Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C.CCOC(C)=O>[CH3:44][O:43][C:41](=[O:42])[CH2:40][O:32][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH3:31]
Reactant: COC(=O)CCl
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 57.7 %

Procedure:
To a solution of N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (150 mg, 0.327 mmol, example 48) in DMF (5 mL) was added K2CO3 (90 mg, 0.654 mmol) and methyl chloroacetate (0.06 mL, 0.654 mmol, CAS RN 96-34-4) at 25° C. and the resulting mixture was heated to 70° C. for 16 hours. The mixture was diluted with EtOAc (25 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude material thus obtained was purified by column chromatography over silica gel (30% EtOAc in n-hexane) to give 100 mg of the title compound. Pale yellow solid (58%). MS (ESI): m/z=531.0 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:20][CH2:21][CH:22]([CH3:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH:22]([CH3:32])[CH2:21][O:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:31][CH:30]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCOCC(C)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCOCC(C)Oc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1.7 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.8 g of 4-(2-hexyloxy-1-methylethoxy)-benzyl bromide, and the resulting solution was stirred overnight at room temperature. The crude product which had been obtained similarly to the procedures in Preparation Example 3 was isolated through column chromatography [eluting with benzene/ethyl acetate (18/1)] to give 3.4 g of the aimed product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:32])([C@@H:14]([CH:21]([OH:31])[C:22]4[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=4)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:32])([C@@H:14]([C:21]([C:22]4[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=4)=[O:31])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The above methyl 5-(((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(hydroxy)methyl)thiophene-2-carboxylate was dissolved in anhydrous methylene chloride (3 mL). Pyridine (0.1 mL) and then Dess-Martin periodinane (204 mg, 0.48 mmol) were added. The reaction mixture was stirred at RT for 1 hr and quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL) and saturated aqueous sodium thiosulfate solution (2.5 mL). The mixture was stirred at RT for 30 min. The aqueous layer was separated and extracted with methylene chloride (2×2 mL). The combined organic solutions were dried (Na2SO4). Silica gel flash chromatography (20-100% ethyl acetate in heptanes) gave methyl 5-((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbonyl)thiophene-2-carboxylate (113 mg, 0.25 mmol, 78% yield for steps (b)+(c)) as a solid. MS found: (M+H)+=451.1.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>CCOCC>[CH3:1][N:2]([CH3:12])[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[B:24]([OH:29])[OH:25])(=[O:4])=[O:5]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
A solution of N,N-dimethylbenzenesulfonamide (9.25 g; 50 mmol) in dry Et2O (150 ml) under N2 was cooled to −70° C. and added a solution of 2.5 M n-BuLi in hexane (24 ml; 60 mmol) such that the reaction temperature was kept below −60° C. The cooling bath was removed and the reaction mixture allowed to slowly warm up to +20° C. The reaction mixture was re-cooled to −70° C. and B(Oi-Pr)3 (16.1 ml; 70 mmol) was added. The reaction mixture was left cold and allowed to warm up over night, 1 M HCl (100 ml) was added and stirring was continued at rt. for 1 h. The reaction mixture was then extracted with Et2O (2×50 ml) and the combined organic fractions extracted with 1 M NaOH (4×50 ml). The combined aqueous fractions were neutralized with 1 M HCl and extracted with Et2O (4×100 ml). The combined organic fractions were dried (Na2SO4) and evaporated to dryness, washed with Et2O/hexane to give 3.4 g (30%) product.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)CC(C)C>[N:16]1([C:2]2[N:11]=[CH:10][C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: COc1cc2cnc(Cl)nc2cc1OC
Reactant: C1CNCCN1
Solvent: CC(C)CCO
Product: COc1cc2cnc(N3CCNCC3)nc2cc1OC
Yield: 91 %

Procedure:
Refluxed for 2 hours in isoamyl alcohol (15 ml) were 0.63 g of 2-chloro-6,7-dimethoxyquinazoline (synthesized by the method described in Japanese Patent Laid-Open No. 36390/1972) and 0.72 g of anhydrous piperazine. Isoamyl alcohol was thereafter distilled off under reduced pressure, followed by extraction with 2N--NaOH and chloroform. The chloroform layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure to obtain 0.7 g of the intended product (yield: 91%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:35][CH2:36][OH:37])[N:12]=[C:13]3[C:22]4[C:17](=[C:18]([O:23][CH2:24][C:25]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=5[CH3:33])[CH:19]=[CH:20][CH:21]=4)[C:16](=[O:34])[C:15]=1[C:14]=23.ClC1C=CC2N(CCO)N=C3C4C(=CC=CC=4OCC4C(C)=CC(C)=CC=4C)C(=O)C=1C=23>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:35][CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])[N:12]=[C:13]3[C:22]4[C:17](=[C:18]([O:23][CH2:24][C:25]5[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=5[CH3:33])[CH:19]=[CH:20][CH:21]=4)[C:16](=[O:34])[C:15]=1[C:14]=23
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCO)c(C)c1
Agent: Cc1cc(C)c(COc2cccc3c2-c2nn(CCO)c4ccc(Cl)c(c24)C3=O)c(C)c1
Product: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCOS(C)(=O)=O)c(C)c1

Procedure:
Starting with methanesulfonyl chloride and the mixture of regioisomers of 5-chloro-2-(2-hydroxyethyl)7- [(2,4,6-trimethylphenyl)methoxy]anthra- [1, 9-cd]pyrazol-6(2H)-one II and 5-chloro-2-(2-hydroxyethyl)10- [(2,4,6-trimethylphenyl)methoxy]anthra- [1, 9-cd] pyrazol-6(2 H)-one III, using the procedure of example 3, the title compound was prepared.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].C[O:27][C:28]1[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]2[C:29]=1[CH2:30][CH2:31][CH:32]([C:40]([O:42][CH3:43])=[O:41])[CH2:33]2>O.C(#N)C>[O:27]=[C:28]1[CH:37]=[CH:36][C:35](=[O:38])[C:34]2[CH2:33][CH:32]([C:40]([O:42][CH3:43])=[O:41])[CH2:31][CH2:30][C:29]1=2
Reactant: COC(=O)C1CCc2c(OC)ccc(OC)c2C1
Agent: [Ce]
Solvent: CC#N
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)C1CCC2=C(C1)C(=O)C=CC2=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98.4 %

Procedure:
A solution of 19.74 g (0.036 mol) of ammonium ceric nitrate in 120 ml of water was added to a stirred solution of 3.00 g (0.012 mol) of methyl rac-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate in 54 ml of acetonitrile. The mixture was stirred at room temperature for 25 minutes and then diluted with 150 ml of water. The solution was extracted with three 150 ml portions of diethyl ether and the combined diethyl ether extracts were washed with 150 ml of water, dried and evaporated to yield 2.60 g (98.5%) of methyl rac-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene-2-carboxylate in the form of a bright yellow solid of melting point 41°-42° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH3:18])[C:13](=O)[CH2:12][CH2:11]2.C1(=O)C2C(=CC=CC=2)CCC1.[ClH:31]>C1(C)C=CC=CC=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[ClH:7].[ClH:31].[CH3:18][C@@H:14]1[C:15]2[C:10](=[CH:9][C:8]([Cl:7])=[CH:17][CH:16]=2)[CH2:11][CH2:12][C@@H:13]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC1C(=O)CCc2cc(Cl)ccc21
Reactant: C1CNCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C1CCCc2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C[C@@H]1c2ccc(Cl)cc2CC[C@@H]1N1CCNCC1
Reaction time: 23 h

Procedure:
To 15 g of 4A molecular sieves in 250 ml of dry toluene were added piperazine (6.37 g) and 6-chloro-1-methyl-2-tetralone (8.6 g). Using a Dean-Stark water trap, the mixture was stirred and heated at reflux under a nitrogen atmosphere. After 23 hours, NMR analysis of a sample of the reaction solution showed the presence of tetralone. Fifty mg of p-toluenesulfonic acid were added, and the mixture was stirred and refluxed for an additional 26 hours. An additional 10 g of 4A sieves was added, and reflux was continued for an additional 10 hours. The sieves were filtered, and toluene was evaporated from the filtrate. The residue was dissolved in a mixture of 200 ml of THF and 20 ml of methanol. To the resulting solution, stirred under nitrogen and with ice bath cooling, was added sodium cyanoborohydride (2.68 g). Gaseous HCl was added to the solution, in portions, until the solution remained acidic. After stirring overnight at room temperature, solvents were removed on a rotary evaporator, and the residue was partitioned between ether and dilute hydrochloric acid. The acidic solution was separated and made basic in the cold with sodium hydroxide. The oil which separated was extracted with ether, and the ether solution was dried (MgSO4). Removal of the ether left 8.1 g of an oil. The oil was combined with 1 g of the product from a previous small scale reaction. A solution of the total in ethanol was treated with excess gaseous HCl. The crystals which separated were filtered and digested on the steam bath with 100 ml of methanol. The several crops of crystals obtained from the methanol were combined and recrystallized from ethanol to provide 6.3 g of the title compound. When dried at 120° C. in vacuo, the dihydrochloride lost one mol of hydrogen chloride and gave the following:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10](CC(O)=O)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1CCC[CH2:27]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:27][OH:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)C[C@@H]1C(=O)N(Cc2ccccc2)CC[C@H]1c1ccc(F)cc1
Product: OC[C@@H]1CN(Cc2ccccc2)CC[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of trans (4R)-1-benzyl-3-carboxymethyl-4-(4′-fluorophenyl)-piperidine-2-one (1.97 g) in tetrahydrofuran (20 ml) was treated with borane-tetrahydrofuran complex (19.6 ml, 1 molar) and heated at reflux for 6 hours. After cooling, the reaction was quenched with 1 molar hydrochloric acid, then stirred and heated at reflux for a further 1 hour. The mixture was cooled to ambient temperature, the pH adjusted to 9 with 1 molar sodium hydroxide, and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with saturated sodium chloride and evaporated to give trans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethylpiperidine (1.59 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].Cl>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[C:26]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][NH:9]3)=[CH:4][CH:3]=2)=[O:22])=[C:19]([CH3:18])[N:27]=1
Reactant: Cc1nc(-c2ccc(F)cc2F)ccc1C(=O)O
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Agent: Cl
Product: Cc1nc(-c2ccc(F)cc2F)ccc1C(=O)Nc1ccc2c(c1)NCCC2

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (73 mg, 0.30 mmol) and 2-methyl-6-(2,4-difluorophenyl)nicotinic acid (D106) (82 mg, 0.33 mmol) then converted to the HCl salt as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ (ppm): 8.46 (d, 1H), 8.11 (d, 1H), 7.93-8.01 (m, 2H), 7.81 (d, 1H), 7.40 (d, 1H), 7.25 (m, 2H), 3.55 (m, 2H), 2.96 (t, 2H), 2.88 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([CH2:15][O:16]C(=O)C)[CH:8]=3.C[O-].[Na+].P([O-])([O-])([O-])=O>CO.C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([CH2:15][OH:16])[CH:8]=3
Reactant: CC(=O)OCc1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2cc(CO)ccc2-c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 97.1 %

Procedure:
3-bromo-7-acetoxymethyl-9-fluorenone (1.18 g) was suspended in methanol (102 ml) and THF (23 ml). To this suspension was added 0.045M NaOMe (6.6 ml). The reaction mixture was stirred at room temperature for 1.25 hours. It was then neutralized with 0.2M pH 7 phosphate buffer. The tetrahydrofuran and methanol were removed under reduced pressure. Reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried and evaporated gave the product (1.0 g).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.C(O)(=O)C>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of dimethyl methylphosphonate (17.93 g, 144 mmol) in THF (270 mL) at −78° C. was slowly added n-BuLi (2.5M, 64.2 mL, 160.6 mmol). The reaction mixture was stirred for 1 h and (3-chloro-phenyl)-acetic acid methyl ester (26.93 g, 146 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred for 24 h. Acetic acid (15 mL) was added and the volatiles were removed in vacuo. The residue was diluted with CH2Cl2 and the organic solution was washed carefully with saturated aqueous NaHCO3 (3 times). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (20% EtOAc in hexanes to EtOAc) provided the title compound (9.28 g).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:28])=[CH:25][N:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[F:39][C:2]([F:1])([F:38])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][N:24]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCNC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
Methyl 3-(6-(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino) nicotinamido)propanoate (13 mg, 0.023 mmol) was dissolved in 1 mL methanol. 100 μL 1N aqueous sodium hydroxide was added. The resulting solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 5 mL water and the solution adjusted to pH 3 by addition of 1N aqueous HCl. The resulting mixture was extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated to give a colorless film. Residual solvent was removed under a stream of nitrogen to give 3-(6-(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoic acid (7.6 mg, 64%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 9.24 (br s, 1H), 8.06-8.14 (m, 2H), 7.55-7.65 (m, 4H), 7.52 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H). 6.40 (d, J=9.8 Hz, 1H), 4.46-4.55 (m, 1H), 3.64-3.72 (m, 2H), 2.52-2.59 (m, 2H), 2.04-2.32 (m, 4H). MS (M+H) 540.4.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[CH2:36][O:37][C:38]1[C:46]([CH:47]3[CH2:49][CH2:48]3)=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:50])[CH:39]=1)[CH2:33]2.CS(N)(=O)=O.[CH3:56][O:57][CH2:58][CH2:59][S:60]([NH2:63])(=[O:62])=[O:61]>>[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[CH2:36][O:37][C:38]1[C:46]([CH:47]3[CH2:48][CH2:49]3)=[CH:45][C:41]([C:42]([NH:63][S:60]([CH2:59][CH2:58][O:57][CH3:56])(=[O:62])=[O:61])=[O:43])=[C:40]([F:50])[CH:39]=1)[CH2:33]2
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained (0.16 g, 40%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.73-8.59 (m, 1H), 7.60-7.48 (m, 1H), 6.69-6.56 (m, 1H), 4.15-4.06 (m, 2H), 3.90-3.75 (m, 4H), 3.31 (s, 3H), 2.35-2.24 (m, 1H), 2.10-1.73 (m, 13H), 1.69-1.59 (m, 2H), 0.98-0.87 (m, 2H), 0.68-0.60 (m, 2H); MS (ES−) m/z 464.3 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[C:13]([O:18][CH3:19])[C:12]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:11]([O:27][CH3:28])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:31]=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[OH-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]([O:27][CH3:28])[C:12]([CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[C:13]([O:18][CH3:19])[C:14]=1[C:15](=[O:16])[NH2:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(C(=O)O)c(OC)c1CN1CCOCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)OC(C)(C)C)c(C(N)=O)c(OC)c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A solution of 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (50%). A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 h and then concentrated to dryness using a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), and concentrated. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixture of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03 mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodium hydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6 mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc, and concentrated. Purification by column chromatography afforded a solid residue, which was made into slurry in a mixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered and washed with hexanes to provide 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one (56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z: 426.0; MP 237.0-239.1° C.