant: COC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)[O-]
Yield: 85.8 %

Procedure:
A solution of (S)-4-tert-butoxycarbonylamino-2-hydroxybutyric acid methyl ester (1.52 g, 6.52 mmol) in methanol (20.0 mL) was treated with lithium hydroxide monohydrate (273.8 mg, 6.52 mmol) and water (2.0 mL) for 30 min, concentrated, and dried under vacuum to give a white solid (1.26 g)