Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11](C(O)=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].[BH4-].[Na+].Cl.OC(C(CCCC(O)CCCCC)CCCC1C=CC([C:43]([OH:45])=[O:44])=CC=1)C>O.CCOCC>[OH:3][CH:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:15][C:16]=1[C:43]([OH:45])=[O:44])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCCC(O)CCCC(CCCc1ccccc1C(=O)O)C(C)O

Procedure:
4-(4-Acetyl-8-hydroxytridecyl)benzoic acid (7.2 g., 0.02 mole) is dissolved in a solution of sodium hydroxide (1.2 g., 0.03 mole) in water (80 ml.). Sodium borohydride (0.76 g., 0.02 mole) is added and the resulting solution is let stand at 25°-27° C. for 21 hours. The mixture is then acidified to Congo Red with concentrated hydrochloric acid. The thick oil which separates is taken up in ether, washed with water, and dried over magnesium sulfate. The ether is evaporated and the crude product chromatographed on a column containing 100 g. of silica gel. Elution with 4% methanol in chloroform affords 4.9 g. (68%) of pure 4-[4-(1-hydroxyethyl)-8-hydroxytridecyl]benzoic acid as a colorless viscous oil which gradually partially solidifies to a wax.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][N:21]=[C:20]3[N:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:30]=[CH:31][C:19]=23)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.C1COCC1>[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]3[N:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:30]=[CH:31][C:19]=23)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2ncc3c(N4CCC[C@H](NC(=O)OC(C)(C)C)C4)c(C(=O)O)cnc32)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Water (5 mL) and lithium hydroxide (1.5 g, 63 mmol) were added to a solution of ethyl 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.9 g, 3.7 mmol) in MeOH (5 mL) and THF (5 mL). The mixture heated at 50° C. with stirring for 2 h. The mixture was allowed to cool to room and concentrated under reduced pressure. The residue was neutralized with 2N HCl and extracted twice with EtOAc. The organic extract was dried with Na2SO4 and concentrated under reduced pressure to give the sub-title compound (1.6 g (89%). LCMS calc. for C25H32N5O5 (M+H)+: m/z=482.2. Found: 482.1.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(CCCc2ccccc2NCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCc2ccccc2NCc2ccccc2)cc1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of ethyl 4-[3-(2-(benzylamino)phenyl)propyl]benzoate (1 g) in methanol (50 ml) was added 1N sodium hydroxide (13.4 ml). The mixture was stirred for 2 hours, heated at reflux for 10 minutes, the solvent was evaporated, the residue mixed with water (50 ml) and acidified to pH4 with 2N HCl. The mixture was extracted with ethyl acetate (3×20 ml) and the extracts washed with brine (2×20 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with petroleum ether (60-80) (25 ml) to give the title compound (0.55 g; 118° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])(O)=O.[Na+].[NH4+:43].[OH-].C1(S(Cl)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl.CO.CCOCC.O>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:43])[C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (3.7 g, 10 mmol) dissolved in CHCl3 was treated with mCPBA (50% purity, 4.8 g, 13 mmol). The reaction was stirred at ambient temperature for 18 hours. Saturated aqueous NaHCO3 (100 mL) and H2O (50 mL) were then added to the reaction and the layers were separated. The aqueous layer was extracted with additional CHCl3. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a black oil. The oil was dissolved in methanol (53 mL) and treated with concentrated NH4OH solution (3.6 mL, 53 mmol). The solution was stirred and benzene sulfonyl chloride (2.9 mL, 53 mmol) was carefully added. The resulting reaction mixture was stirred at ambient temperature for 2 hours before adding additional concentrated NH4OH solution (3.6 mL, 53 mmol) and benzene sulfonyl chloride (2.9 mL, 53 mmol). Stirring was continued for 18 hours and then reaction mixture was concentrated under reduced pressure. The resulting material was treated with saturated aqueous NaHCO3 (50 mL) and H2O (50 mL), and then extracted with CHCl3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The oil was treated with Et2O and the mixture was stirred until a precipitate formed. The solid was isolated by filtration to give 3.1 g of (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([CH2:22][S:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][CH:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C.[OH-].[K+]>C(O)C>[C:18]([O:17][C:15](=[O:16])[CH:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:5]([CH2:22][S:23][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:4]([OH:43])=[O:3])([CH3:20])([CH3:21])[CH3:19]
Reactant: CCOC(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
To a stirred solution of the ester of example 33 (2.1 g, 3.31 mmol) in ethanol (11 mL) was added 17.4 ml of a 10% aqueous solution of potassium hydroxide. The resulting mixture was stirred for 24 hours. After evaporation of the solvent, the obtained residue was taken-up into 50 ml of water and washed with diethyl ether (2×50 mL). The aqueous layer was then acidified to pH 3 with a 10% aqueous solution of hydrochloric acid at 0° C. and immediately extracted with ethyl acetate (5×50 ml). The organic extracts were combined, washed with water, and dried over anhydrous magnesium sulfate. Evaporation under vacuum gave the crude product which was purified by flash chromatography (SiO2, 70% hexane-30% ethyl acetate) to afford 880 mg of the desired compound: 1H NMR (CDCl3, 400 MHz) δ 7.31 (m, 15H), 3.04 (t, 1H), 2.95 (m, 1H), 2.25 (m, 2H), 1.85 (m, 1H), 1.44 (s, 18H); 13C NMR (CDCl3, 400 MHz) 173.9, 168.5, 144.9, 129.7, 128.3, 128.0, 82.0, 51.9, 43.3, 33.7, 30,5, 27.2.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:16]O>>[CH3:16][O:13][C:12]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:14]
Reactant: CO
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: Cl
Product: COC(=O)C1(c2ccccc2)CCCC1
Yield: 88 %

Procedure:
A solution of 1-phenyl-1-cyclopentanecarboxylic acid (2.00 g, 10.51 mmol) in 30 mL methanol saturated with HCl was stirred at reflux for two hours. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was dissolved in 50 mL dichloromethane and washed with 2N sodium hydroxide (3×25 mL). The organic layer was washed with water (2×25 mL) and dried (Na2SO4). Evaporation of the solvent gave 1.89 g (88%) of methyl-1-phenyl-1-cyclopentanecarboxylate as a pale yellow liquid and was used in the next step without further purification. CIMS 205 m/z (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=[CH:17]3)=[CH:10][CH:9]=1.Cl[CH2:29][C:30]1[C:31]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[N:32][O:33][C:34]=1[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[Cl:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:45])[C:38]=1[C:31]1[C:30]([CH2:29][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=[CH:17]4)=[CH:12][CH:13]=2)=[C:34]([CH:35]([CH3:37])[CH3:36])[O:33][N:32]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Temperature: 65 °C
Yield: 48.3 %

Procedure:
Cesium carbonate (352 g, 1.08 mol) was added to a mechanically stirred solution of methyl 6-(4-hydroxyphenyl)-1-naphthoate (199 g, 0.72 mol) in dimethylformamide (1 L) under N2. The resulting suspension was heated to 65° C. for 30 min followed by addition of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (280 g, 0.92 mol) in dimethylformamide (500 mL). The mixture was heated at 65° C. for 18 h, cooled to room temperature and partitioned between ethyl acetate (1 L) and water (1 L). The ethyl acetate layer was backwashed with water (2×1 L) and concentrated to a thick black syrup. This syrup was triturated with hexane (500 mL) and ethyl acetate (300 mL) for 2 h. Filtration gave 190 g of the product as beige crystals. 1H NMR (DMSO-d6); δ 8.77 (d, J=9 Hz, 1H), 8.23-8.20 (m, 2H), 8.09 (d, J=7 Hz, 1H), 7.92 (dd, J=2, 9 Hz, 1H), 7.69 (d, J=9 Hz, 2H), 7.63-7.51 (m, 4H), 6.91 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.92 (s, 3H), 3.45 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 546 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:17]1[C:21]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[NH:20][CH:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:1]1([NH:7][C:8]([N:24]2[CH2:25][CH2:26][C:21]3([N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:18](=[O:34])[CH:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:20]3)[CH2:22][CH2:23]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CCC2(CC1)NC(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C

Procedure:
Phenyl isocyanate (0.16 ml, 1.49 mmol) was added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (502 mg, 1.49 mmol) in toluene (12.4 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. After removal of the solvent, the desired product 1,3-dibenzyl-2-oxo-1,4,8-triaza-spiro[4,5]decane-8-carboxylic acid phenylamide was obtained by means of preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].Cl>>[CH:25]([C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[O:26]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A 1 liter three neck round bottom flask equipped with equalizing addition funnel, magnetic stirer and temperature monitoring device was charged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction was chilled to −78° C. under nitrogen followed by slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, such that the temperature of the reaction did not rise above −65° C. The contents were held at −78° C. for one hour, 0° C. for two hours, then chilled back to −78° C. Excess N,N-dimethylformamide (100 mL, 1.37 mol) was added. The contents were warmed to room temperature and stirred for two hours. Aqueous 1 N HCl was added to the reaction until the pH reached 1. The reaction was washed with water (2×200 mL), saturated ammonium chloride solution (2×200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, 10% ethyl acetate, 90% hexanes) to yield, upon concentration of the appropriate fractions, N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid (7.36 g, 65%): mp 69-73° C. 1H HMR (CDCl3/300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H), 1.37 (s, 9H). ESHRMS m/z 274.1060 (M+H+, Calc'd 274.1055). Anal. Calc'd for C13H14F3NO2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:15][C:16](=[O:67])[C@@H:17]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:66][C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][C:62]=1[Cl:65])[CH2:58][O:57][C:54]1[CH:55]=[CH:56][C:51]([C@H:49]2[CH2:48][O:47][C:43]3=[CH:44][C:45]4[CH2:46][C@@H:37]([C:35]([NH:34][C@@H:17]([CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]6[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=6[CH3:33])=[CH:21][CH:20]=5)[C:16]([OH:67])=[O:15])=[O:36])[N:38]([C:11]([C:9]5[N:10]=[C:6]([CH3:5])[O:7][CH:8]=5)=[O:13])[CH2:39][C:40]=4[CH:41]=[C:42]3[O:50]2)=[CH:52][CH:53]=1
Reactant: Cc1nc(C(=O)O)co1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)co1
Reaction time: 0.67 h

Procedure:
EDC (5 eq.) and 2-methyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. To this solution was added (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester and stirred for 12 h. The reaction mixture was directly purified over silica (heaxnes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 866.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]([OH:22])[CH2:13][NH:14][C:15](=O)[O:16]C(C)(C)C)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[O:22][C:15](=[O:16])[NH:14][CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C1CNC(=O)O1
Temperature: 70 °C

Procedure:
To a solution of tert-butyl [2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]carbamate (140 mg, 0.40 mmol) (Peak 1, single enantiomer from step 2, Example 324) in tetrahydrofuran (2.5 mL), N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) and N,N-carbonyldiimidazole (130 mg, 0.80 mmol). The reaction was refluxed at 70° C. for 10 minutes. The reaction was evaporated to dryness. Purification on silica gel using (0-50%) ethyl acetate in hexane gave the desired compound as a single enantiomer, 78 mg, 69%. LCMS calculated for C13H15ClNO4 (M+H)+: m/z=284.1; found: 284.1.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[I:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH2:16])[CH3:15])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[I:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][C:2](=[O:3])[O:4][CH3:5])[CH3:15])=[CH:11][CH:12]=1
Reactant: CC(N)Cc1ccc(I)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NC(C)Cc1ccc(I)cc1
Reaction time: 1 h

Procedure:
0.53 ml (6.89 mmol) methyl chloroformate are added to a mixture of 1.50 g (5.75 mmol) 1-(4-iodophenyl)propane-2-amine and 1.16 ml pyridine (14.3 mmol) in 30 ml DCM at 0° C. and the reaction mixture is stirred for 1 h at constant temperature. Further DCM is added and the organic solution is consecutively washed with aq. HCl-solution (0.5 mol/l) and water, dried with MgSO4 and the solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[CH3:40][O:41][C@@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1>>[Br:1][C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@@H:19]([O:41][CH3:40])[CH2:18][O:21]2)[N:6]=1
Reactant: CO[C@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 93) gave tert-Butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:16][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
5,6,6′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g), 4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) were suspended in dimethyl sulfoxide (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (483 mg, yield 72%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C([Sn](CCCC)(CCCC)/[CH:52]=[CH:53]\[O:54][CH2:55][CH3:56])CCC.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[N:6]3[C:2]=2/[CH:52]=[CH:53]/[O:54][CH2:55][CH3:56])=[CH:16][CH:17]=1)#[N:22]
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(Br)n12
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCO/C=C/c1c(-c2ccc(C#N)cc2)nc2cccc(C(=O)OC)n12
Temperature: 70 °C
Yield: 74 %

Procedure:
To a degassed solution of (A3) in DMF (0.1 M), Cs2CO3 (1.1 eq.), tris(dibenzenzylideneacetone)dipalladium(0) (0.05 eq.), tri-t-butylphosphonium tetrafluoroborate (0.15 eq.) and tributyl[(Z)-2-ethoxyvinyl]stannane (2.0 eq.) were added at RT and the reaction mixture was heated to 70° C. for 12 h. After cooling down, the solvent was reduced in vacuo and the residue partioned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column on silica using a gradient of EtOAc/Petroleum ether from 30:70 to 50:50 to yield (74%) the title compound as a yellow oil, it is a mixture of regioisomers (cis/trans=4:1). 1H NMR (300 MHz, CDCl3, 300K) δ 8.10 (2H, d, J=8.3 Hz), 7.90 (1H, d, J=8.7 Hz), 7.70 (2H, d, J=8.3 Hz), 7.40 (1H, d, J=6.4 Hz), 7.35-7.25 (1H, m), 6.32 (1H, d, J=6.7 Hz), 5.65 (1H, d, J=6.4 Hz), 3.97 (3H, s), 3.74 (2H, q, J=7.0 Hz), 1.03 (3H, t, J=7.0 Hz). MS (ES+) C20H17N3O3 requires: 347, found: 348 (M+H)+.