Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[CH:35]=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[C:35]([OH:6])=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C=O)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of sodium chlorite (1.19 g; 13.13 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.03 g; 8.59 mmol; 3.6 eq.) in water (7 mL) was added dropwise to a mixture of 2-methyl-2-butene (2.39 mL) and 3-(5-fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (705 mg; 2.39 mmol; 1 eq.) in 1,4-dioxane (7 mL). The reaction mixture was stirred at room temperature for 16 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The precipitate was filtered off and dried to afford the title compound (625 mg, 84%) as a white solid. 1H NMR (CDCl3) δ 8.17 (dd, J=8.8, 6.7 Hz, 1H), 6.85 (ddd, J=8.9, 7.6, 2.3 Hz, 1H), 6.35 (dd, J=9.9, 2.3 Hz, 1H), 5.25-4.87 (m, 1H), 4.41 (ddd, J=10.1, 6.4, 1.2 Hz, 2H), 4.11 (ddd, J=10.0, 4.0, 1.1 Hz, 2H), 1.45 (s, 9H). HPLC (max plot) 96.4%; Rt 3.60 min.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.N(C(N1CCCCC1)=O)=N[C:27](N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.O[C:57]1[CH:66]=[CH:65][C:60]([C:61]([O:63][CH3:64])=[O:62])=[CH:59][CH:58]=1>C1COCC1.C1(C)C=CC=CC=1>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][C:57]3[CH:66]=[CH:65][C:60]([C:61]([O:63][CH2:64][CH3:27])=[O:62])=[CH:59][CH:58]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCC(Oc1ccc(C(=O)OCC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptan-1-ol (280 mg, 0.83 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 314.1 mg, 1.24 mmol) at 0° C., followed by the addition of tributylphosphine (0.31 mL, 1.24 mmol) and methyl 4-hydroxybenzoate (151.5 mg, 1 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving ethyl 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoate. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoic acid (330 mg).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[C:12]1(=[O:18])OC(=O)C[CH2:13]1.N1C=CC=CC=1.[Cl:25]CCl>CN(C1C=CN=CC=1)C>[Cl:25][CH2:13][C:12]([O:11][CH2:10]/[CH:9]=[C:7](\[CH3:8])/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[O:18]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: ClCCl
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)=CCC/C(C)=C/COC(=O)CCl
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
Geraniol [1] (1.542 g, 10 mmol), succinic anhydride (1.201 g, 12 mmol) and 4-DMAP (10 mg, cat) were suspended in anhydrous dichloromethane (50 ml) under an atmosphere of dry nitrogen. Pyridine (0.791 g, 10 mmol) was added and the reaction mixture was stirred for 24 hrs at room temperature. The reaction mixture was successively washed with 2N HCl and H2O, dried over Na2SO4 and the solvent was evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to yield product [2] as yellow liquid in 99% yield. The product was pure according to 1H NMR and directly subjected to the next step without further purification. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=12.24 (br s, 1H), 5.29 (t, J=7.0 Hz, 1H), 5.08 (t, 6.7, 1H), 4.55 (d, J=7.1 Hz, 2H), 2.49 (m, 2H), 2.03 (m, 4H), 1.67 (s, 3H), 1.66 (s, 3H), 1.59 (s, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=173.3, 172.2, 141.2, 131.1, 123.7, 118.5, 60.7, 38.9, 28.7, 28.6, 25.8, 25.5, 17.5, 16.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)C>N1C=CC=CC=1>[C:20]([NH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of ethyl 2-(5-amino-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate (6.91 g, 26.3 mmol) in pyridine (62 mL) was added acetic anhydride (3 ml, 31.5 mmol). The reaction was stirred at room temperature for 16 h. Ethanol was added and the mixture was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 10 to 100% ethyl acetate/isohexane) yielding ethyl 2-(5-acetamido-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate as a solid (7.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])(=[O:13])=[O:12].OC1C2N=NNC=2C=CC=1.[OH:33][CH:34]([CH:37]1[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]1)[CH2:35][NH2:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:33][CH:34]([CH:37]1[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]1)[CH2:35][NH:36][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:15]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Reactant: CC1(C)OCC(C(O)CN)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3c(F)cc(F)cc3F)c2)O1
Temperature: -10 °C
Reaction time: 6 h

Procedure:
5.96 g (18 mmol) of 3-[N-(2,4,6-trifluorophenyl)sulfamoyl]-benzoic acid is dissolved in 50 ml of dry dimethylformamide under argon atmosphere, 2.76 g (18 mmol) of hydroxybenzotriazole and 2.9 (18 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine are added and the solution is cooled to -10° C. At this temperature, 3.71 g (18 mmol) of dicyclohexylcarbodiimide is added to the solution. Then it is stirred for 1 hour at -10° C. and 6 hours at room temperature. The turbid reaction solution is filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is dissolved in 100 ml of ethyl acetate, the solution is shaken out five times with saturated sodium bicarbonate solution and twice with water, the organic phase is dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 4.91 g (10.35 mmol)=57.5% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22]2[CH:27]=[N:26][CH:25]=[C:24]([Cl:28])[N:23]=2)[CH3:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:28][C:24]1[N:23]=[C:22]([NH:21][C@H:19]([C:15]2[CH:14]=[C:13]([NH:12][S:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=2)[CH3:20])[CH:27]=[N:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NS(=O)(=O)c2cccnc2)c1
Reaction time: 17 h
Yield: 28.2 %

Procedure:
To a suspension of pyridine-3-sulfonylchloride hydrochloride (94 mg, 0.44 mmol) and N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (100 mg, 0.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.17 mL, 1.2 mmol) dropwise at room temperature and the mixture was stirred for 17 hours. After this time the mixture was diluted with ethyl acetate (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×20 mL) and brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-(3-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}phenyl)pyridine-3-sulfonamide (44 mg, 28%) as a pale yellow foam.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[P:12]([OH:15])([OH:14])[OH:13].P(Cl)(Cl)Cl>S1(CCCC1)(=O)=O>[CH:6]1[CH:7]=[N:2][CH:3]=[C:4]([CH2:8][C:9]([P:12]([OH:15])([OH:14])=[O:13])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:5]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 3-pyridylacetic acid hydrochloride (50 g, 0.288 mol) and phosphorous acid (35.4 g, 0.432 mol) in sulfolane (180 ml) is heated to 75° C. for 30 min. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (85.6 ml, 0.98 mol) while maintaining the temperature between 35-45° C. The mixture is heated to 63-67° C. for 3 hours whereby a thick white mass results. It is then cooled to 0-5° C. and quenched by slow addition of water (500 ml) at 0-5° C. over a period of 1 hour. The resulting clear solution is charcoalized and heated at 100° C. for 3 hrs, cooled to ambient temperature and then cooled 0-5° C. After stirring for 2 hrs at 0-5° C. the crystallized product is filtered, washed sequentially with chilled water (100 ml), rectified spirit (75 ml) and dried in air oven at 55-60° C. until loss on drying is less than 0.5% w/w. Yield 60.4 g, (70.47%), appearance: white crystalline solid, purity >99.0%.
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C=CC=CC=1N)CC2.C(OC(=O)C)(=O)C.[OH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][C:45](=O)[CH3:46])[CH2:32][CH2:31]2>N1C=CC=CC=1>[CH2:45]([NH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH:33]1[CH2:32][CH2:31][C:30]2[CH:29]=[C:28]([OH:27])[CH:37]=[CH:36][C:35]=2[CH2:34]1)[CH3:46]
Reactant: CC(=O)Nc1ccccc1C1CCc2cc(O)ccc2C1
Agent: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCNc1ccccc1C1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (3.7 g), acetic anhydride (19 ml) and pyridine (19 ml) was stirred for 1 hour at room temperature. The reaction solution was concentrated in vacuo, then ethyl acetate (20 ml) and chloroform (5 ml) were added thereto, the crystal that was precipitated was filtered and dried. Synthesized from the total amount of the resulting N-[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide according to an analogous synthetic method to Example 364 described below, the total amount of N-[2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide was used according to an analogous synthetic method to Example 337 described below to provide the title compound (2.3 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:27]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:27][O:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1OC
Yield: 89.9 %

Procedure:
Dissolve compound 8 (1.2 g, 3.4 mmol) in DMF (20 ml), add anhydrous K2CO3 (0.7 g, 5.1 mmol), MeI (0.96 g, 6.8 mmol), react at 60° C. for 2h. After completion of the reaction, cool the mixture, filter and evaporate the DMF from filtrate under reduced pressure, feed the redissolved residue solution to a silica gel column, evaporate the solvent in the eluent to obtain a colorless oil (1.12 g, 90%). 1H NMR (400 MHz, DMSO-d6): 1.62 (s, 3H), 1.71 (s, 3H), 3.23 (d, J=6.4 Hz, 2H), 3.68 (s, 3H), 3.86 (s, 3H), 3.90 (s, 3H), 5.10 (t, J=6.4 Hz, 1H), 6.98 (d, J=16.0 Hz, 1H), 7.18 (s, 1H), 7.28 (t, J=7.2 Hz, 1H), 7.30 (d, J=16.0 Hz, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.53 (d, J=7.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([OH:17])[CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[S:5][CH:6]=1.[C:18]([C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[CH:19]>CCN(CC)CC.[Cu]I>[F:13][C:12]([F:15])([F:14])[C:11]([NH:10][CH2:9][CH2:8][CH:7]([OH:17])[C:4]1[S:5][CH:6]=[C:2]([C:19]#[C:18][C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:16]
Reactant: O=C(NCCC(O)c1cc(Br)cs1)C(F)(F)F
Reactant: C#CC1(O)CCCCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(NCCC(O)c1cc(C#CC2(O)CCCCC2)cs1)C(F)(F)F
Reaction time: 8 h

Procedure:
Solution of N-(3-(4-bromothiophen-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.77 g, 2.32 mmol) and 1-ethynylcyclohexanol (0.48 g, 3.87 mmol) in Et3N (10 mL) was degassed by bubbling Ar for 5 min. CuI (0.0482 g, 0.253 mmol) and PdCl2(Ph3P)2 (0.0874 g, 0.125 mmol) were added to the reaction mixture and degassed by alternating vacuum/Ar once. The reaction mixture was stirred at +80° C. overnight, partitioned between EtOAc and aqueous NH4Cl (25%). Aqueous layer was additionally extracted with EtOAc and combined organic layers were washed with brine. Concentration under reduced pressure followed by flash chromatography purification (10%-75% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-hydroxy-3-(4-((1-hydroxycyclohexyl)ethynyl)thiophen-2-yl)propyl)acetamide as a light yellow oil. Yield (0.52 g, 60%); 1H NMR (400 MHz, DMSO-d6) δ 9.37 (br.s, 1H), 7.52 (d, J=1.3 Hz, 1H), 6.92 (d, J=1.3 Hz, 1H), 5.78 (d, J=4.7 Hz, 1H), 5.34 (s, 1H), 4.74-4.81 (m, 1H), 3.20-3.30 (m, 2H), 1.84-1.91 (m, 2H), 1.74-1.84 (m, 2H), 1.56-1.65 (m, 2H), 1.38-1.56 (m, 6H).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Temperature: 90 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-methylimidazolidine-2,4-dione (2.00 g), 4-methoxybenzyl chloride (2.85 mL) and potassium carbonate (3.15 g) were added N,N-dimethylformamide (20 mL) and potassium iodide (0.29 g), and the mixture was stirred at 90° C. for 9 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate/diisopropyl ether to give the title compound (2.82 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](O)=[O:9].S(Cl)([Cl:14])=O>>[CH3:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([Cl:14])=[O:9]
Reactant: Cc1ccccc1CC(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccccc1CC(=O)Cl

Procedure:
A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brown oil.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10](Cl)=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:34])[C:20]=1[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[O:23]>>[C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([O:23]/[C:22](/[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[CH:21]\[C:20]3[C:19]([Cl:34])=[CH:18][N:17]=[CH:16][C:15]=3[Cl:14])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: Cc1ccc(C2(C(=O)Cl)CC2)cc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)C2(c3ccc(C)cc3)CC2)cc1OC

Procedure:
The compound was obtained starting from 1-p-tolyl-cyclopropanecarbonyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(OC)(O[CH3:19])(=O)=O>>[CH3:19][O:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C(=NO)c1csc(C)n1
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Yield: 84.5 %

Procedure:
Ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.3 g.) and dimethyl sulfate (0.18 g.) were reacted according to a similar manner to that of Preparation 8-5) to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.27 g.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 27 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and pivaloyl chloride, the title compound was obtained as a white solid (87%), mp 181.5°-2.5° C.; MS(CI): 389 (M+H); NMR (300 MHz,DMSO-d6): 1.05(s, 9H), 1.37-1.66(m, 4H), 2.24(m, 2H), 2.45(s, 2H), 2.97(m, 2H), 3.31(s, 2H), 3.56(m, 1H), 4.30(s, 1H), 6.91(m, 4H), 7.06(d, 1H, J=8.1 Hz), 7.17-7.27(m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:29])[N:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)[CH3:17])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([N:41]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:36][CH:35]=[CH:34]2.O.[C:57]([OH:61])(=[O:60])[CH:58]=O>>[C:52]([O:51][C:49]([N:41]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][CH:58]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:16]([CH3:17])[C:15]([NH:14][C:5]4[CH:6]=[CH:7][C:8]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[C:3]([C:1]#[N:2])[CH:4]=4)=[O:29])=[CH:21][CH:22]=3)[C:57]([OH:61])=[O:60])=[CH:40][CH:39]=2)[CH:34]=[CH:35][N:36]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(B(O)O)cc2)cc1C#N
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1C#N
Yield: 88 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 25C (277 mg, 0.67 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 25D (460 mg, 88%) as a yellow solid. MS (ESI) m/z 787.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:10])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1cc(Cl)ccc1NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=NNc1ccc(Cl)cc1C
Temperature: 35 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of 0.55 g (2.85 mmol) of (4-chloro-2-methyl-phenyl)-hydrazine in acetic acid (5 ml), was added 0.34 g (2.91 mmol) of ethyl pyruvate. The mixture was stirred 2 hours at 35° C., poured onto an aqueous solution of sat. NaHCO3 and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo, to afford 0.702 g (97%) of 2-[(4-chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester as a light orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([NH2:36])[CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]2)=[CH:30][C:31]=1[NH:36][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Reactant: COc1ccccc1CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1CCCCC(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Reaction time: 12 h
Yield: 49.9 %

Procedure:
A 25-mL RB-flask was charged with 5-(2-methoxyphenyl)pentanoic acid (53.0 mg, 0.250 mmol), tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (59.0 mg, 0.200 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.400 mmol, 62.0 mg), 4-dimethylaminopyridine (10 mg) in DMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL) The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, hexanes:EtOAc 6:1) to afford tert-butyl 4-(4-fluoro-3-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate (48.4 mg, 50.0%): 1H NMR (400 MHz, CDCl3) δ 8.36-8.13 (m, 1H), 7.39 (s, 1H), 7.26-7.06 (m, 2H), 7.06-6.92 (m, 1H), 6.92-6.75 (m, 3H), 4.41-4.02 (m, 2H), 3.80 (s, 3H), 2.90-2.70 (m, 2H), 2.70-2.63 (m, 2H), 2.63-2.51 (m, 1H), 2.49-2.32 (m, 2H), 1.87-1.72 (m, 4H), 1.72-1.63 (m, 2H), 1.63-1.52 (m, 2H), 1.48 (s, 9H).