Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1.[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:40][C:41]1[C:42]([C:51]([F:53])([F:52])[F:54])=[N:43][N:44]([CH2:47][C:48]([N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][C:28]=3[O:38][CH3:39])[CH2:37][CH2:36]2)=[O:49])[C:45]=1[CH3:46]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cc(Cl)ccc1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(Cl)ccc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-2-methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.02 (s, 1H), 6.93 (m, 2H), 5.36 (s, 2H), 3.82 (s, 3H), 3.60 (m, 4H), 3.03 (m, 2H), 2.95 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=451.1, found=451.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([CH2:15][CH3:16])[C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.O>[Br:14][C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[N:8][N:9]([CH2:15][CH3:16])[C:10]=2[CH:11]=1
Reactant: CCn1ncc2c(C(=O)OC)cc(Br)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a stirred solution of 6-bromo-1-ethyl-1H-indazole-4-carboxylic acid methyl ester (700 mg, 2.47 mmol) in THF (35 mL) was added a solution of LiOH.H2O (312 mg, 7.42 mmol) in water (15 mL) and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and washed with EtOAc (2×25 mL). The aqueous layer was acidified (pH ˜5) with 1N HCl. The precipitated solid was collected by filtration and dried to furnish 6-bromo-1-ethyl-1H-indazole-4-carboxylic acid as a white solid (450 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[C:5]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[O:6].C1C(=O)N([Br:24])C(=O)C1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([CH2:16][Br:24])[CH:13]=[CH:12][C:4]=1[C:5]([NH:7][S:8]([CH3:11])(=[O:9])=[O:10])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1C(=O)NS(C)(=O)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1C(=O)NS(C)(=O)=O
Yield: 56.5 %

Procedure:
2-Methoxy-4-methyl-N-(methylsulfonyl)benzamide (Preparation 24, 500 mg, 2.06 mmol), N-bromosuccimide (402 mg, 2.36 mmol), azobisisobutyronitrile (10 mg, 0.06 mmol) and carbon tetrachloride (20 mL) were combined and stirred at reflux under nitrogen, whilst being irradiated with light from a lamp for 1 hour. After cooling, the mixture was evaporated, the residue suspended in water (30 mL) and extracted with EtOAc (1×30 mL). The organic layer was separated, washed with saturated brine (2×20 mL), dried over sodium sulfate, filtered and evaporated to give a solid, which was triturated with diethyl ether:hexane (1:4) to yield the title compound as a white solid (375 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1Cl
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of o-chlorobenzoic acid (2.0 kg.) and chlorosulfonic acid (10.5 kg.) is heated at 90°-100° C. for 5 hours. The reaction mixture is cooled to 25° C. and then slowly poured into a 10 liter mixture of ice and water. The addition requires about 1 hour, and the temperature is maintained below 10° C. during this period by the addition of more ice. The final volume of slurry after the quench is about 40 liters. The solid material is collected and thoroughly washed on the funnel with fresh water. The crude wet cake is dissolved in 16 liters of diethyl ether. The ether layer is washed once with 2 liters of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The filtered ether solution is concentrated in vacuo with the continual addition of hexane. The resulting hexane slurry is concentrated to a final volume of approximately 8 liters and filtered. The crystalline cake is washed with hexane and dried in the atmosphere to give 2.5 kg. of product (76.8% of theory), m.p. 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:11][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(Cl)c1OCCc1ccccc1
Reaction time: 120 h
Yield: 70 %

Procedure:
To 3,5-dichlorosalicylaldehyde (229 mg, 1.2 mmol) in DMF (5 ml) was added K2CO3 (1.06 g, 7.7 mmol) followed by (2-bromoethyl)benzene (0.14 ml, 1.0 mmol). The mixture was stirred under argon for five days then diluted with H2O (30 ml), extracted with Et2O (3×50 ml), dried (MgSO4), filtered, and concentrated in vacuo to give the title compound as a white powder (207 mg, 0.7 mmol, 70%); δH (CDCl3) 3.17 (2H, t), 4.31 (2H, t), 7.19-7.36 (5H, m), 7.60 (1H, d), 7.67 (1H, d), 9.95 (1H, s).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-]>O1CCCC1>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:10][CH2:11][CH2:6][CH:7]=[CH2:8])=[CH:7][CH:8]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
5-Bromo-1-pentene (1.5 g) was gently heated with magnesium turnings (1 g) in anhydrous tetrahydrofuran (15 ml) until reaction started. The mixture was left to reflux without further heating to give the Grignard reagent, then allowed to cool to room temperature. Biphenyl-4-carboxylic acid methoxy-methyl amide (4 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and chilled in an ice bath. The Grignard reagent was added dropwise with vigorous stirring. Following addition, the mixture was allowed to warm to room temperature and stirring continued for 2 hours. Saturated NH4Cl solution (50 ml) was added and the mixture extracted with petrol. Drying with Na2SO4 followed by evaporation gave an oil. Column chromatography (petrol:ethyl acetate 5:1) gave the title compound as a white solid (70%). δC (CDCl3, 62.9 MHz): 23.4, 33.3, 37.8, 115.4, 127.3, 127.3, 128.2, 128.7, 129.0, 135.8, 138.1, 139.9, 145.6 and 199.9. δH (CDCl3, 250 MHz): 1.88 (2H, quintet, J 7.32), 2.17 (2H, quintet, J 7.32), 3.00 (2H, t, J 7.32), 5.03 (2H, m), 5.84 (1H, m), 7.62 (2H, d, J 7.9), 7.47 (3H, m), 7.67 (2H, d, J 7.9) and 8.03 (2H, d, J 7.9).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[CH2:29][CH2:30][CH:31]=O>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:31][CH2:30][CH2:29][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:22]3=[O:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CCCN1CCCCCC1=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1CCCCCC1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate and 3-(2-oxohexahydro-1H-azepin-1-yl)propanal using methods similar to Example 669: step 4 to provide a clear oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (t, J=7.09 Hz, 3 H), 1.47-1.58 (m, 4 H), 1.58-1.74 (m, 4 H), 2.36-2.44 (m, 2 H), 3.15 (q, J=6.74 Hz, 2 H), 3.28-3.38 (m, 4 H), 3.94 (s, 2 H), 4.26 (q, J=7.07 Hz, 2 H), 7.07-7.16 (m, 3 H), 7.27-7.34 (m, 2 H), 7.62 (t, J=5.62 Hz, 1 H), 7.77 (d, J=1.82 Hz, 1 H); ES+ MS: 428 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CCO.[NH3:20]>C1COCC1>[NH2:20][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:9][N+:10]([O-:12])=[O:11]
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Reactant: N
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 48.8 %

Procedure:
To 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio-2-nitroethylene were added 45 ml of EtOH, 10 ml of THF and 1.02 g of 25% aqueous ammonia and the mixture was stirred at an external temperature of 60° C. for 5.5 hours. During this period, 1.02 g each of 25% aqueous ammonia was added after 1, 2 and 3 hours of reaction. The reaction mixture was ice-cooled and stirred, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that order, and dried. The procedure gave 1.11 g of the title compound as white crystals.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH:12]([OH:15])[CH2:13][OH:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[OH:1][C@H:2]([CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO

Procedure:
The reaction was terminated by the removal of cells by centrifuging at 4000×g for 20 minutes. The pH of the recovered cell-free supernatant was adjusted to 7.5 using 2M NaOH. MgSO4.1.6H2O (15% w/v based on anhydrous) was dissolved in the cell-free supernatant and the resulting solution was extracted twice with an equal volume of 2-pentanone. The solvent phases were collected and the solvent removed under reduced pressure in a rotary evaporator at 45° C. yielding an orange viscous oil. This was re-dissolved in 50 ml dry, distilled 2-pentanone and again the solvent was removed by rotary evaporation to afford t-butyl 3,5,6-trihydroxyhexanoate (5.08 g, 80% isolated yield). Diastereomeric excess was determined as follows; a sample of t-butyl 3,5,6-trihydroxyhexanoate (30 mg) was derivatised by reaction for at least 10 minutes at room temperature in an excess of trifluoroacetic anhydride, excess anhydride was removed under a stream of dry nitrogen and the residual oil diluted with dichloromethane (1 ml). The sample was analysed using a Chiralcel Dex CB column (25 metre) at a temperature of 140° C. (isothermal). The diastereomers eluted at 14.4 minutes (3R,5S diastereomer) and 115.7 minutes (3S,5S diastereomer). The diastereomeric excess of the sample was found by this method to be 99.7%.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]2[NH:27][CH:26]=[N:25][CH:24]=2)[C:11]1=N)[CH3:9]>>[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]2[NH:27][CH:26]=[N:25][CH:24]=2)[C:11]1=[O:3])[CH3:9]
Reactant: CCn1c(=N)c(-c2cnc[nH]2)cc2c(C)nc(SC)nc21
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=O)c(-c2cnc[nH]2)cc2c(C)nc(SC)nc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (15.0 mL) was added to a flask charged with crude 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-imine and heated to 100° C. After 30 minutes, the reaction was allowed to cool to room temperature and concentrated in vacuo. The acetylated residue was then treated with 6 N HCl (16 mL) and heated to 95° C. for 30 minutes then transferred to a large flask. A saturated solution of NaHCO3 (150 mL) was added at 0° C. to about pH=8.0. The aqueous phase was washed thrice with ethyl acetate (100 mL) and the organic layers combined, then washed with brine and dried over Na2SO4. The drying agent was filtered off and the organic layers were concentrated in vacuo to afford crude 8-ethyl-6-(1H-imidazol-5-yl)-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one which was used in the subsequent step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[C:22]2[C:23](=[O:36])[C:24]3[CH:25]=[C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]4=[N:28][C:29]=3[N:30]([CH3:31])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17]([CH3:38])([CH3:37])[O:16][C:15]=2[CH:14]=1.Cl>ClCCl>[C:1]([C:18]1[C:17]([CH3:38])([CH3:37])[O:16][C:15]2[CH:14]=[C:13]([O:12][CH3:11])[C:22]3[C:23](=[O:36])[C:24]4[CH:25]=[C:26]5[CH:35]=[CH:34][CH:33]=[CH:32][C:27]5=[N:28][C:29]=4[N:30]([CH3:31])[C:21]=3[C:20]=2[CH:19]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C=CC(C)(C)O2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)C1=Cc2c(cc(OC)c3c(=O)c4cc5ccccc5nc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.81 mmol of butyryl chloride and 0.673 mmol of AlCl3 in 2 ml of anhydrous dichloromethane is added in small portions to 0.135 mmol of the product of Example 2 in 2 ml of dichloromethane at 0° C. The reaction mixture is stirred for 4 hours at ambient temperature and then poured into a 10% solution of HCl. Following conventional treatment of the organic phases, and evaporation thereof under reduced pressure, chromatography of the residue on silica gel (dichloromethane/methanol gradient) allows the expected product to be isolated.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:44])[CH2:13][C@H:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[N:36][CH:35]=1)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8].C1COCC1.C(OCC)C>C(OCC)C>[C:7]([O:11][C:12](=[O:44])[CH2:13][C@H:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[N:36][CH:35]=1)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1cncc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccccc1OCCc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To lithium aluminum hydride (0.45 mL of 1.0 M solution in diethyl ether) in diethyl ether (7 mL) at −65° C. was added (S)-3-[2-(2-isoquinolin-4-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester in 1:1 THF/diethylether (4 mL). After 1 hour, the reaction was quenched by addition of 1.0N sodium hydroxide (2 mL) and the reaction was warmed to room temperature. The organic layer was separated and evaporated. The resulting residue was chromatographed on silica gel eluting with 10% diethyl ether in ethyl acetate to give (S)-3-[2-(2-isoquinolin-4-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a colorless foam (39 mg). MS (APCI) m/z 485.1 (M+1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4cncnc4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3cccc(-c4cncnc4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
The reaction mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(pyrimidin-5-yl)phenyl)benzo[d]thiazol-6-yl)acetate (9 mg, 0.0157 mmol), excess NaOH, in MeOH/THF (1:1, 2 mL) was heated at 45° C. overnight. After reaction finished, the solvent was removed and the residue was dissolved in MeOH and purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C30H26ClN3O3S: 544.1 (M+H+); Found: 544.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 9.18 (s, 1H), 9.16 (s, 2H), 8.40 (s, 1H), 8.12 (d, J=4 Hz, 1H), 7.91-7.88 (m, 2H), 7.71-7.67 (m, 2H), 7.60-7.58 (m, 3H), 5.26 (s, 1H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH:41]=O)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][N:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:7][CH2:8]1)[CH3:1])=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCNC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1

Procedure:
Trans-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (250 mg) obtained in Example 221 is suspended in dichloromethane (8 ml), and thereto are added 3-t-butoxycarbonylaminopropanal (198 mg) and triethylamine (160 μl) under ice-cooling, and the mixture is stirred for several minutes. Then, sodium triacetoxy borohydride (243 mg) and the reaction solution is warmed to room temperature, and stirred for 4 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture is extracted with chloroform. The organic layer is washed successively with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, then 1/1) to give the title compound (312 mg).
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCCCC1(CCCC)CCc2c(O)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A mixture of 2,2-dibutyl-3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (2.643 g), 2-chloromethylquinoline (1.7 g), and potassium carbonate (1.67 g) in N,N-dimethylformamide (16 ml) was stirred at 80° C. for 4 hours. The cooled mixture was poured into water. The separated oil was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated in vacuo. The crude product was chromatographed on silica gel using 25% ethyl acetate in n-hexane as eluent to yield 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (3.09 g) as a pale yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:26]([O:28]C)=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:26]([OH:28])=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:11]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Yield: 98.4 %

Procedure:
The same procedures as in Example 111 were carried out from the compound obtained in Example 58 (4.0 g), 1 mol/L of an aqueous sodium hydroxide solution (16 mL), and methanol (160 mL), to give the captioned compound (3.8 g, 98%) as an oily product.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:17]=1C(Cl)=O>O1CCCC1>[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:17]=1[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: -36 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere a 50 gallon kettle was charged with 50.9 kg of tetrahydrofuran, 5.2 kg of monoethyl malonate and about 5 g of 2,2'-dipyridyl. After cooling the mixture to -36° C., 41.6 kg of n-butyllithium (15% in hexane) was added over 3 hours maintaining the temperature at -25° to -35° C. The resultant slurry was cooled further to -60° C. and then treated over about 50 minutes with the acid chloride of part (a) at -62° to -54° C. The green/yellow mixture was stirred for 2 hours at ambient temperature and allowed to warm further overnight. The mixture (-24° C.) was quenched (vacuum) into ambient dilute hydrochloric acid (15 L of muriatic acid and 61 L of deionized water). The quench mixture was separated and the organic phase was washed with 2×40 L of deionized water. The combined aqueous phases were back extracted with 40 L of hexane-ether (1:1). All organic layers were combined and washed with 100 L of saturated sodium bicarbonate solution; again back extracting the aqueous phase with 40 L of hexane-ether (1:1). The combined organic layers were concentrated to an oil in vacuo followed by dissolution in 20 L of hexane and repeated concentration to dryness. The hot oil was finally dissolved in 19 L of hexane. The solution was cooled to -5° C. and the crystallized solids were filtered using 4.8 L of cold (-6° C.) hexane as wash. The material was dried in vacuo at room temperature affording 4234 g of product suitable for use in the next step. A second crop was obtained by concentrating the combined filtrate and wash and cooling to low temperature. The combined yield for the first and second crops was 4841 g (74.9%).