Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][Br:34])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)benzotriazole was prepared from the bromination of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.274 g (0.0223 mol) 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole was kept in oil-bath with temperature of 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)benzotriazole was 6.6 g (82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:20])[CH:14]=2)[NH:9]1.[NH2:21][C:22]1([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C:22]([CH3:24])([CH3:23])[C:25]([OH:27])=[O:26])[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2ccccc2Br)Nc2ccc(Cl)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1ccccc1C1CC(C)(C)c2cc(Cl)ccc2N1)C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 2-(2-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 1-amino-cyclopropanecarboxylic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (127 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 371.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:18][C:19]([OH:21])=[O:20])([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([CH2:7][C:8]([CH2:18][C:19]([OH:21])=[O:20])([C:14]([CH3:15])([CH3:16])[CH3:17])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccccc1)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(CC(=O)O)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Dissolve 3-phenyl-2-t-butylcarboxymethylpropionic acid, ethyl ester (2.68 g, 9.17 mmol) in ethanol (95%, 60 mL) and water (30 mL). Treat with potassium hydroxide (2.94 g, 52 mmol). Stir at room temperature for 3 hours. Add water (75 mL) and extract with ethyl et her (2×50 mL). Extract the combined ethereal phases with water (75 mL) and acidify the combined aqueous phases with aqueous 1M tartaric acid (pH 2-3). Extract with ethyl acetate (2×125 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Take the residue up in methylene chloride and filter to give 3-phenyl-2-t-butylcarboxymethylpropionic acid as a pale yellow solid (1.96 g, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.NCCSC[C@@H](C(O)=O)N.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:18][CH2:17][C@@H:16]([C:19]([OH:21])=[O:20])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(NCCI)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)O

Procedure:
S-Benzyloxycarbonylaminoethyl-L-cysteine is prepared from benzyloxycarbonyl-2-iodoethylamine and L-cysteine by the method of H. Lindley (Austral. J. Chem., 12, 296,1959). The α-amino group is protected with tert-butoxycarbonyl using di-tert-butyl dicarbonate. The resulting fully protected S-2-aminoethyl-L-cysteine is condensed with L-proline-tert-butyl ester in the presence of N,N'-dicyclohexylcarbodiimide. This intermediate is readily purified by medium pressure liquid chromatography on silica in ethyl acetate/hexane (1:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([N+:22]([O-])=O)[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:6]>[Pd].CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([NH2:22])[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: CNc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1N

Procedure:
A solution of 4-(4-methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide (1 eq) and 10% palladium on carbon (0.1 eq) in methanol was stirred at room temperature and flushed with nitrogen. Hydrogen was flushed through the reaction for 1-2 hours or until the reaction was determined to be complete by HPLC. Nitrogen was flushed through the reaction for 15 minutes before the reaction was filtered through a celite pad. The celite pad was washed with excess methanol before it was all removed by evaporation under reduced pressure to afford the product as a light yellow solid. LCMS m/z 303.2 (MH+), tR=1.5 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.[Cl:37][C:38]1[C:39]([F:46])=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42].CCCP(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:42][CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[C:38]([Cl:37])[C:39]=1[F:46])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Agent: CCCP(=O)=O
Agent: CO[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.55 g, 5.89 mmol) in CH2Cl2 (50 mL) were added 3-chloro-2-fluoro-benzylamine (1.03 g, 6.48 mmol), propylphosphonic anhydride (50% in EtOAc, 5.20 mL, 8.83 mmol) and DIPEA (3.08 mL, 17.7 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 7:3) to give (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.35; MS (UPLC): 405.1/407.2 [M+H]+, 349.1/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.12 min and (2R,3R,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-3-fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.5; MS (UPLC): 405.1/407.2 [M+H]+, 349.0/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.20 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:42]([N:44](CC)[CH2:45][CH2:46]N)[CH3:43].NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:42]([N:44]([CH2:45][CH3:46])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:29]=[N:30]1)[CH3:43]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: CCN(CC)CCN
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCN(CC)CCNCCn1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Yield: 42 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting N,N-diethyl-1,2-ethanediamine (50 mg, 0.43 mmol) for the 2-aminoethanol to afford 12 mg of the title compound (42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: BrCc1ccncc1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(Cc2ccncc2)c2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
(1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 0.5 mmol), 4-bromomethyl-pyridine (98 mg, 0.6 mmol) and Cs2CO3 (245 mg, 0.75 mmol) were dissolved in DMF (2 mL). The mixture was stirred at room temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as little yellow solid (140 mg, 76%). LC/MS m/e calcd. for C22H17ClN2O: 360, observed (M+H)+: 361.2 1HNMR (400 MHz, MeOD-d4) δppm 2.22-2.37 (m, 2 H) 3.32-3.40 (m, 1 H) 5.39 (s, 2 H) 6.15 (d, J=7.58 Hz, 1 H) 6.74-6.85 (m, 1 H) 6.92 (d, J=7.83 Hz, 1 H) 7.10-7.19 (m, 1 H) 7.24-7.42 (m, 4 H) 7.93 (d, J=6.32 Hz, 2 H) 8.80 (d, J=6.06 Hz, 2 H). MS calcd. for C22H17ClN2O 360, obsd. (ESI+) [(M+H)+] 361.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:8]2[CH2:9][CH2:10][CH:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:6][CH2:7]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: COC(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Temperature: 90 °C

Procedure:
To a stirred, room temperature, mixture of isonipecotic acid methyl ester hydrochloride (5.00 g, 2.78×10-2 mole), potassium carbonate (7.70 g, 5.57×10-2 mole), and DMF (100 ml) was added 1-(2-bromoethyl)-4-methoxybenzene (5.99 g, 2.78×10-2 mole). The reaction was then immersed in an oil bath which had been preheated to ca. 90° C. The reaction was heated at ca. 90° C. for ca. 17 hours and was then poured into a separatory funnel containing water and a 2:1 mixture of ethyl acetate:toluene. The two phases were mixed and the aqueous layer was separated. The organic layer was washed two times with H20 and once with saturated aqueous NaCl before being dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil. Purification by flash chromatography (ethyl acetate) and crystallization from cyclohexane gave 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester as a colorless solid: 3.98 g (52%), m.p. 66°-68° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[O:11][N:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH:32]2[CH2:34][CH2:33]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[CH:13]=2)=[O:16])[CH:32]2[CH2:33][CH2:34]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)on2)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)no2)C2CC2)CC1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid and 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=1.27 min; Mass spectrum (ESI+): m/z=455 [M+H]+.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][N:26]=[C:21]3[CH:20]=2)=[CH:9]1)C1C=CC=CC=1.N.[Na].O>O1CCCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[C:10]2[C:19]1[NH:27][C:22]2=[N:23][CH:24]=[CH:25][N:26]=[C:21]2[CH:20]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2Cc1ccccc1
Agent: N
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(-c3cc4nccnc4[nH]3)c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
A cooled (−78° C.) solution of 6-(1-benzyl-5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [50 mg, Example 1(m)] in tetrahydrofuran (20 mL) was treated with liquid ammonia (20 mL) then with sodium (100 mg). After stirring at −78° C. for 30 minutes the reaction mixture was allowed to warm slowly to ambient temperature, then treated with water (50 mL) and then extracted three times with ethyl acetate (50 mL). The combined extracts were dried over sodium sulfate and then evaporated. The residue was triturated with diethyl ether to give the title compound (14 mg) as a brown solid, m.p. 268-271° C. MS: 265.24 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:6]2=[N:7][C:8]=1[CH3:9]>C(Cl)Cl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:9][C:8]1[N:7]=[C:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]2=[CH:4][C:3]=1[CH:2]=[O:1]
Reactant: Cc1nc2c(cc1CO)CCCCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2c(cc1C=O)CCCCC2
Reaction time: 4 h
Yield: 72.5 %

Procedure:
In an atmosphere of argon, 3-hydroxymethyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (5.24 g, 27.4 mmol) was dissolved in methylene chloride (150.0 ml), and the solution was mixed with manganese dioxide (15.88 g, 137.0 mmol) at room temperature and stirred at the same temperature for 4 hours. The reaction solution was diluted with ethyl acetate and then filtered. The solvent in the resulting filtrate was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (3.76 g, 74.0%) as white powder.
Reaction SMILES: C(N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C(=O)C1C=CC(O)=CC=1)C.ClCC(OCC)=O.C([O:42][C:43](=[O:77])[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C:52](=[O:76])[N:53]([CH2:74][CH3:75])[C:54]2[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:55]=2[CH:62]2[CH2:71][CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[C:67]([O:72][CH3:73])[CH:68]=3)[CH2:63]2)=[CH:48][CH:47]=1)C.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:74]([N:53]([C:54]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:55]=1[CH:62]1[CH2:71][CH2:70][C:69]2[C:64](=[CH:65][CH:66]=[C:67]([O:72][CH3:73])[CH:68]=2)[CH2:63]1)[C:52]([C:49]1[CH:48]=[CH:47][C:46]([O:45][CH2:44][C:43]([OH:77])=[O:42])=[CH:51][CH:50]=1)=[O:76])[CH3:75]
Reactant: CCOC(=O)COc1ccc(C(=O)N(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Agent: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(=O)CCl
Solvent: C1CCOC1
Solvent: O
Product: CCN(C(=O)c1ccc(OCC(=O)O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
Synthesized from N-ethyl-4-hydroxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide and ethyl chloroacetate according to an analogous synthetic method to Preparation Example 40, to a solution of the resulting {4-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]carbamoyl}phenoxy}acetic acid ethyl ester (275 mg) in tetrahydrofuran (5 ml) was added an aqueous solution of 1N sodium hydroxide (5 ml) on an ice bath. The solution was stirred for 1.5 hours while warming to room temperature, then the reaction solution was acidified with 2N hydrochloric acid on the ice bath. Water was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo to provide the title compound (246 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(CCCCCCc3nnn[nH]3)oc2-c2ccccc2)cc1
Yield: 35.4 %

Procedure:
The procedure is as in the preceding example, heating 1 g of 7-(4,5-diphenyl-2-oxazolyl)heptanenitrile, twice 0.9 g of sodium azide and twice 0.7 g of ammonium chloride in 20 cm3 of dimethylformamide. The solid residue derived from the extractions is crystallised in a mixture of ethyl acetate (5 cm3) and diisopropyl ether (15 cm3). 0.4 g (35%) of 5-[6-(4,5-diphenyl-2-oxazolyl)hexyl]tetrazole is obtained in the form of white crystals, melting point 132° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][N:30]3[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[CH2:32][O:31]3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][N:30]3[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[CH2:32][O:31]3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CN1OCC(C)(C)C1=O
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN2OCC(C)(C)C2=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a solution of the title compound of Step (A) (0.2 g, 0.327 mmol) in 4 mL of acetonitrile, chlorotrimethylsilane (0.213 g, 1.1 mmol) and sodium iodide (0.294 g, 1.965 mmol) were added the mixture stirred at room temperature for 30 min. Additional portions of chlorotrimethylsilane (0.12 g, 1.84 mmol) and sodium iodide (0.2 g, 1.33 mmol) were added over a 1 hr period and the mixture stirred for an additional 1 hr. The mixture was diluted with 25 mL of water and 1 mL of saturated aqueous sodium thiosulfate was added and the mixture was then extracted with 3×25 mL of EtOAc. The combined organic extracts were then washed once with water and dried and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 68% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 32% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.069 g (40%) of the title compound of this Example as a white solid. m.p. 95°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(OP([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(OCC)=O)C.[O-]CC.[Na+].C(O)C.O>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
4-Fluorobenzaldehyde (9.61 g, 80.0 mmol) in tetrahydrofuran (120 mL) was mixed with ethyl 2-(diethoxyphosphoryl)acetate (17.9 g, 80.0 mmol) under cooling with ice, and then sodium ethoxide-ethanol solution (21 wt %, 44.8 mL, 120 mmol) was added dropwise to the reaction mixture under cooling with ice, and the resulting reaction mixture was stirred at room temperature for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1→10/1 (v/v)) to give the title compound as a colorless oil (14.1 g, yield 91%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25].O>C(O)(=O)C>[C:2]1([C:1]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:25][N:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1C(=O)c1ccccc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-c2nnc(-c3ccccc3)c3ccccc23)cc1
Yield: 100 %

Procedure:
To a cooled solution of 1,2-bis(benzoyl)benzene (286.32, 0.5 g, 1.75 mmol) in glacial acetic acid (12 ml) was added hydrazine monohydrate (3.5 mL) dropwise. The reaction mixture was refluxed for 4 hours. The resulting bright brown solution was added with water to produce pale yellow precipitate, yield 100%. This was used to the next reaction for complex without further purification. MS: m/z 283.0 (M+).