Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C(=O)C.[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:18]=1[C:24]([F:27])([F:26])[F:25]>O>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:18]=1[C:24]([F:27])([F:26])[F:25]
Reactant: OC1CCCCC1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1c(Br)cccc1OC1CCCCC1
Temperature: 100 °C

Procedure:
Cyclohexanol (214 mg) was added to N,N-dimethylacetamide (10 mL), and sodium hydride (60% in mineral oil, 86 mg) was added. The solution was mixed at room temperature for 15 minutes after which time 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (400 mg) was added. The solution was then heated at 100° C. for 1 hour. The solution was cooled, added to water, and extracted with diethyl ether. The extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on silica gel using 5% ethyl acetate in hexanes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:27]([CH3:38])[CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C@@H:27]([CH3:38])[CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c1C#N
Temperature: 85 °C
Yield: 89.7 %

Procedure:
To a 250 mL round-bottom flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.821 g, 4.87 mmol) and tert-butyl (S)-4-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate (1.40 g, 3.75 mmol) in DMSO (15 mL). Triethylamine (2.1 mL, 15 mmol) was added to the mixture, which was then heated to 85° C. for 2 hours. After cooling, the mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, 20-100% EtOAc/heptane gradient). The product-containing fractions were combined and then concentrated in vacuo to give the title compound as light-yellow oil (1.7 g, 90%). ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH2:31])[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:14]([C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[O:15])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: NCCN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCN2CCOCC2)(c2ccccc2)CC1

Procedure:
Prepare by the method of Example 20.9 using 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (7 mmol) and 2-morpholino-ethylamine (7 mmol) to give the title compound: Rf =0.49 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:25])=[C:18]([N+:22]([O-])=O)[C:19]=3[CH3:21])[C:14](=[O:26])[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12]2)=[C:4]([CH3:32])[CH:3]=1>[Fe].C(O)(=O)C>[NH2:22][C:18]1[C:19]([CH3:21])=[C:20]2[C:15]([C:14](=[O:26])[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12][N:11]2[C:5]2[CH:6]=[C:7]([NH2:8])[C:2]([F:1])=[CH:3][C:4]=2[CH3:32])=[CH:16][C:17]=1[F:25]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2C)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(N)c(F)cc2C)c2c(C)c(N)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
Acetic acid (10 ml) and iron powder (1.6 g) were added to ethyl 1-(4-fluoro-2-methyl-5-nitrophenyl)-6-fluoro-8-methyl-7-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.1 g), and the mixture was stirred overnight at 90° C. The catalyst in the reaction mixture was removed by filtration through Celite, and the solvent in the residue was distilled off. The resultant residue was purified by column chromatography on silica gel (chloroform:methanol 20:1) to obtain the title compound (230 mg) as a yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH:6]=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13]>[Ni].[Pd]>[CH3:20][O:19][C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:16]=1[O:17][CH3:18])[CH2:6][CH:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13]
Reactant: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1OC
Agent: [Ni]
Agent: [Pd]
Product: COc1cc(CC2NC(=O)NC2=O)cc(OC)c1OC

Procedure:
boiling an aqueous solution of glycine and urea in a molar ratio of 1:1.8 to 1:5 to form hydantoic acid as an intermediate, and directly cyclizing the hydantoic acid intermediate by adding to the solution concentrated sulfuric acid in a molar ratio of 1:0.3 to 1:1 relative to the glycine to form hydantoin of the Formula (I) as a precipitate and a mother liquor: ##STR8## and separating the precipitate of hydantoin from the mother liquor; (b) condensing the hydantoin formed during step (a) with an aromatic aldehyde of the Formula (II) ##STR9## in an aqueous solution in the presence of ethanolamine or morpholine to obtain a 5-arylidene-methyl-hydantoin of the Formula (III) ##STR10## (c) quantitatively reducing the compound of the Formula (III) prepared in step (b) in a diluted alkaline medium in the presence of a Raney nickel or palladium-on-charcoal catalyst, to obtain a 5-aryl-methyl-hydantoin of the Formula (IV) ##STR11## and; (d) subjecting the compound of the Formula (IV) to alkaline hydrolysis to yield the compound of the Formula (V).
Reaction SMILES: B(F)(F)F.CCOCC.C(O[C:14]1([O:31][C@@H:30]([C@@H:32]([C@@H:37]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[C@H:25]([NH:26][C:27](=[O:29])[CH3:28])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[CH2:19]1)[C:15](=[O:18])[O:16][CH3:17])(=O)C.[CH3:47][CH:48]([CH2:50][CH2:51][CH2:52][C@H:53]([C@@H:55]1[C@:72]2([CH3:73])[C@H:58]([C@H:59]3[C@H:69]([CH2:70][CH2:71]2)[C@:67]2([CH3:68])[C:62]([CH2:63][C@@H:64]([O:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][SH:81])[CH2:65][CH2:66]2)=[CH:61][CH2:60]3)[CH2:57][CH2:56]1)[CH3:54])[CH3:49]>C(Cl)(Cl)Cl>[C:22]([O:21][C@@H:20]1[C@@H:25]([NH:26][C:27](=[O:29])[CH3:28])[C@H:30]([C@@H:32]([C@@H:37]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:31][C:14]([S:81][CH2:80][CH2:79][CH2:78][CH2:77][CH2:76][CH2:75][O:74][C@H:64]2[CH2:65][CH2:66][C@@:67]3([CH3:68])[C:62](=[CH:61][CH2:60][C@@H:59]4[C@@H:69]3[CH2:70][CH2:71][C@@:72]3([CH3:73])[C@H:58]4[CH2:57][CH2:56][C@@H:55]3[C@H:53]([CH3:54])[CH2:52][CH2:51][CH2:50][CH:48]([CH3:47])[CH3:49])[CH2:63]2)([C:15](=[O:18])[O:16][CH3:17])[CH2:19]1)(=[O:24])[CH3:23]
Reactant: COC(=O)C1(OC(C)=O)C[C@H](OC(C)=O)[C@@H](NC(C)=O)[C@H]([C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)C[C@H](OC(C)=O)[C@@H](NC(C)=O)[C@H]([C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
Boron trifluoride etherate (700 μl, 5.5 mmol) is added to a solution of methyl 2,4,7,8,9-penta-O-acetyl-N-acetyl-D-neuraminate (1.01 g, 1.96 mmol) and 6-(5-cholesten-3β-yloxy)-hexane-1-thiol (0.98 g, 1.96 mmol) in dry chloroform (5 ml). The mixture is stirred under nitrogen for 5 hours at room temperature, and washed with aqueous sodium bicarbonate and water. The dried solution is concentrated to a residue which is put on a silica gel column and eluted with chloroform-ethyl ether-methanol (31:10:1). The β-anomer is isolated as a glass (400 mg), [α]D -38.5° (c 1.5, chloroform).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:20]=[N:21][C:22]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Cl)nn2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)nn2)cs1
Yield: 70 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(6-chloropyridazin-3-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 123-1 and 4-fluorophenylboric acid (292 mg) were dissolved in dioxane (6 mL) and aqueous sodium carbonate solution (2 mol/L, 3 mL), tetrakis(triphenylphosphine)palladium (80 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (400 mg) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(O[C:27](OCC)(OCC)[CH2:28][CH3:29])C>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:27]([CH2:28][CH3:29])=[N:23][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(CC)(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Product: CCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1

Procedure:
N-Cyclopropyl-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 40) (50 mg) in triethylorthopropionate (5 ml) was heated at 150° C. for 18 hours. The excess triethylorthopropionate was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-4′-(5-ethyl-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2ncc(C(=O)O)c(Cl)c2cc1OC
Yield: 116.4 %

Procedure:
4-chloro-6,7-dimethoxy-3-quinolinecarboxylic ethyl ester (ex RSL) (50 g) was suspended in ethanol (400 ml) and aqueous 2M sodium hydroxide (400 ml) was added with stirring, stirred for 24 hours. The reaction mixture was diluted with water (400 ml), cooled in an ice/water bath and brought to pH4 by carefully addition of concentrated hydrochloric acid. The resulting solid was filtered off, washed with water and dried in a vacuum oven at 50° C. To give 4-chloro-6,7-dimethoxy-3-quinolinecarboxylic acid (52.7 g, 98.7%).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:16]=1.[OH-].[Na+]>>[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1
Reactant: CCOC(=O)c1cncc(OC[C@@H]2CCCN2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC[C@H]1COc1cncc(C(=O)O)c1

Procedure:
A sample of the compound from Example 100 above is hydrolyzed with 1N NaOH according to standard methods. The product is purified by chromatography on silica gel and converted into the title compound by treatment with HCl in ether according to Example 14c.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1.[C:32]([O:36][C:37](=[O:46])[CH2:38][O:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:35])([CH3:34])[CH3:33].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:32]([O:36][C:37]([CH2:38][O:39][CH:40]1[CH2:41][CH2:42][N:43]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:44][CH2:45]1)=[O:46])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (13.27 mmol) sodium triacetoxyborohydride were added batchwise to a mixture of 2.58 g (11.06 mmol) benzyl 4-oxo-piperidine-1-carboxylate and 2.80 g (12.36 mmol) tert-butyl(piperidin-4-yloxy)-acetate in 30 mL THF and the reaction mixture was stirred overnight at RT. It was combined with 50 mL 1 M NaOH, the mixture was stirred for 1 h at RT, combined with EtOAc, the organic phase was separated off and dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by chromatography (Alox, DCM/MeOH 100:1).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].CN1CCOCC1.[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](Cl)=[O:48].C(O)C(N)(CO)CO>ClCCl>[OH:7][NH:8][C:9]([C:11]1([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][N:14]([C:47]([C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[F:44])=[O:48])[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(NOC1CCCCO1)C1(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccccc1F)N1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CC1
Reaction time: 2 h

Procedure:
To a solution of N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 [L) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH2:23][CH2:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH2:23][CH2:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1=Cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C=C(C(=O)O)CCC3)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.8 %

Procedure:
To methyl 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1245 mg, 3.10 mmol) dissolved in a mixed solvent of methanol (10 ml) and THF (10 ml) was added a 1N aqueous solution of sodium hydroxide (9.3 ml), and the resulting mixture was stirred at room temperature for 23 hours. The reaction mixture was mixed with 1 N hydrochloric acid (9.3 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water, and was dried under reduced pressure to obtain 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (1150 mg, 2.97 mmol, 96%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH:11]2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=3[CH:42]=2)=[CH:6][CH:5]=1)(O)=[O:2].[O:43]([C@@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][N:33]1[C:32]2[CH:42]=[C:28]([CH2:27][O:26][CH:11]3[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([C:1]([N:52]5[CH2:53][CH2:54][CH:50]([O:43][C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)[CH2:51]5)=[O:2])=[CH:9][CH:8]=4)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:12]3)[CH:29]=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)O)cc3)cc21
Reactant: c1ccc(O[C@@H]2CCNC2)cc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)N4CCC(Oc5ccccc5)C4)cc3)cc21

Procedure:
Analogously to Example 255b, 0.207 g of benzyl 4-(4-carboxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 243b) and 0.0832 g of (R)-3-phenoxypyrrolidine are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (EtOAc); Rt=5.33.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([OH:22])=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2.[H-].[Na+].C(OCC)(=O)C>CN1CCCC1=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([O:22][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccc(SC)cc3)ccc2c1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Add 4-fluoro-benzaldehyde (2.20 mL, 20.3 mmol) to a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (3.0 g, 10.1 mmol) and 60% sodium hydride (400 mg, 10.1 mmol) in 1-methyl-2-pyrolidinone (30 mL). Heat the reaction to 170° C. for 70 minutes, then cool to ambient temperature. Dilute the reaction with ethyl acetate (200 mL) and wash twice with 5% aqueous lithium chloride (500 mL), brine, 1N aqueous hydrochloric acid, dry with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/hexane mixtures to give 1.29 g of 4-[6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-yloxy]-benzaldehyde (32%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:10][CH:11]([CH3:15])[C:12](Cl)=[O:13]>N1C=CC=CC=1.O1CCCC1>[CH2:1]([O:9][C:12](=[O:13])[CH:11]([Cl:10])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: CC(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)C(C)Cl
Reaction time: 24 h

Procedure:
Racemic 2-chloropropionate octyl ester was prepared by reacting 130 gm (1.0 mol) of n-octanol with 127 gm (1.0 mol) of 2-chloropropionyl chloride in 240 ml of pyridine and 50 ml of tetrahydrofuran. The reaction was carried out for 24 hours after which the solution was washed with 100 ml of 1 N HCl and 100 ml of distilled water. 500 ml of ether was added, then washed with 3×500 ml of saturated solution of NaHCO3 and 500 ml of saturated solution of NaCl. The organic phase was finally dried over MgSO4. The total weight of 2-chloropropionate octyl ester obtained was 248 gm.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].O>S(=O)(=O)(O)O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N+:1]([O-:4])=[O:2])=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cccc(-c2ccccc2F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccc(-c2cc([N+](=O)[O-])ccc2F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 110.6 %

Procedure:
A solution of 420 mg potassium nitrate in 5 ml concentrated sulfuric acid was added dropwise to a stirred solution of 1 g 3-(2-fluorophenyl)-benzoic acid in 25 ml concentrated sulfuric acid at 0° C. The mixture was stirred at 0° C. for 20 minutes and then poured into iced water. The resulting precipitate was extracted into ethyl acetate and the extracts were combined, dried and evaporated, yielding the product as a white solid (1.2 g, 100% yield), m.p. 272°-274° C. after recrystallization from ethyl acetate. NMR (DMSO-d6, 250 MHz): 8.4 (m, 2H), 8.16 (d, 1H, J=2 Hz), 8.05 (multiplets, 1H), 7.9 (multiplets, 1H), 7.66 (m, 2H), 3.4 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[O:10])[CH:5]=[CH:4][C:3]=1Br.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:27](#[N:29])[CH3:28]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[O:10])[CH:5]=[CH:4][C:3]=1[C:6]1[N:7]([CH3:2])[N:29]=[C:27]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:28]=1
Reactant: CC#N
Reactant: Nc1nc(NC(=O)c2ccccc2F)ccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1-c1ccc(NC(=O)c2ccccc2F)nc1N
Temperature: 85 °C
Yield: 4 %

Procedure:
A mixture of N-(6-amino-5-bromo(2-pyridyl))(2-fluorophenyl)carboxamide (61) (16 mg, 0.05 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (4 mg, 10% mol) and K3PO4 (11 mg, 0.05 mmol) in 0.5 ml ACN, 0.5 ml dioxane, 0.2 ml H2O was bubbled with argon before heated at 85° C. for 4 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated to dryness. Flash silica gel column purification (0-90% B, A: hexane; B: 50% EA in hexane) furnished 2.2 mg crude desired product as yellow solid which was re-purified on prep HPLC to give 0.8 mg N-[6-amino-5-(1-methyl-3-phenylpyrazol-5-yl)(2-pyridyl)](2-fluorophenyl)carboxamide (69) as off-white solid. (yield: 4%, purity>90%).