Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C=CC(O)=CC=1)O.[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20].[OH-].[Na+]>CC(C)=O.CO>[CH2:1]([NH:9][CH2:20][CH2:19][C:18]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CC(=O)O
Reactant: CCCCCCCCN
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCCCCNCCC(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
To a mixture of n-octylamine (516 g, 4.0 mols), hydroquinone (200 mg) and methanol (400 ml), acrylic acid (144 g, 2.0 mols) was added dropwise with stirring while cooling with ice. After addition, the mixture was refluxed while heating for 4 hours. After cooled to room temperature, NaOH (80 g, 2.0 mols) was added. The reaction mixture was despersed in 6 liters of acetone, and filtration and drying were carried out to obtain the Na salt of N-n-octyl-β-alanine as white crystals having a melting point (dec.) of 242° C. (349 g Yield: 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([S:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27](Br)=[C:26]([CH3:32])[CH:25]=2)[CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=1)[CH3:2].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([S:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:40]3[CH:41]=[CH:42][C:37]([C:36]([F:47])([F:46])[F:35])=[CH:38][CH:39]=3)=[C:26]([CH3:32])[CH:25]=2)[CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of racemic 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid ethyl ester (0.200 g, 0.360 mmol) in toluene (2 mL) is added palladium tetrakis triphenylphosphine (0.0267 g, 0.020 mmol), 4-trifluoromethyl phenyl boronic acid (0.135 g, 0.720 mmol), and potassium fluoride (0.0416 g, 0.720 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At reflux, water (1.0 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and celite is added, followed by water. This mixture is then filtered through a pad of celite. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The product is purified by flash column chromatography (0.150 g, 0.240 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](O)=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].B.C1COCC1.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCCO)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (2.64 g, 9.2 mmol) in THF (50 mL) was added dropwise a 1 M borane-THF complex THF solution (38.4 mL, 38.4 mmol) under ice cooling. The reaction solution was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.17 g of the title compound.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([O:13][OH:14])([CH2:11][CH3:12])([CH3:10])[CH3:9]>CCCCCC>[CH3:6][C:5]([O:14][O:13][C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CCC(C)(C)OO
Reactant: CC(=O)C=C(C)C
Solvent: CCCCCC
Product: CCC(C)(C)OOC(C)(C)CC(C)=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A reaction mixture of 11.8 g (0.12 mole) of mesityl oxide, 30 g of Amberlyst 15® sulfonic acid type ion-exchange resin, and 15.6 g (0.15 mole) of 89% t-amyl hydroperoxide was stirred at 25°-30° C. for 20 hours and at 40° C. for 1 hour. Hexane was added and the ion-exchange resin separated by filtration. The filtrate was washed with sodium bisulfite solution and with water and the organic layer dried over anhydrous magnesium sulfate. The hexane solvent was removed under reduced pressure and the 11.7 g of recovered product identified by its infrared spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[C:17](OC(=O)C)(=[O:19])C.O>C(O)=O>[CH:17]([NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:3]=1)=[O:19]
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CNC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
3-Amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (1.907 g) (prepared as described in European Pat. No. 0022570) was dissolved in formic acid (20 ml). The solution was stirred at 60° and acetic anhydride (2.4 ml) added dropwise. The mixture was heated for 1 hour at 60° and then poured into water and stirred to decompose the residual excess anhydride. 3-Formamido-1-(3-trifluoromethylphenyl)-2-pyrazoline resulted as a crystalline solid m.p. 128°-129°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=4)=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 160 °C
Yield: 24.8 %

Procedure:
A mixture of N-(3-hydroxy-phenyl)-acetamide (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(3-acetylamino-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 26%) as a white solid.
Reaction SMILES: [C:1]([NH:16][C@@H:17]1[C@@H:46]([OH:47])[C@H:45]([OH:48])[C@@H:44]([CH2:49][OH:50])[O:43][C@@H:18]1[O:19][CH:20]([CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:51]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67](O)=[O:68])(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:51]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([O:47][C@H:46]1[C@H:45]([OH:48])[C@@H:44]([CH2:49][OH:50])[O:43][C@H:18]([O:19][CH:20]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@@H:17]1[NH:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:68])(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(O)CCCCCCCNC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)N[C@H]1[C@@H](OC(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CCCCCCCCCCCCCC(=O)N[C@H]1[C@@H](OC(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1OC(=O)CCCCCCCNC(=O)c1ccccc1

Procedure:
In the same manner as in Example 8, Step 4, 2-benzyloxycarbonyl-1-(benzyloxycarbonylmethyl)ethyl 2-deoxy-2-tetradecanoylamino-α-D-glucopyranoside was once protected with an isopropylidene group and then reacted with 8-benzoylaminooctanoic acid, followed by removal of the isopropylidene group to obtain the titled compound as a colorless oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[NH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[C:20]([CH2:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])=[CH:19]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([NH:17][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=1)=[O:16])[CH:19]=[C:20]2[CH2:28][CH2:29][C:30]([OH:32])([CH3:31])[CH3:33]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: CC(C)(O)CCc1cn(N)c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(CCC(C)(C)O)c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic acid (516 mg, 4 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (566 mg, 4 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (662 mg, 4 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 4%-10% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid [5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (450 mg, 44%). MS: 434 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.25 (s, 1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.02 (m, 1H), 7.58 (m, 1H), 7.43 (m, 3H), 7.06 (m, 1H), 4.29 (s, OH, 1H), 2.78 (s, 3H), 2.72 (m, 2H), 1.77 (m, 2H), 120 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:15](/[CH3:28])=[CH:16]/[C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10](=[O:12])[C:9]([CH3:13])([CH3:14])[C:8]2[CH:7]=[C:6](/[C:15](/[CH3:28])=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)C(=O)CC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)C(=O)CC2(C)C
Yield: 70 %

Procedure:
2 g of ethyl (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-7-oxonaphth-2-yl)-1-propenyl]-benzoate are stirred with 0.7 g of potassium hydroxide in a mixture of 25 ml of ethanol and 1.5 ml of water for 3 hours at 80° C. The entire reaction mass is introduced into 100 ml of water, after which the mixture is acidified with 2 N hydrochloric acid, and the resulting precipitate is filtered off, washed with cold methanol and dried to give 1.3 g of the title compound of melting point 260°-261° C.
Reaction SMILES: C([N:3]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11][CH2:10][N:9]([CH:23]([CH2:30][CH2:31][CH:32]([N:39]2[CH2:50][CH2:49][N:48]([CH2:51][C:52]([O:54]C(C)(C)C)=[O:53])[CH2:47][CH2:46][N:45](C=O)[CH2:44][CH2:43][N:42]([CH2:61][C:62]([O:64]C(C)(C)C)=[O:63])[CH2:41][CH2:40]2)[C:33]([O:35]C(C)C)=[O:34])[C:24]([O:26]C(C)C)=[O:25])[CH2:8][CH2:7][N:6]([CH2:69][C:70]([O:72]C(C)(C)C)=[O:71])[CH2:5][CH2:4]1)=O.O.[Li+].[OH-].Cl>C(O)C>[C:52]([CH2:51][N:48]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43][N:42]([CH2:61][C:62]([OH:64])=[O:63])[CH2:41][CH2:40][N:39]([CH:32]([CH2:31][CH2:30][CH:23]([N:9]2[CH2:8][CH2:7][N:6]([CH2:69][C:70]([OH:72])=[O:71])[CH2:5][CH2:4][NH:3][CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]2)[C:24]([OH:26])=[O:25])[C:33]([OH:35])=[O:34])[CH2:50][CH2:49]1)([OH:54])=[O:53]
Reactant: CC(C)OC(=O)C(CCC(C(=O)OC(C)C)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1)N1CCN(CC(=O)OC(C)(C)C)CCN(C=O)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCN(C(CCC(C(=O)O)N2CCN(CC(=O)O)CCNCCN(CC(=O)O)CC2)C(=O)O)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a 250 mL RB flask the ester of Example 4 (1.77 g, 1.63 mmol) was dissolved in ethanol (30 ml) and water was added until the solution turned slightly turbid. The temperature was elevated to 100° C. and 1N LiOH (13 mL) was added. After maintaining the mixture at 100° C. for 7 hours, the reaction was stirred at 50° C. for a further 18 hours. The solution was adjusted to pH 0.5 with 5N HCl (aq), and the mixture was refluxed for 1.5 hours and stirred at ambient temperature for an additional 18 hours. The material was loaded onto a bed of AG5OW-X8 [80 mL, (H+ -form)] strongly acidic cation exchange resin. After rinsing with water (1100 mL), the target material was eluted from the bed using 0.25N NH4OH solution. The fractions containing the title product were combined and evaporated to afford 0.79 g (79%) as a glassy solid. 1H NMR (D2O) δ 3.81 (br, 2H), 3.58-2.78 (br, 40H), 2.135 (br, 2H), 1.85 (br, 2H). 13C NMR (D2O): 22.5, 23.1, 40.6, 46.4, 48.6, 54.5, 62.6, 170.3, 175.7. MS (FAB): m/e 719.4 (MH+).
Reaction SMILES: F[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:21]1([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Fc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: C1COCCN1
Product: FC(F)(F)c1cc(N2CCOCC2)c2c(c1)ncn2-c1ccccc1
Temperature: 245 °C
Yield: 13.1 %

Procedure:
To 7-fluoro-1-phenyl-5-trifluoromethylbenzimidazole (400 mg, 1.4 mmol) was added morpholine (1 ml, 1.1 mmol) and the mixture heated in a Personal Chemistry Smith Creator™ microwave for ten 30 minute periods at 245° C. The residue was chromatographed over silica gel to give the title compound as a solid (50 mg, 10%) m/z, 348.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:12][NH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]Br>[CH3:12][NH:13][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN
Reactant: O=C(O)c1cccnc1Cl
Agent: [Cu]Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNc1ncccc1C(=O)O
Temperature: 100 °C
Reaction time: 20 h

Procedure:
30.0 g (0.19 mol) of 2-chloronicotinic acid was dissolved in N,N-dimethylformamide (400 mL), and 31.0 g (0.38 mol) of methylamine hydrochloride, 105 g (0.76 mol) of potassium carbonate, and 2.73 g (19.0 mmol) of copper(I) bromide were added to the solution. The mixture was stirred for 20 hours at 100° C. After the mixture was cooled to room temperature, insoluble materials were filtered off, and the filtrate was concentrated. A 10% aqueous solution of sodium hydroxide was added to the residue thus obtained, and the mixture was washed with diethyl ether. Concentrated hydrochloric acid was added to the aqueous phase to adjust the aqueous phase to pH 6 to 7, and a solid obtained by concentrating the aqueous phase was dried. Thus, crude 2-(methylamino)nicotinic acid was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:32])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22](=[O:31])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[Li+].[BH4-]>C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])=[CH:8][CH:9]=2)=[O:32])=[C:16]([C:22](=[O:31])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH:17]=1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2{4-[4-Chloro-2-(5-chloro-pyridin-2-ylcarbamoyl)-phenylcarbamoyl]-phenyl}-2-methyl-propionic acid methyl ester (485.0 mg, 1 mmol) in THF was added LiBH4 (2.0 ml, 2.0 M solution in THF). The mixture was stirred at 60° C. over night. The reaction mixture was cooled, and quenched with sat'd NH4Cl. HPLC purification gave 2{4-[4-Chloro-2-(5-chloro-pyridin-2-ylcarbamoyl)-phenylcarbamoyl]-phenyl}-2-methyl-propyl alcohol as white solid. MS found: (M+1)+=457.9.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:31][CH:32]=1)[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 71 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.59 g) and [(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.58 g) as starting materials, 5-benzyloxy-N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.74 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, 5-hydroxy-N-[(4-hydroxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained. melting point: 241-243° C.
Reaction SMILES: C(O)(=O)C(O)=O.C[O:8][CH:9](OC)[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=2)[C:12]1=[O:22]>>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:22])[CH:11]([CH2:10][CH:9]=[O:8])[CH2:20][CH2:19]2
Reactant: COC(CC1CCc2cc(Cl)ccc2C1=O)OC
Agent: O=C(O)C(=O)O
Product: O=CCC1CCc2cc(Cl)ccc2C1=O
Yield: 98 %

Procedure:
For the cleavage of the acetal, 8 ml of 10% aqueous oxalic acid solution were applied to 50 g of silica gel and 2.1 of 6-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal were chromatographed on this mixture with methylene chloride as the eluent. There were obtained 1.7 g (98%) of 6-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthalene-acetaldehyde.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=O)[CH2:18][C:19]([C:21]1C=C[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)[CH:22]=1)=O)(C)(C)C.[C:36](O)([C:38](F)(F)F)=[O:37]>C(Cl)Cl>[Cl:14][C:12]1[C:11]([CH3:15])=[CH:10][C:9]2[N:16]=[C:17]([C:18]3[CH:19]=[CH:21][CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)[CH:24]=3)[CH2:38][C:36](=[O:37])[NH:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M77) (0.36 g, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (220 mg, 81%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:27][C:28]([NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[S:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23]C3)=[O:20])[S:18][C:11]=12.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(N3CCCCC3)=O)SC=12>>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:27][C:28]([NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[S:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([N:21]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:20])[S:18][C:11]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCCC4)sc23)c(F)c1
Agent: Cl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1

Procedure:
Following the procedure described above for the synthesis of compound 136a (example 93) but substituting compound 135d (example 92, table 11) for the compound 8o (example 37, table 6), title compound 136b was obtained. Characterization of this material is provided in Table 12.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([N:11]=[C:12]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:10][O:9][C:6]1[N:5]2[N:11]=[C:12]([C:14]([F:20])([F:19])[C:15]([F:16])([F:17])[F:18])[CH:13]=[C:4]2[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(CO)c2cc(C(F)(F)C(F)(F)F)nn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=O)c2cc(C(F)(F)C(F)(F)F)nn12
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
Activated manganese dioxide (3.75 g) was added to a solution of the compound of Example 353 (1.28 g) in chloroform (50 mL). The mixture was stirred at 50° C. for 4 hours. Subsequently, the mixture was filtered through Celite and the filtrate was concentrated to afford the title compound as a colorless powder (1.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27][O:14][C:12]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Br:1])[CH:13]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=Cc1ccc(O)cc1OCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(C=O)c(OCc2ccccc2Br)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-bromobenzyloxy)-4-hydroxybenzaldehyde (60 mg, 020 mmol) in DMF (10 ml) were added t-butyl-2-bromoethylcarbamate (43.70 g, 0.20 mmol) and K2CO3 (54.18 mg, 0.39 mmol), followed by stirring at 100° C. for 3 hours. After completion of the reaction, the solution was extracted with a saturated aqueous NH4Cl solution and ethyl acetate. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum. The residue was purified through column chromatography (ethyl acetate/n-hexane=1/9→1/5) to afford the object compound (pale yellowish solid, 69 mg, 79.3%).