Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:55][O:56][CH2:57][C:58]1([NH2:63])[CH2:62][CH2:61][CH2:60][CH2:59]1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:63][C:58]4([CH2:57][O:56][CH3:55])[CH2:62][CH2:61][CH2:60][CH2:59]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: COCC1(N)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4)c3O)nc2)CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (30 mg, 0.098 mmol), EDCI (28.2 mg, 0.147 mmol), and HOBT hydrate (22.50 mg, 0.147 mmol) in DMF (1 mL) and added Hunig's base (50.6 mg, 0.392 mmol). Then 1-(methoxymethyl)cyclopentanamine (19.0 mg, 0.147 mmol) was added and the reaction mixture was stirred at ambient temperature for 20 h. The reaction mixture was purified using HPLC (45-70% ACN in water, TFA-buffered) to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.80 (m, 6 H) 2.00-2.13 (m, 2 H) 3.27 (s, 3H) 3.60 (s, 2H) 7.79 (d, J=8.59 Hz, 2 H) 7.96-8.78 (m, 6 H) 8.79-8.99 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 418.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.[CH:14]#[C:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.CCCCCCC>C(#N)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:14]([C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1)#[C:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)C1Oc2ccc(Br)cc2O1
Reactant: C#CCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc2c(c1)OC(C(C)=O)O2
Yield: 99.9 %

Procedure:
A solution of 1-(5-bromobenzo[d][1,3]dioxol-2-yl)ethanone (4.13 g), copper (I) iodide (0.16 g), pent-1-yne (2.32 g), triphenylphosphine palladium chloride (1.19 g) and triethylamine (7 ml) in acetonitrile (40 ml) was stirred overnight at 50° C. Then 100 ml of heptane were added and the organic layer was washed successively with a 2M HCl solution and three times with water, dried over MgSO4 and concentrated. The crude reaction mixture was purified by flash chromatography on silica gel (eluant heptane/ethyl acetate 97/3) to give 3.91 g (22%) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)cc1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to afford the title compound as an off-white solid. Yield: 35 mg (42%).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]#[N:12]>CCOCC>[Cl:9][C:10]([Cl:14])([Cl:13])[C:11](=[NH:12])[O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(CC)OC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-pentanol (1 mmol) in anhydrous Et2O (0.2 mL) was added dropwise to NaH (0.1 mmol; 60% in mineral oil) suspended in Et2O (1 mL) under nitrogen. The mixture was stirred for 10 min at room temperature and then added dropwise over a period of 20 min to a solution of trichloroacetonitrile (1.5 mmol) in Et2O (1 mL) at −5° C. under nitrogen. The reaction mixture was warmed to room temperature, and stirred for 2 h. After removal of solvent, the residue was triturated with MeOH/hexane with vigorous stirring to give precipitates, which were filtered off and washed with cold hexane. The filtrate was evaporated under reduced pressure to give 3-pentyl trichloroacetimidate. The freshly prepared 3-pentyl trichloroacetimidate (0.75 mmol) and CF3SO3H (0.075 mmol) were added to a solution of azido carboxylate ester (2A) (0.6 mmol) in CH2Cl2 (5 mL) under nitrogen. The reaction mixture was stirred at room temperature for 24 h, during which more imidate and CF3SO3H (0.075 mmol) were added 5 times every 4 h period. The reaction was quenched with 5% aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane) to afford the product (14B). Azide (14B) can then be converted to amine (1) as described above.
Reaction SMILES: C(OC([NH:8][C:9]1([C:39]([OH:41])=[O:40])[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:30][CH2:29][CH2:28][C@@H:27]4[C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[F:38])=[CH:22][C:21]=23)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:42]>O1CCOCC1>[ClH:42].[NH2:8][C:9]1([C:39]([OH:41])=[O:40])[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:30][CH2:29][CH2:28][C@@H:27]4[C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[F:38])=[CH:22][C:21]=23)=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(C(=O)O)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
(R)-4-((tert-butoxycarbonyl)amino)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.17 mmol) added to 4N HCl in Dioxane (5 mL) was stirred at 20-35° C. for 3 h. The reaction mixture was concentrated under reduced pressure to afford crude. The crude obtained was washed with diethyl ether and dried to afford 58 mg of the title compound as a pale brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O-].[Na+].O.O.C([O-])(=O)C.[Zn+2:22].C([O-])(=O)C>CO>[Zn:22].[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CO
Solvent: O
Product: [Zn]

Procedure:
L-phenylalanine (2.00 g, 12.1 mmol) was added to an MeOH solution of NaOMe (prepared with Na: 0.30 g, MeOH: 50 ml) at 0° C. and stirred. An MeOH solution (30 ml) of zinc acetate dihydrate (1.30 g) was then slowly dropwise added thereto at room temperature. After stirring for 3 hours, the precipitated crystal (in suspension) was recovered by filtration, washed with water, air dried, and then dried under a reduced pressure (5 mmHg, 80° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N:11]2[C:15](=[O:16])[N:14]([CH:17]([F:19])[F:18])[C:13]([CH3:20])=[N:12]2)=[C:6]([F:21])[CH:5]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Cl:3][C:4]1[C:9]([O:10][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:8][C:7]([N:11]2[C:15](=[O:16])[N:14]([CH:17]([F:18])[F:19])[C:13]([CH3:20])=[N:12]2)=[C:6]([F:21])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 80 °C
Yield: 76.1 %

Procedure:
To a stirred mixture of 0.91 g (0.019 mole) of sodium hydride in 30 mL of N,N-dimethylformamide was added slowly a solution of 5.50 g (0.019 mole) of 1-[4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 30 mL of N,N-dimethylformamide. To this mixture was added 2.68 g (0.019 mole) of 4-fluoronitrobenzene. The resultant mixture was stirred at room temperature for approximately 18 hours and then was heated at 80° C. for one hour. The mixture was allowed to cool and was poured into ice water. The aqueous mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 6.0 g of 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 115°-117° C., Compound 4 of Table 1.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[N:25](CC4C=CC(OC)=CC=4)[N:26]=[C:27]([CH3:28])[C:20]=23)=[C:14]([F:38])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[NH:25][N:26]=[C:27]([CH3:28])[C:20]=23)=[C:14]([F:38])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N(Cc5ccccc5)C(C)=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(Cc1ccccc1)c1ccc(Oc2ccnc3[nH]nc(C)c23)c(F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To a flask containing N-benzyl-N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)acetamide (38 mg, 0.074 mmol) at ambient temperature under a drying tube was added TFA (2 mL). The mixture was heated to 50° C. and stirred for 4 hours. The reaction was cooled to ambient temperature and concentrated. The residue was treated with 5 mL 10% sodium carbonate and then 5 mL dichloromethane. The mixture was rapidly stirred and the layers separated. The aqueous phase was extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was loaded onto a Biotage 12S column with dichloromethane and eluted with 7/3 EtOAc/hexanes to provide the desired product as a white foam (17 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ 11.68 (br s, 1H), 8.35 (m, 1H), 7.31 (m, 3H), 7.23 (m, 3H), 6.93 (m, 2H), 6.16 (d, 1H), 4.93 (s, 2H), 2.73 (s, 3H), 2.00 (br s, 3H). LCMS (APCI+): m/z 391 (M+1) detected.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[N:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:36])([CH3:35])[CH2:33][OH:34])[CH2:28][CH2:27]1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:34][CH2:33][C:32]([OH:36])([CH:29]2[CH2:30][CH2:31][N:26]([C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][N:18]=3)[CH2:27][CH2:28]2)[CH3:35])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2ncnc(N3CCC(C(C)(O)CO)CC3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(N3CCC(C(C)(O)COS(=O)(=O)c4ccc(C)cc4)CC3)c2cc1OC
Reaction time: 3 h

Procedure:
Toluene-4-sulphonylchloride (0.285 g) was added at 0° to a stirred solution of 2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]propane-1,2-diol (0.35 g) in pyridine (3 cm3) and the mixture was stirred for 3 hours. The mixture was poured into a mixture of chloroform (20 cm3) and saturated sodium bicarbonate solution (20 cm3) and the dried (MgSO4) chloroform layer was evaporated. The residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give an oil which was crystallised from ethyl acetate to afford 1-[4-toluenesulphonyloxy]-2-hydroxy-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]propane, m.p. 120°-124° (0.285 g).
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]=1[OH:43]>CO.O1CCOCC1.[OH-].[Na+]>[Cl:10][C:8]1[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:19]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]([OH:43])=[C:4]([CH:9]=1)[C:3]([OH:44])=[O:2]
Reactant: CCCc1c(O)c(C(=O)OC)cc(Cl)c1OCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCc1c(O)c(C(=O)O)cc(Cl)c1OCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Yield: 71.6 %

Procedure:
A solution of 0.30 g of 5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid methyl ester in 10 mL of methanol, 5 mL of dioxane and 2.5 mL of 1N sodium hydroxide was left at room temperature for 3 days. The solvent was removed under reduced pressure and the residue was acidified and extracted with ethyl acetate. The dried extract was concentrated and chromatographed on 30 g of silica gel using acetic acid:ethyl acetate:toluene (1:25:75) to give 0.21 g of 5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1.[NH4+].[Cl-]>CN(C=O)C.O>[CH2:3]([O:10][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Br:11])[CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Sodium hydride (60% in mineral oil, 40.9 g, 1.0 mol) in DMF (800 mL) was cooled to 0° C., and benzyl alcohol (105 mL, 1.0 mol) was slowly added. After stirring for 1 hour at ambient temperature, 3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture allowed to stir for 16 hours. Saturated NH4Cl solution (500 mL) was added followed by water (400 mL), and the mixture was extracted with Et2O (5×300 mL). The combined Et2O extracts were washed with 50% brine (6×300 mL), dried (MgSO4), concentrated and the residue recrystallized from Et2O to afford a white solid (161 g, 72%): 1H NMR (CDCl3, 300 MHz) δ5.10 (s, 2H), 7.50-7.35 (m, 6H), 8.37-8.27 (m, 2H); MS (CI/NH3) m/z: 264/266 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C@@:13]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([Br:35])[N:29]=1)([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37].CO>>[Br:35][C:30]1[N:29]=[C:28]([C@:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:4]([NH2:37])=[O:3])[C:33]([F:34])=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@@](C)(OC[C@](C)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F)C(F)(F)F
Reactant: N
Solvent: CO
Product: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F

Procedure:
A solution of (R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (16.93 g, 28.1 mmol) in a NH3/MeOH (7M, 482 ml) was stirred at 50° C. in a sealed vessel for 26 h. The reaction mixture was evaporated and the residue was crystallized from DCM to yield 9.11 g of the title compound as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=1)=[O:6])C.[OH-].[Li+]>C1COCC1>[CH2:17]([O:16][C:14]([CH2:13][C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:19])=[O:3])[S:9][CH:10]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)Cc1csc(NC(=O)C(=O)OCC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(NC(=O)C(=O)O)n1
Yield: 33.3 %

Procedure:
To N-(4-ethoxycarbonylmethyl-thiazol-2-yl)-oxalamic acid ethyl ester (1 g) was added THF (5 mL) and 2 N lithium hydroxide (4 mL). A white precipitated formed and after 1 h the reaction mixture was acidified to pH5 and the white precipitate recovered by filtration, and triturated with a 1:1 mixture of ether and ethyl acetate to remove unreacted starting material. The solid residue was dried in a vacuum oven to give N-(4-ethoxycarbonylmethyl-thiazol-2-yl)-oxalamic acid (300 mg).
Reaction SMILES: [NH2:1][O:2][CH3:3].Cl.CC(O[Na])=O.[CH3:10][NH:11][C:12]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[C:17](=O)[CH2:16][CH2:15][CH2:14][CH2:13]1>CO.O.O>[CH3:3][O:2][N:1]=[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25])[NH:11][CH3:10]
Reactant: CON
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC1(c2ccccc2Cl)CCCCC1=NOC
Temperature: 25 °C

Procedure:
To as solution of NH2OMe. HCl and CH3COONa. H2O in MeOH:H2O (7:3) stirred at room temperature for 15 minutes, was added ketamine and the resulting solution was stirred at reflux for 16 hrs before cooling to room temperature. The reaction mixture was filtered and the filtrate was partitioned between CH2Cl2 and sat. NaHCO3 solution. The filtrate was extracted with CH2Cl2 (2×30 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over anhydrous. Na2SO4 and concentrated under reduced pressure. The crude reaction mixture received was purified over silica gel column chromatography by eluting with initially CH2Cl2 and later with (1:9) MeOH:CH2Cl2 to receive methoxime 3 as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.9-8.0 (m, 1H), 7.2-7.4 (m, 3H), 3.91-4.0 (m, 3H), 3.3 (td, J=4.10, 13.96 Hz, 1H), 3.2 (td, J=4.49, 13.73 Hz, 1H), 2.4-2.5 (m, 3H), 2.1-2.3 (m, 1H), 1.6-1.8 (m, 3H), 1.4-1.5 (m, 1H), 1.2-1.4 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 156.3, 135.5, 132.4, 132.2, 131.9, 131.0, 128.3, 67.4, 62.7, 39.4, 28.8, 26.1, 24.7, 22.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][SH:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S-:16].[Na+].II.Cl>O.C1COCC1.CCO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][S:16][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)O
Reactant: C[S-]
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CSSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 67.9 %

Procedure:
(R)-2-((tert-butoxycarbonyl)amino)-3-mercaptopropanoic acid (Boc-L-Cys-OH) (110 mg, 0.5 mmol) was dissolved in H2O/THF (50% v/v, 20 mL). To the solution was added sodium thiomethoxide (350 mg, 5.0 mmol) at 0° C. Then, a solution of iodine in 95% EtOH was added dropwise until the color of the reaction system changed from colorless to brown. The mixture was stirred for 5.5 h with warming to room temperature. After removing THF under reduced pressure, reaction mixture was neutralized by 1 N HCl aq. until pH 2-3. The solution was extracted with EtOAc. The extract was washed with saturated NaS2O4 aq. and brine, and dried over MgSO4. Concentration under reduced pressure followed by flash chromatography over silica gel in EtOAc/Hexanes/AcOH (75:25:1) gave Boc-L-Csm-OH (90.8 mg, 68% yield). 1H NMR (360 MHz, CDCl3) δ 5.34 (s, 1H), 4.63 (br, s, 1H), 3.26-3.16 (m, 2H), 2.43 (m, 3H), 1.47 (s, 9H); LRMS (ESI) m/z calcd for C9H18NO4S2 (M+H)+ 268.1. found 268.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(SCc2ccccn2)cc1
Yield: 71.4 %

Procedure:
4-nitrobenzenethiol (6.0 g) was dissolved in THF (120 ml), and to the solution was 1N sodium hydroxide (120 ml) and then, 2-(chloromethyl)pyridine hydrochloride (7.6 g), and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-[[(4-nitrophenyl)sulfanyl]methyl]pyridine (6.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylaniline (3.55 g) in pyridine (95 mL) was added benzoyl chloride (2.66 mL). The mixture was stirred at room temperature for 1 hr and the solvent was evaporated under reduced pressure. To the residue was added 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (4.35 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].[N:31]1([CH2:37][CH2:38]Cl)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:37][CH2:38][O:1][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([NH:15][C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)=[O:17])[CH:11]=[CH:12][C:13]=2[CH3:14])=[O:6])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(O)c1
Reactant: ClCCN1CCCCC1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(OCCN2CCCCC2)c1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 7, N-[3-(3-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-piperidinoethyl chloride to give the title compound in 55% yield; NMR Spectrum: (DMSOd6) 1.39 (m, 2H), 1.49 (s, 4H), 2.2 (s, 3H), 2.42 (s, 4H), 2.65 (t, 2H), 4.15 (t, 2H), 7.15 (m, 1H), 7.26 (d, 1H), 7.41 (t, 1H), 7.55 (m, 2H), 7.62 (m,2H),7.86 (s, 1H), 8.12 (d, 1H), 8.24 (m, 1H), 8.52 (m, 1H), 8.61 (s, 1H), 8.99 (d, 1H), 9.89 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 509.