Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH3:29])=[C:24]([OH:27])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39]Br)([CH3:33])([CH3:32])[CH3:31]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:28][CH3:29])[N:20]=[CH:19][N:18]=[C:17]2[NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:2]([Cl:1])[CH:3]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1OCCCNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
CsOH monohydrate (0.452 g, 2.69 mmol) was added to a mixture of 4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ol (1 g, 2.45 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (0.64 g, 2.69 mmol), tetrabutylammonium iodide (5 mg) and 4 Å molecular sieves (2 g) in DMF (10 mL) at room temp. Stir for 3 hours. The reaction mixture was then filtered through celite and washed with EtOAc (30 mL). The organic solution was washed with water (20 mL) and concentrated. FLC (10:1 EtOAc:Hexanes) provided desired product (1.02 g, 73.7%).
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1>[CH3:18][CH:17]1[CH2:16][CH2:15][N:14]([C:19](=[O:21])[CH3:20])[CH2:13][CH:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(=O)Cl
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(C)C(N(C)c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
To a stirred solution of the product from Method C (0.03 grams, 0.114 mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added (0.018 grams, 0.228 mmol) of acetylchloride and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO3). The organic layer was washed again with saturated NaHCO3, dried-over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane) affording 0.005 mg (15%) of the title compound as a colorless oil. LRMS: 288.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:4]1[C:3]2[O:9][CH2:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)cccc2N1
Yield: 86.8 %

Procedure:
2-Amino-6-fluorophenol (95MF2085) (0.256 g, 2.0 mmol), 2-chloroacetyl chloride (0.25 g, 2.2 mmol) and K2CO3 (0.583 g, 4.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF45) (0.29 g)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[F:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=O.N>>[F:13][C:14]1[C:15]([C:16]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: O=C(Cl)c1cccnc1F
Reactant: N#Cc1cccc(C(N)=NO)c1
Agent: N
Product: N#Cc1cccc(-c2noc(-c3cccnc3F)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 2-fluoronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 1 H), 7.95 (m, 1 H), 8.17 (m, 1 H), 8.17 (m, 1 H), 8.43 (m, 1 H), 8.6 (m, 1 H), 8.8 (m, 1 H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:43]([CH3:45])=[CH2:44])[C:7]([O:30][C@@H:31]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)C>[Pd].O1CCCC1>[C:1]([C:4]1[N:5]=[C:6]([CH:43]([CH3:45])[CH3:44])[C:7]([O:30][C@@H:31]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2]
Reactant: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a mixture of tert-butyl (3R)-3-{[5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-3-(prop-1-en-2-yl)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (300 mg), ethanol (6 mL), and tetrahydrofuran (6 mL) was added 10% palladium-supported carbon (50% wet product) (260 mg), followed by stirring at room temperature overnight under a hydrogen gas atmosphere (4 atm). The reaction mixture was filtered through celite, and then the solvent was evaporated under reduced pressure and washed with diisopropyl ether to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-isopropyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (253 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C=O)C>C1COCC1>[CH2:19]([O:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 27.5 %

Procedure:
In THF (200 ml) was dissolved 2,3-difluoro-6-nitrophenol (10.0 g, 57.1 mmol), followed by the addition of potassium carbonate (15.8 g, 114.2 mmol) and benzyl bromide (7.47 ml, 62.8 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 6 hours. DMF (100 ml) was added to the reaction mixture and the mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with ether (100 ml), washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 100 g), whereby from the hexane/ethyl acetate (4/1) eluate fractions, the title compound (4.17 g, 28%) was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[CH3:37][N:38]([CH3:45])[CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:42]3[CH2:43][CH2:44][CH:39]([N:38]([CH3:45])[CH3:37])[CH2:40][CH2:41]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(c2cc(-c3ccc(F)cc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 36.2 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (53.3 mg) was reacted with 4-(dimethylamino)piperidine (15.4 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (22.6 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (318 mg) in DMF (5 mL) was added sodium hydride (71 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 2-bromo-4′fluoroacetophenone (317 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a peach colored solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:8][C:9]1[C:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:13][C:12]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][CH:30]=[C:29]3Cl)=[CH:11][N:10]=1>CN(C=O)C>[Cl:8][C:9]1[C:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[CH:13][C:12]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][CH:30]=[C:29]3[O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][N:10]=1
Reactant: O=S(=O)(Nc1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl)c1ccc(F)cc1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccnc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
(Some starting materials may be obtained from Aldrich, St. Louis, Mo.) To a solution of 2-methoxyethanol (0.2 mL, 2 mmol) in DMF (10 mL) at 0° C. was added sodium hydride, 60% dispersion in mineral oil (0.09 mL, 2 mmol). After the addition, the ice bath was removed. The reaction mixture was warmed up to rt and continued to stir at rt. After 20 min, N-(2-chloro-5-(4-chloroquinolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.1 g, 0.2 mmol) was added. It was continued to stir for 20 h. LC/MS showed total conversion. Reaction was quenched with water. The resulting mixture was partitioned between EtOAc/water. The organic layer was washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (12 g) chromatography with hexanes:acetone=80%:20% as the solvent system to afford the desired product as light yellow solid (25 mg). A peak at 28 min was collected. The solvent was removed in vacuo to afford the desired product as light yellow solid (80.0 mg). MS (ESI pos. ion) m/z: calc'd for C23H19ClFN3O4S: 487.1; found: 488.4 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.53 (s, 3 H) 3.90-4.00 (m, 2 H) 4.35-4.49 (m, 2 H) 6.84 (d, J=5.26 Hz, 1 H) 7.19 (t, J=8.55 Hz, 2 H) 7.88 (ddd, J=8.62, 4.17, 3.87 Hz, 3 H) 8.17 (d, J=8.77 Hz, 1 H) 8.33 (d, J=2.34 Hz, 1 H) 8.43 (d, J=1.90 Hz, 1 H) 8.50 (d, J=2.34 Hz, 1 H) 8.81 (d, J=5.26 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[CH:12]=1.C([Li])CCC.CN([CH:22]=[O:23])C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[C:12]=1[CH:22]=[O:23]
Reactant: Cn1cc(-c2ccccc2F)nn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccc2F)c1C=O
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a pre cooled (−70° C. to −78° C.) solution of 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole 3 (51 g, 287.84 mmol) under nitrogen atmosphere in THF (1200 ml) was added n-Butyllithium (138.16 ml, 345.41 mmol, 2.5M solution in hexane) and stirred for 2 h. Then DMF (1200 ml, 14794.844 mmol) was added and stirred at −78° C. for 30 min. The reaction was monitored by TLC and UPLC. The reaction mixture was slowly quenched with ice cold water (1000 ml) and the aqueous layer was extracted with ethyl acetate (5×1000 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude mass (50 g, 84.66% mass balance). It was purified by gravity column using 20% ethyl acetate in pet ether as an eluent to afford desired product 4-(2-Fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (40 g, 67.72%) as reddish solid. Then it was triturated with methyl tert-butyl ether (1000 ml) and hexane (500 ml), the supernant layer was decanted and the solid was dried to furnish desired product 4-(2-Fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (32 g, 54.18% yield) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:14][CH3:15])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(OC)c(O)c1

Procedure:
A solution of 3-Hydroxy-4-methoxybenzoic acid (25 g, 148.67 mmol) and p-Toluenesulfonic acid monohydrate (3.17 g, 16.66 mmol) in abs ethanol (300 ml) was refluxed for 6 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with EtOAc (60 ml) and washed with water (20 ml). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[CH2:20][S:21][CH2:22][CH2:23][OH:24])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[CH2:20][S:21][CH2:22][CH2:23][O:24][C:26](=[O:28])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CSCCO)NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCSCC(=O)NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 60 °C
Yield: 75 %

Procedure:
0.49 g of N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (b) above] was added to a mixture of 0.48 ml of acetic anhydride and 0.43 ml of pyridine, and the resulting mixture was warmed at 60° C. for 2 hours. At the end of this time, the reaction mixture was poured into ice-water and a saturated aqueous solution of sodium hydrogencarbonate was added to it. The resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.41 g (yield 75%) of the title compound as an oil.
Reaction SMILES: C([C:3]1[N:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[C:9]([CH3:17])[C:8]([F:18])=[C:7](F)[C:6]=2[F:20])C.C(OC([NH:36][CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:36][CH:37]1[CH2:41][CH2:40][N:39]([C:7]2[C:6]([F:20])=[C:5]3[C:10]([C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3][N:4]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[C:9]([CH3:17])[C:8]=2[F:18])[CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCc1c(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c2n1-c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 0.40 g (1.00 mmol) of ethyl 6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.22 g (1.18 mmol) of 3-t-butoxycarbonylaminopyrrolidine, 0.30 g (3.00 mmol) of triethylamine, and 15 ml of acetonitrile was refluxed for 18 hours. The mixture was cooled and concentrated. The residue was dissolved in 10 ml of 6N hydrochloric acid, refluxed for three hours, and cooled to room temperature. The solids were filtered, washed with water and ether, and suspended in water. The suspension was made basic (pH 12) and filtered through a fiberglass pad, and the filtrate was neutralized to pH 6.7. The solids were filtered and washed with water and ether to give 0.38 g of the title compound, mp 230°-232° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][C:14](=[O:20])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][C:14](=[O:20])[CH:13]=[CH:12]2)[CH2:7][O:8][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of (S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (8K) (0.5175 g, 1.34 mmol) in DMF (5.0 mL), was added imidazole (0.204 g, 4.02 mmol), followed by tert-butyldimethylsilyl chloride (0.243 g, 1.61 mmol) at 0° C. The reaction mixture was warmed to room temperature overnight. Additional imidazole (0.2 g) and tert-butyldimethylsilyl chloride (0.30 g) were added and the mixture stirred for another 2 hours. The reaction mixture was the diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 20 to 60% ethyl acetate/hexanes) to give a yellow foam (0.500 g). LCMS-ESI+ (m/z): calcd for C28H39ClNO3Si: 501.1;
Reaction SMILES: C([O:8][NH:9][C:10](=[O:34])[C@H:11]([N:15]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[OH:8][NH:9][C:10](=[O:34])[C@H:11]([N:15]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOCc2ccccc2)C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NO)C(C)C)cc1

Procedure:
N-Benzyloxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide (see example 29a) is reacted with hydrogen in the presence of 10% palladium on charcoal catalyst at room temperature and atmospheric pressure to yield N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide. After conversion to the hydrochloride salt, a white solid is obtained, m.p. 169°-170° C. (dec).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][C:14]([OH:16])=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][C:14]([Cl:3])=[O:16]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
30.93 g of thionyl chloride are added dropwise to a warmed, mechanically stirred mixture of 45.12 g of 2,6-dichlorophenylacetic acid in 125 ml of toluene. The reaction mixture is then maintained at reflux for 5 hrs and cooled overnight at RT. The reaction mixture is concentrated in vacuo and the concentrate dissolved in hot petroleum ether and the solids filtered. The filtrate is concentrated in vacuo to give a dark amber liquid, which is distilled to give a clear pinkish liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([O:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1)=[O:43]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([O:44][C:45]2[CH:46]=[CH:47][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:53][CH:54]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 220 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.104 mL of triethylamine in 4.0 mL of THF was added 127 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 264 mg of 4-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidine-1-carboxylate in the form of a colorless amorphous substance as a crude product. ESI+: 623
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:19])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.SC[CH2:22][C:23]([OH:25])=[O:24].C1CCN2C(=NCCC2)CC1>C1COCC1.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:19][CH2:22][C:23]([OH:25])=[O:24])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCS
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(O)CCSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.42 h
Yield: 80.2 %

Procedure:
To a solution of solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (141 mg, 0.50 mmol) in THF (3 mL) was added 3-mercaptopropionic acid (88 μL, 1.0 mmol) followed by DBU (320 μL, 2.1 mmol). The solution was stirred for 25 min, diluted with 1% NaHCO3, and extracted with ethyl acetate. The aqueous layer was acidified with 3% HCl to afford a white precipitate. The solids were collected by filtration, washed with water and dried to afford 128.8 mg (79% yield) of the titled compound as a white solid. API-MS m/z 322 (MH+), 320 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.