Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:4])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:7]1[CH2:8][CH2:9][CH2:10][C:5]([C:2](=[O:4])[CH3:3])([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:6]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)C1(Cc2ccc(Cl)cc2)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A suspension of 3-Acetyl-3-(4-Chlorobenzyl)-piperidine hydrochloride (0.7 g, 2.43 mmol) in acetonitrile (20 mL) was treated with solid sodium bicarbonate (200 mg, 4.8 mmol) and benzyl chloride (369 mg, 2.9 mol) and heated to reflux for 2 hours. The reaction was then cooled to room temperature, poured into saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 2% methanol/chloroform to give 492 mg of the title compound. 1H NMR CDCl3 δ 7.40-7.25 (m, 5H), 7.22 (d,=8.5 Hz, 2H), 6.90 (d,=8.5 Hz, 2H), 3.45 (m, 2H), 3.00 (m, 1H), 2.80-2.50 (m, 3H), 2.20-1.90 (m, 4H), 2.00 (s, 3H), 1.60-1.50 (m, 2H), 1.30-1.10 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])[CH:19]=1.[CH3:34][NH:35][CH3:36].Cl.CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O>[CH3:34][N:35]([CH3:36])[C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:33])([C:25]([F:27])([F:28])[F:26])[C:29]([F:31])([F:30])[F:32])[CH:19]=3)[N:4]=2)=[CH:15][CH:14]=1
Reactant: CNC
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: Cc1oc(-c2ccc(C(=O)N(C)C)cc2)nc1COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To 25 mg (0.05 mmol) of 4-{5-methyl-4-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxymethyl]-oxazol-2-yl}-benzoic acid (example 81) in 1.5 ml of CH2Cl2 were added 8.6 mg (0.11 mol) of dimethylamine.HCl and 23 μl (0.11 mmol) of NMM. The solution was cooled to 0° C. and 13.1 mg (0.07 mmol, 1.3 eq) of EDCI and 1.4 mg (0.01 mmol) of HOBT were added. The mixture was stirred at room temperature overnight. Water was added and the inorganic phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography with CH2Cl2/MeOH 98:2 gave 22 mg (83%) N,N-dimethyl-4-{5-methyl-4-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxymethyl]-oxazol-2-yl}-benzamide as a colorless oil, MS: 501 (M−H)−.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=1)(=[O:3])[CH3:2].CC1C=CC(S(O[CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(O)cc(C)c1-c1cccc(CO)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Temperature: 90 °C
Reaction time: 21 h
Yield: 60.1 %

Procedure:
To a solution of [4-hydroxy-3′-(hydroxymethyl)-6-methylbiphenyl-2-yl]methyl acetate (1.02 g, 3.56 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (1.25 g, 4.27 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.640 g, 4.32 mmol), and the mixture was stirred at 90° C. for 21 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0) to give the title compound (0.87 g, yield 60%) as a colorless oil.
Reaction SMILES: [ClH:1].[OH:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([OH:11])[CH2:5][C:4]1([CH3:13])[CH3:12]>C(O)(C)C>[Cl-:1].[OH:2][NH+:3]1[C:8]([CH3:9])([CH3:10])[CH2:7][CH:6]([OH:11])[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CC(C)O
Product: CC1(C)CC(O)CC(C)(C)[NH+]1O
Product: [Cl-]
Temperature: 20 °C

Procedure:
67 mL of isopropanol is cooled to 0° C. and saturated with HCl gas. This solution is added dropwise to a mechanically stirred solution of 50 g (0.29 mol) 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine in 130 mL of isopropanol, maintaining a reaction temperature of about 20° C. by occasionally cooling with an ice bath. The HCl salt is vacuum filtered and washed with isopropanol, giving a pale yellow solid. 5.0 g of this crude product is recrystallized from 100 mL isopropanol affording 3 g of a white crystalline solid, mp>260° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si](C(C)C)(C(C)C)C(C)C)[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:11]=[C:12]([CH3:27])[CH:13]=[C:14]([OH:16])[CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(O)cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of Intermediate 54d (300 mg, 0.38 mmol) in THF (4 mL) was added a solution of tetrabutylammonium fluoride in THF (1M, 0.49 mL, 0.49 mmol). Stirred at RT for 0.5 h, then diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the impure product as a solid (210 mg). This was further purified by HPLC (XBridge C18 column, 40-85% MeCN in H2O, 0.1% NH4OH) to give the title compound (73 mg, 30%). LCMS (Method 5): Rt 4.44 min, m/z 635.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.81-1.98 (2H, m), 1.99-2.18 (2H, m), 2.27 (3H, s), 3.10-3.18 (4H, m), 4.79-4.88 (1H, m), 5.55 (1H, t, J=4.3 Hz), 6.31 (1H, s), 6.59-6.64 (1H, m), 6.67-6.71 (1H, m), 6.71-6.74 (1H, m), 7.09-7.19 (2H, m), 7.25-7.41 (4H, m), 7.58-7.65 (2H, m), 8.06 (1H, br s), 9.65 (1H, br s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[N:7](C(OCC1C=CC=CC=1)=O)[CH2:6][CH2:5]2.C(O)C.C1CCCCC=1>[Pd].O>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[NH:7][CH:6]=[CH:5]2
Reactant: O=C(OCc1ccccc1)N1CCc2cc(O)c(O)cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: O
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
11.4 g of benzyl 5,6-dihydroxy-2,3-dihydroindole-1-carboxylate, 60 ml of ethanol, 5.7 g of 10% palladium-on-charcoal, 5.7 ml of water and 23 ml of cyclohexene were mixed together, and the mixture was maintained at reflux for one hour.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:17][CH3:18])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:35](Cl)(=[O:37])[CH3:36]>CC(C)=O>[C:35]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:16](=[N:19][O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH2:17][CH3:18])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:11])(=[O:37])[CH3:36]
Reactant: CCC(=NOCc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=NOCc1ccc(Cl)cc1)c1cc(Cl)ccc1N(C(C)=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a mixture of N-{4-chloro-2-[1-(4-chlorobenzyloxyimino)propyl]phenyl}trifluoromethanesulfonamide (compound 11) (150 mg, 0.33 mmol) and K2CO3 (137 mg, 0.99 mmol) in acetone (5 mL) was added acetyl chloride (70 μL, 0.99 mmol), and the reaction allowed to stir at RT for 2 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in CHCl3 (20 mL), washed with H2O (15 mL) dried over MgSO4 and concentrated under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with EtOAc/PE, 1:19) to afford N-acetyl-N-{4-chloro-2-[1-(4-chlorobenzyloxyimino)propyl]phenyl}trifluoromethanesulfonamide 307 (156 mg, 95%), as a pale yellow solid. M.p. 64-66° C. 1H n.m.r. (400 MHz, CDCl3) δ 7.51, d, J=2.4 Hz, 1H; 7.42, dd, J=2.4 and 8.8 Hz, 1H, 7.30, m, 4H, 7.23, d, J=2.4 Hz, 1H, 5.12, m, 2H, 2.83, m, 1H, 2.67, m, 1H, 1.91, s, 3H, 1.18, t, J=7.6 Hz, 3H.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[N:6][NH:7][C:8]=1[CH:9]([O:12][CH3:13])[O:10][CH3:11].I[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[N:6][N:7]([CH3:20])[C:8]=1[CH:9]([O:12][CH3:13])[O:10][CH3:11]
Reactant: CI
Reactant: COC(OC)c1[nH]nc(-c2nccs2)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1c(Br)c(-c2nccs2)nn1C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
Under a nitrogen atmosphere, sodium hydride 60% in oil (0.236 g, 5.92 mmol) was added portionwise to a solution of 2-[4-bromo-5-(dimethoxymethyl)-1H-pyrazol-3-yl]-1,3-thiazole (8c) (900 mg, 2.96 mmol) in dry dimethylformamide (5 mL). After 10 minutes stirring, iodomethane (0.28 mL, 4.44 mmol) was added and the reaction mixture was stirred at room temperature for 40 minutes. Water (15 mL) was added and the mixture was extracted with ethyl acetate (2×15 mL). The organic layer was washed with brine (2×10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 100/0 to 95/5) to provide 2-[4-bromo-5-(dimethoxymethyl)-1-methyl-1H-pyrazol-3-yl]-1,3-thiazole (8d) (586 mg, 1.84 mmol, 62%) and the regioisomer 2-[4-bromo-3-(dimethoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,3-thiazole (199 mg, 0.62 mmol, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-bromoacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.[Br:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:21]([F:24])=[N:22][CH:23]=1>C(O)CC.O.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[Br:17][C:18]1[CH:19]=[C:20]([C@@H:25]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@H:26]([OH:12])[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=2)[C:21]([F:24])=[N:22][CH:23]=1
Reactant: CC(C)(C)OCl
Reactant: Fc1ncc(Br)cc1/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of tert-butyl carbamate (189 mg, 1.612 mmol) in propanol (7 mL) was added sodium hydroxide (54.1 mg, 1.352 mmol) in water (4 mL) followed by tert-butyl hypochlorite (172 mg, 1.586 mmol) (freshly prepared following an org synthesis prep). After 5 min the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (20.26 mg, 0.026 mmol) in propanol (4 mL). To this solution was added a solution of (E)-5-bromo-2-fluoro-3-(4-(trifluoromethyl)styryl)pyridine (180 mg, 0.520 mmol) in propanol (10 mL). To this solution was added potassium osmate dihydrate (7.66 mg, 0.021 mmol) in one portion. The reaction turned light orange and was allowed to stir at 0° C. overnight allowing the reaction to warm up to room temperature. The reaction was quenched with a 10% solution of sodium thiosulfate and stirred for 30 min. The reaction was then extracted with diethylether (3×). The combined organic extracts were combined washed with water, then brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by silica gel chromatography 25% EtOAc/75% Hexanes to 50%/50% EtOAc/Hexanes to afford tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethylcarbamate (250 mg, 0.530 mmol, 99% yield) as an inseparable mixture with its regioisomer. LC/Mass spec. (Analytical HPLC method 2): RT=2.78 min. Mass=503.07 (MNa)+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[N:8]=2)[CH:2]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:33]([CH3:37])[C:34](O)=[O:35])[CH:24]=[CH:25][C:26]=1[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:20][C:21]1[CH:22]=[C:23]([CH:33]([CH3:37])[C:34]([NH:14][CH2:13][C:12]2[C:7]([C:3]3[CH:2]=[C:1]([CH3:19])[CH:6]=[CH:5][CH:4]=3)=[N:8][C:9]([C:15]([F:16])([F:18])[F:17])=[CH:10][CH:11]=2)=[O:35])[CH:24]=[CH:25][C:26]=1[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Reaction time: 48 h
Yield: 0 %

Procedure:
To a stirred solution of (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (3.5 g, 13.143 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (5.415 g, 19.715 mmol) in tetrahydrofuran (102 mL) was added 1-hydroxybenzotriazolhydrate (1.834 mL, 13.143 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.213 g, 13.143 mmol) and N-ethyldiisopropylamine (6.676 mL, 39.429 mmol). The reaction mixture was stirred for 48 h. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: ethyl acetate/cyclohexane 2:1) to afford a white solid (2.65 mg, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1cc(Cl)ccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 150 °C
Reaction time: 72 h
Yield: 21.2 %

Procedure:
2-Amino-4-chloropyridine (2.00 g) was dissolved in N-methylpyrrolidone (31.8 ml), and then 4-nitrophenol (6.51 g) and N,N-diisopropylethylamine (15.9 ml) were added thereto under a nitrogen atmosphere, followed by stirring at 150° C. for 3 days. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide (32 ml). The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (764 mg, 21.2%) as a brown solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:34][C:35]([F:53])([F:52])[C:36]([C:39]1[CH:48]=[CH:47][C:46]2[CH2:45][C@H:44]([C:49]([OH:51])=O)[CH2:43][CH2:42][C:41]=2[N:40]=1)([CH3:38])[CH3:37].Cl.[NH2:55][C@@H:56]([C:58]1[C:63]([F:64])=[CH:62][C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([CH3:70])[CH:59]=1)[CH3:57]>CN1CCCC1=O>[F:64][C:63]1[CH:62]=[C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[C:60]([CH3:70])=[CH:59][C:58]=1[C@H:56]([NH:55][C:49]([CH:44]1[CH2:43][CH2:42][C:41]2[N:40]=[C:39]([C:36]([CH3:38])([CH3:37])[C:35]([F:53])([F:34])[F:52])[CH:48]=[CH:47][C:46]=2[CH2:45]1)=[O:51])[CH3:57]
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 45.9 %

Procedure:
A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19.8 mg, 0.0522 mmol) and N,N-diisopropylethylamine (28 uL, 0.16 mmol) in N-methylpyrrolidinone (300 uL) was added to (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (15 mg, 0.052 mmol) in a 2 mL vial, and the mixture stirred at room temperature for 1 h, before a solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (18 mg, 0.063 mmol) in N-methylpyrrolidinone (200 uL) was added. After 18 h the mixture was filtered and purified by reverse-phase HPLC (30-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (12.3 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.41 (app dd, J=7.7, 12.0 Hz, 1H), 7.53 (app dd, J=3.3, 8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.6 Hz, 1H), 5.09 (app hextet, J=7.3 Hz, 1H), 3.01 (s, 3H), 2.92-2.78 (m, 4H), 2.71-2.61 (m, 1H), 2.26 (s, 3H), 2.06-1.97 (m, 1H), 1.87-1.69 (m, 1H), 1.53 (s, 3H), 1.35 (d, J=7.1 Hz, 3H); m/z=516.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][N:25]([CH3:34])[C:26]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][N:25]([CH2:24][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)[C:26]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: CN(Cc1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1)C(=O)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cncc(-c2cnc3c(c2)CCCN3)c1)C(=O)C1CCOCC1
Reaction time: 16 h
Yield: 91 %

Procedure:
6-(5-{[Methyl-(tetrahydro-pyran-4-carbonyl)-amino]-methyl}-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (70 mg, 0.15 mmol) is dissolved in DCM (2.0 mL) and trifluoroacetic acid (0.5 mL) is added. The mixture is stirred for 16 hrs and the solvent is removed in vacuo. The residue is dissolved in MeOH and filtered through StratoSphere PL-HCO3 MP SPE cartridge, concentrated and dried to give 50 mg of crude tetrahydro-pyran-4-carboxylic acid methyl-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethyl]-amide which is used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1)=[O:20]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:36])[F:37])[CH2:25][CH2:26]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)N1CCN(CCc2ccccc2C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCN(CCc3ccccc3C(F)(F)F)CC2)cc1
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.256 g) in dimethylformamide (4 mL) under argon was treated with 55% sodium hydride (0.06 g), stirred for 15 minutes and then the above 1-(2-bromo-1-oxoethyl)-4-[2-[2-(trifluoromethyl)phenyl]ethyl]piperazine (0.5 g) in dimethylformamide (2 mL) was added. The mixture was stirred at room temperature for 23 hours and worked up as in Example 20. The crude product was purified by flash chromatography over silica gel (ethyl acetate-toluene; 1:1 increasing to 4:1) to afford 0.21 g of alpha-oxo-4-[2-oxo-2-[4-[2-[2-(trifiuoromethyl)phenyl]ethyl]-1-piperazinyl]ethoxy]-benzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15]>O>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: NCCO
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Product: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
Monoethanolamine (38 ml; 0.62 mol) was added to a suspension of 4-chloro-3-nitrobenzonitrile (51.6 g; 0.28 mol) in 270 ml water. The reaction mixture was refluxed for one hour at 100°-110° C. (oil bath). After cooling to room temperature, the orange precipitate was filtered, washed with water and air-dried to give 55.8 g 4-(2-hydroxyethylamino)-3-nitrobenzonitrile (m.p.=132°-134° C.). The yield was about 95%, with the overall yield for the reaction sequence, illustrated below, being about 81%. ##STR6##