Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:17](OC)=[O:18])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:3])[CH3:2].[BH4-].[Li+]>C1COCC1.CCOCC>[OH:18][CH2:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:8]=1
Reactant: COC(=O)c1cc(CCNC(C)=O)cc2ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)NCCc1cc(CO)c2ccccc2c1

Procedure:
Methyl 3-[2-(acetylamino)ethyl]-naphthalenecarboxylate (1 eq.) from the previous step was taken up in THF (0.18 M). To this solution was then added lithium borohydride (12 eq.) and the resulting solution was vigorously stirred at 50° C. for 5 h. The reaction mixture thus obtained was diluted further with ether and carefully quenched with 1 N aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:14][F:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH2:5][CH:4]([NH:3][O:2][CH3:1])[CH2:14][F:15]
Reactant: CON=C(CF)Cc1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(CF)Cc1ccc(Cl)cc1Cl
Temperature: 23 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-(2,4-dichloro-phenyl)-3-fluoro-propan-2-one O-methyl-oxime (0.36 g; 1.4 mmol) in acetic acid (2.8 ml) was added portionwise sodium cyanoborohydride 95% (0.18 g; 2.8 mmol). The mixture was stirred for 18 hours at 23° C. Most of acetic acid was removed under reduced pressure. The residue was poured in water (10 ml) and was extracted with dichloromethane (3×10 ml). Combined organics were dried over sodium sulfate and solvent was removed in vacuo. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 95:5) to afford 0.27 g (75% of theory) of N-[2-(2,4-dichlorophenyl)-1-fluoromethyl-ethyl]-O-methyl-hydroxylamine as a yellow oil.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3]CC)=[O:2].Cl.C(O)(=O)C>O>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCCC1CCCC1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCCC1CCCC1=O
Reaction time: 0.5 h

Procedure:
A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately 1/2 hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.
Reaction SMILES: O1CCOCC1.O.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[F:16][C:17]1[C:18]([F:29])=[CH:19][C:20]2[NH:25]C(=O)[O:23][C:22](=O)[C:21]=2[CH:28]=1>C(N(CC)CC)C>[NH2:25][C:20]1[CH:19]=[C:18]([F:29])[C:17]([F:16])=[CH:28][C:21]=1[C:22]([NH:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])=[O:23]
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)o1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)c1cc(F)c(F)cc1N
Temperature: 70 °C
Yield: 71.1 %

Procedure:
Into a mixed liquor of 280 ml of dioxane with 70 ml of water were dissolved 19 g of glycine ethyl ester hydrochloride, and 21.7 g of 6,7-difluoro-2H-3,1-benzoxazine-2,4(1H)-dione were added and 14.7 g of triethylamine were added dropwise at room temperature under stirring. After stirring further for 30 minutes, the mixture was heated to 70° C. and stirred for 1,5 hours. Dioxane was distilled off, 150 ml of water were added, then the crystals deposited were collected by filtration, washed with water, and dried. They were recrystallized from ethyl acetate to obtain 20 g of title compound. m.p. 147° C.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[S:58]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59]1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:63]([C:60]3[CH:61]=[CH:62][S:58][CH:59]=3)(=[O:65])=[O:64])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccsc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-thiophenesulfonyl chloride (47 mg, 0.256 mmol), the title compound was obtained as a white solid (68 mg, 56% yield). MS (ESI): 490.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1ON=C(CC2C=CC=CC=2)C=1)CCCCCCCCCCC.C([Li])CCC.[C:54](=[O:56])=[O:55].C(C1ON=C(C(C2C=CC=CC=2)C(O)=O)C=1)CCCCCCCCCCC>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:54]([OH:56])=[O:55])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Reactant: O=C=O
Agent: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)no1
Agent: CCCCCCCCCCCCc1cc(Cc2ccccc2)no1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)on1
Temperature: -78 °C

Procedure:
To a cold (-78° C.), stirred suspension of 3-dodecyl-5-(phenylmethyl)isoxazole and 5-dodecyl-3-(phenylmethyl)isoxazole (1.64 g, 0.00500 mol) in dry tetrahydrofuran (150 mL) was added dropwise over 3 minutes a 2.06M solution (5.0 mL, 0.010 mol) of n-butyl lithium in hexanes, and the mixture was stirred for 80 minutes under nitrogen. The resulting orange solution was poured into freshly crushed dry ice (~300 g), the mixture was covered with parafilm with a small hole to allow CO2 (g) to escape, and allowed to warm to room temperature over 3 hours. The residue was partitioned between ether and 0.1M HCl. The organic layer was washed (saturated NaCl), dried (MgSO4), and rotoevaporated to a yellow oil. The oil was dissolved in petroleum ether (50 mL). A solid crystallized. It was filtered off and dried in vacuo to give a white solid containing the title compound and 5-dodecyl-α-phenyl-3-isoxazole acetic acid; yield 1.70 g (91 %); mp 88°-97° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH:14]=[CH:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[CH:9]([CH2:10][CH2:11]2)[CH2:8][C:7](=[O:21])[CH2:6][CH2:5]1.O.[C:24]1(C)C(S(O)(=O)=O)=CC=C[CH:29]=1.C(OCC)(OCC)OCC>C(O)C>[CH2:24]([O:21][C:7]1[CH2:6][CH2:5][C@@:4]2([CH3:22])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:3]2[C@H:2]([OH:1])[CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:20])[CH:8]=1)[CH3:29]
Reactant: C[C@]12CCC(=O)CC1CC[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)C(=O)C=C[C@@H]12
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: CCOC1=CC2=CC[C@@H]3[C@H]([C@H](O)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Temperature: 5 °C

Procedure:
11α-Hydroxyandrostendione (429.5 g) and toluene sulfonic acid hydrate (7.1) were charged to a reaction flask under nitrogen. Ethanol (2.58 L) was added to the reactor, and the resulting solution cooled to 5° C. Triethyl orthoformate (334.5 g) was added to the solution over a 15 minute period at 0° to 15° C. After the triethyl orthoformate addition was complete the reaction mixture was warmed to 40° C. and reacted at that temperature for 2 hours, after which the temperature was increased to reflux and reaction continued under reflux for an additional 3 hours. The reaction mixture was cooled under vacuum and the solvent removed under vacuum to yield 3-ethoxy-11α-hydroxy-androsta-3,5-diene-17-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15](N)[N:16]=[C:4]2[N:3]=1.N([O-])=O.[Na+].C(OCC)(=O)C.C(Cl)[Cl:29]>Cl.O.C(Cl)Cl.C(OCC)(=O)C>[Cl:29][C:15]1[N:16]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]2[N:14]=1
Reactant: Cc1cc(-c2ccccc2)n2nc(N)nc2n1
Reactant: ClCCl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2ccccc2)n2nc(Cl)nc2n1
Reaction time: 0.17 h

Procedure:
To 2.0 g (8.9 mmol) of 5-methyl-7-phenyl-1,2,4triazolo[1,5-a]pyrimidin-2-amine stirring in 25 ml of concentrated hydrochloric acid, 1.2 g (17.4 mmol) of sodium nitrite dissolved in 4.0 ml of water was added dropwise at ambient temperature. After the addition, the reaction suspension was warmed at about 60° for 15 minutes followed by stirring another 10 minutes without heat. Ethyl acetate (150 ml) and excess water were added. The ethyl acetate layer was separated whereby a certain amount of insoluble material present was ignored and the extract washed with water (2X), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid residue. Silica gel column chromatography (methylene chloride followed by 10:1 methylene chloride/ethyl acetate) afforded the title compound, m.p. 179°-181° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[NH4+]>COCCOC.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C[Sn](C)(C)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Microencapsulated Pd(OAc)2 (prepared as described in Example 1, 0.25 g, 2 mol %, based on palladium content) was added to a solution of 4-bromo nitrobenzene (1 mmol), trimethylphenyltin (1.5 mmol) and ammonium acetate (3 mmol) in 1,2-dimethoxyethane (5 mL) and stirred at 90° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with ether (50 mL) and filtered through a polyethylene frit (20-micron porosity). The filtrate was washed with water (2×20 mL), brine (20 mL) and dried (MgSO4). Evaporation under reduced pressure and purification by column chromatography gave 4-nitrobiphenyl, 90%: IR, 1H NMR and 13C NMR identical with sample obtained from the Suzuki reaction in Example 5.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4]C)[OH:2].[CH3:10][Si:11]([CH3:14])([CH3:13])Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:10][Si:11]([CH3:14])([CH3:13])[O:2][CH2:1][C:3]([CH2:8][O:9][Si:11]([CH3:14])([CH3:13])[CH3:10])([CH3:4])[CH2:6][O:7][Si:11]([CH3:14])([CH3:13])[CH3:10]
Reactant: CCC(CO)(CO)CO
Reactant: C[Si](C)(C)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CC(CO[Si](C)(C)C)(CO[Si](C)(C)C)CO[Si](C)(C)C

Procedure:
1 mole of trimethylol propane, 4 moles of trimethylchlorosilane and 0.003 moles of triethylbenzyl ammonium chloride were reacted at the reflux temperature (54°-104° C.) as in Example 1 and then worked up by distillation.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CS(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=2)=[CH:20][CH:21]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCCOCc1ccccc1
Temperature: 90 °C

Procedure:
31.6 g of 2-benzyloxyethyl-2-(4-hydroxyphenoxy)propionate were dissolved in 100 ml of dimethylsulfoxide, 15.2 g of potassium carbonate were added thereto, then the mixture was heated at 90° C. for one hour with stirring. 20.0 g of 2-chloro-5-trifluoromethylpyridine were added dropwise to this solution which was then maintained at 90° C. for a further two hours. After cooling the reaction solution to room temperature, it was poured into ice-water, then extracted with ether. The ether layer was dried and filtered, and the ether was distillated off. The end product of 2-benzyloxyethyl-2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]propionate (a compound also produced in Example 20) was obtained in a yield of 41.0 g (m.p. 44°-47° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][CH:40]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:32]=[C:31]([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)[CH:30]=[CH:29][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[C:15]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:11].Cl>CO.O1CCOCC1>[CH3:10][OH:11].[NH2:21][CH2:20][C:15]1[C:14]([CH2:13][NH:12][C:10](=[O:11])[C:9]2[CH:29]=[CH:30][C:31]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:32][C:8]=2[NH:7][CH2:6][CH2:5][C:4]2[CH:38]=[CH:39][CH:40]=[C:2]([F:1])[CH:3]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(-c2cn[nH]c2)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ncccc1CNC(=O)c1ccc(-c2cn[nH]c2)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 179.7 %

Procedure:
To a solution of tert-butyl (3-((2-(3-fluorophenethylamino)-6-(1H-pyrazol-4-yl)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (737 mg, 1.27 mmol) in methanol (6 mL) at 0° C. was added a solution of 4M HCl in 1,4-dioxane (3 mL). The mixture was warmed to room temperature and stirred for 2 hrs. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave N-((2-(aminomethyl)pyridin-3-yl)methyl)-2-(3-fluorophenethylamino)-6-(1H-pyrazol-4-yl)nicotinamide compound with methanol (1:1) as a pale yellow solid (545 mg, 89%). LRMS (M+H+) m/z 446.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH:27]3[CH2:32][O:31]C(C)(C)[O:29][CH2:28]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[Na+].[I-].CO>CC#N>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH:27]([CH2:32][OH:31])[CH2:28][OH:29])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C3COC(C)(C)OC3)no2)cc1OCC
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C(CO)CO)no2)cc1OCC
Yield: 60.1 %

Procedure:
To a solution of the product of Step A (0.0346 g; 0.0743 mmol) and NaI (0.033 g; 0.22 mmol) in anhydrous CH3CN (1 ml) Me3SiCl (0.1 ml) was added at room temperature under N2. After stirring for 30 min at room temperature MeOH (2 ml) was added and the resulting mixture was evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc (5 ml) and 1% NaHCO3 (5 ml). The precipitate formed was filtered off, washed with H2O (5 ml), fresh EtOAc (5 ml) and dried to give the title compound (0.019 g; 61%) as creamy solid. 1H-NMR (DMSO-d6) 1.28-1.41 (m, 6H): 3.2-3.4 (m, 2H+H2O); 3.5-4.02 (m, 7H); 4.07-4.18 (m, 4H); 4.6 (broad s, 2H); 6.52 (d, 1H, J=6 Hz); 7.06-7.19 (m, 3H); 7.58 (d, 1H, J=3 Hz); 7.72 (dd, 1H, J=9 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[N:3]=[N:2]1.O>C(O)(=O)C.[Pd].[C]>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[N:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]nn2)cc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2c[nH]nn2)cc1
Yield: 71 %

Procedure:
A 5 g portion of 4-triazolylnitrobenzene dissolved in 20 ml of acetic acid was mixed with 0.3 g of 10% Pd-carbon and subjected to hydrogenation under a hydrogen pressure of 3 kg/cm2. The reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with sodium bicarbonate aqueous solution and water in that order and dried, and the solvent was removed by evaporation under a reduced pressure to obtain 3 g of 4-triazolylaniline with a yield of 71%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([CH3:36])[CH:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([CH3:36])[CH:28]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: Cc1cc(N2CCC(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3)CC2)ccc1C(=O)O

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-2-methyl-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-2-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:20])=O>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1F
Product: O=C(Cl)c1ccc(C(F)(F)C(F)(F)F)cc1F
Temperature: 60 °C
Reaction time: 22 h
Yield: 93.4 %

Procedure:
To 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (1 g, 3.87 mmol) was added thionyl chloride (3.67 mL, 50.36 mmol) and the reaction was stirred at 60° C. for 22 hours. Excess thionyl chloride was removed in vacuo to yield 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl chloride (1 g, 93%) as a viscous yellow liquid.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:3].C(N(CC)CC)C.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>O1CCCC1>[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([S:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:29])=[O:28])[CH2:6][CH2:5]1)=[O:3]
Reactant: NC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a suspension of 4-aminocarbonylpiperidine (12.8 g, 100 mmol) in dry tetrahydrofuran (250 μL) containing triethylamine (20.2 g, 200 mmol) stirring at room temperature under argon, was added 1-naphthalenesulfonyl chloride (25 g, 110 mmol). After 16 h the solvent was evaporated under vacuum, and a solution of 25% methanol in diethyl ether (250 mL) was added to the residue. The resulting mixture was stirred for 2 h before the solid was filtered. The solid was washed with diethyl ether (50 mL twice), then water (50 mL twice), followed by diethyl ether (50 mL twice) again before drying under vacuum. This provided 4-aminocarbonyl-1-(1-naphthylsulfonyl)piperidine (27.9 g, 88% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(F)cc4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(F)cc4n3)cc21

Procedure:
2-(7-Fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.Br[CH2:38][C:39]#[N:40]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:38][C:39]#[N:40])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: N#CCBr
Product: N#CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
{(3R,4R)-4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-3-fluoropiperidin-1-yl}acetonitrile was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 381) and bromoacetonitrile following General Procedure S.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH3:25][C:26](=O)[CH2:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[C:4]3[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[N:2]=[C:26]([CH3:25])[C:27]=2[C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCCCCC(=O)CC(C)=O
Agent: Cl
Product: CCCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Reference Example 6, 2-amino-3',4',4,5-tetramethoxybenzophenone hydrochloride was reacted with 2,4-nonanedione to give 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-methylquinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 123°-125° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])(=O)C.[NH4+].[H][H]>[Pd].C(O)(=O)C>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [H][H]
Reactant: COc1cccc2c(Cl)c(C)c(C)nc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cccc2cc(C)c(C)nc12
Yield: 127.1 %

Procedure:
1.23 g of 2,3-dimethyl-4-chloro-8-methoxy-quinoline, 1 g of ammonium acetate, 20 ml of acetic acid and 1.2 g of palladium-on-charcoal (5%) are introduced into a Parr flask. The mixture is subjected to a hydrogen pressure of 50 psi for 4 h. The reaction medium is filtered and neutralized with 75 ml of 1 N sodium hydroxide. This mixture is extracted with ethyl acetate (2×75 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. 1.32 g (yield: 77%) of 2,3-dimethyl-8-methoxyquinoline are obtained—m.p.: 138-139° C.