Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:21]=[C:22]([CH:30]([CH3:34])[C:31]([OH:33])=O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[F:27][C:26]([F:29])([F:28])[C:24]1[CH:23]=[C:22]([CH:30]([CH3:34])[C:31]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH3:9])=[O:33])[CH:21]=[C:20]([C:19]([F:18])([F:35])[F:36])[CH:25]=1
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1ccc(Cl)cc1Sc1ccccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCCl
Product: CC(C(=O)N(C)c1ccc(Cl)cc1Sc1ccccc1Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
To a solution of 142 mg (0.5 mmol) of 1-chloro-4-methylamino-3-(2-chloro-phenylsulfanyl)-benzene in 2 ml of 1,2-dichloroethane were added 172 mg (0.6 mmol) of 2-(3,5-bis-trifluoromethyl-phenyl)-propionic acid and the reaction mixture was shaken at 80° C. for 1 h. Dicyclohexyl carbodiimide (97 mg, 0.6 mmol) was added and shaking was continued overnight at the same temperature. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel to yield 56 mg (20%) of the title compound as light yellow oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][O:8][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC(C)(C)C)cc1
Reaction time: 17 h
Yield: 76.8 %

Procedure:
Dissolve ethylene glycol mono-tert-butyl ether (2.62 g, 22.17 mmol) and triethylamine (3.36 g, 11.02 mmol) in 40 mL methylene chloride at 0° C. Dissolve para-toluenesulfonyl chloride (4.2277 g, 22.17 mmol) in 10 mL methylene chloride and add it dropwise to the reaction. After 30 minutes raise the reaction to room temperature and allow it to stir for 17 hours. Dilute the reaction with methylene chloride and wash it with water (1×), 1N HCl (1×), saturated aqueous sodium hydrogen carbonate (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 4.6387 g of crude toluene-4-sulfonic acid 2-tert-butoxyethyl ester. Dissolve this crude material (1.2423 g, 4.56 mmol) and di-benzyl iminodicarboxylate (1.4385 g, 5.04 mmol) (see Synthesis, 1988, 992-994) in 20 mL acetonitrile. Add potassium tert-butoxide (575.9 mg, 5.13 mmol) to the reaction mixture and heat it to reflux for 24 hours. Cool the reaction to room temperature and remove the solvent in vacuo. Dissolve the residue in methylene chloride and wash it with water (1×) and brine (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 1.9215 g of crude material. Purify via Biotage chromatography (EtOAc/Hexanes) to afford 387.8 mg of (2-tert-butoxyethyl)dicarbamic acid benzyl ester (22%). MS (ES): m/z 386.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([NH2:46])[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:47])[NH:39][CH:40]1[CH2:41][CH2:42][CH:43]([NH:46][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:31])[CH2:44][CH2:45]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
{4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-cyclohexyl}-carbamic acid tert-butyl ester was prepared was prepared starting from intermediate M and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester. MS calcd. for C28H34ClN4O4 [(M+H)+] 525.2, obsd. 525.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([OH:10])=[C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(O)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
10 g of 2-amino-4-methoxyphenol was dissolved in 100 ml of methylene chloride. 17 ml of pyridine was added thereto and the mixture was cooled to 5° C. Then, 9.1 g of methanesulfonyl chloride was added dropwise in 10 minutes and stirring gas conducted for 1 hour at 5°-10° C. The solvent was removed by distillation under reduced pressure. To the residue were added 100 ml of ethyl acetate and 50 ml of water. The mixture was adjusted to pH 2 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 14.4 g (yield: 92%) of 4-methoxy-2-methylsulfonylaminophenol having a melting point of 135°-136° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:7]=1[F:14])[CH3:5].C(=O)(O)[O-].[Na+].[BrH:20]>C(Cl)(Cl)Cl>[BrH:20].[F:14][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=1[CH:4]([CH3:5])[CH2:3][NH2:2]
Reactant: COc1ccc(C(C)CN)c(F)c1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: CC(CN)c1ccc(O)cc1F
Yield: 95 %

Procedure:
4.19 g of 1-amino-2-(2-fluoro-4-methoxyphenyl)propane hydrochloride are neutralized with a mixture of chloroform and an aqueous sodium bicarbonate solution. The chloroform layer is separated therefrom and condensed to dryness. Hydrobromic acid is added to the residue, and the mixture is refluxed. Then, the reaction mixture is evaporated, and the residue is recrystallized from a mixture of isopropylalcohol and isopropylether. 4.53 g of 3-fluoro-4-(2-amino-1-methylethyl)phenol hydrobromide are obtained.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][C:10](=[O:42])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)(C)(C)C.[Li+].[OH-].Cl>C1COCC1>[CH:20]1([CH2:19][CH:18]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[O:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:43])=[O:5])=[O:42])=[CH:12][CH:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a mixture of (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid tert-butyl ester (Isomer 2) (0.0865, 0.145 mmol) in THF (1.5 mL) is added LiOH (1 N aqueous, 1.4 mL) and stirred at 70° C. overnight. The reaction mixture is acidified with 1N HCl (1.5 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. to provide 3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid (Isomer 2) (0.0706 g, 90%) as a white solid. MS (ES): 540.0 [M+H]+.
Reaction SMILES: [CH2:1]([OH:7])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:1][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:6]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tetrahydrofurfuryl alcohol (Codexis, 1.6 g, 15.2 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (4.3 g, 22.8 mmol) in portions over 15 minutes. The mixture stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].N([O-])=O.[Na+].[BrH:19]>O>[Br:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14]
Reactant: Br
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Br)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (3e) (0.8 g, 4.0 mmol) in water (2 mL), cooled to 0° C., 48% aqueous HBr (10 mL, 18.5 mmol) was added followed by NaNO2 (0.33 g, 4.8 mmol) taken in water (2 mL) and stirred for 10 min. To the reaction mixture a solution of CuBr (2.7 g, 18.8 mmol) in HBr (10 mL) was added at 0° C. and slowly warmed to room temperature and then heated to 50° C. for 1 h. The reaction mixture was brought to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (2×20 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to provide the bromo 3f (0.6 g, 60%) as a tan colored solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:9][CH:8]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].O>CCOCC.O1CCCC1>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:9][CH:8]=1
Reactant: N#CCCCc1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCCc1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Lithium aluminum hydride (370 mg) is suspended in anhydrous ether (14 ml) under a nitrogen atmosphere and ice cooling, and a solution of 4-(4-pyridyl)butyronitrile (705 mg) in anhydrous ether (10 ml) is added dropwise to the suspension. The mixture is stirred at room temperature for 2.5 hours. Anhydrous sodium sulfate is added to the reaction mixture under ice cooling, and water (0.5 ml) is added drop by drop thereto. Then, tetrahydrofuran is added thereto, and insoluble matter is filtered out. The filtrate is concentrated under reduced pressure to give the titled compound (Reference compound No. 3-1, 827 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:21][CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C(=Cc1ccccc1)C[C@H]1CN(Cc2ccccc2)CCN1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Dissolve (S)-4-benzyl-2-(3-phenyl-allyl)-piperazine-1-carboxylic acid tert-butyl ester (2.37 g, 6.04 mmol) in toluene (50 mL) and treat with trifluoroacetic acid (10.3 g, 90.5 mmol) at room temperature, and stir the reaction mixture. After overnight, dilute the reaction with CH2Cl2, and basify with 2N NaOH (50 mL), extract the aqueous solution with CH2Cl2, wash the combined organic layers brine, dry over Na2SO4. Pass the crude product through a SCX column (10 g), collect the 0.2N NH3/MeOH eluent and concentrate to give 1.46 g of the title compound: mass spectrum (Electrospray): m/z=293.3 (M+1). 1H NMR (400 MHz, CDCl3): δ7.35–7.19 (m, 10H), 6.54–6.47 (m, 1H) 6.18–6.11, 5.70–5.60 (m, 1H), 3.70 (s, 2H), 2.97–2.73 (m, 5H), 2.40–2.18 (m, 2H), 2.09–2.00 (m, 1H), 1.83 (t, 1H, J=9.8 Hz).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][C:7]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:9]([C:10]([NH:12][C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[O:11])[CH:8]=1)=O.Cl>O.[OH-].[Na+]>[OH:3][CH2:4][CH2:5][O:6][C:7]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:9]([C:10]([NH:12][C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[O:11])[CH:8]=1
Reactant: O=COCCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cc(OCCO)c2ccccc2n1

Procedure:
4(2-Formyloxyethoxy)-N(1H-tetrazol-5-yl)quinaldamide (2 g) in water (100 ml) and 2N sodium hydroxide (14 ml) was warmed on a steam bath for 15 minutes, and cooled. The solution was acidified to pH 2 with dilute hydrochloric acid. The solid was collected, crystallised from aqueous dimethylformamide and dried, m.p. 261.5°-262° (d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSc1ccc(Br)cc1
Reactant: NCc1ccccc1
Product: CSc1ccc(NCc2ccccc2)cc1
Yield: 87.6 %

Procedure:
Using the general procedure, 4-bromothioanisole (203 mg, 1.0 mmol) was coupled with benzylamine (164 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (15:1) as eluent afforded the desired product as a white solid (201 mg, 88% yield). Rf=0.4 (hexane/ethyl acetate=10:1).
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.[Br:63]C1C=CC=CC=1C(Cl)=O>ClCCl>[Br:63][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1Br
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Br)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.28 g, 0.92 mmol), triethylamine (0.28 mL, 2.0 mmol) and 2-bromobenzoyl chloride (0.22 g, 1.0 mmol) in dichloromethane (10 mL) gave 2-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.45 g) as a white solid. MS m/z 488, 490 (M+1, M+3).
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[N:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:6][C@H:5]([C:4]([OH:3])=[O:24])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[CH:10][CH:9]=2)=[O:32])=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccncc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O)c1ccncc1

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and isonicotinic acid. δH (DMSO-d6) 8.68 (2H, dd, J 4.5, 1.6 Hz), 8.4 (1H, d, J 7.2 Hz), 7.63 (2H, dd, J 4.5, 1.6 Hz), 7.6-7.4 (3H, m), 7.15 (2H, d, J 8.6 Hz), 6.87 (2H, d, J 8.6 Hz), 5.14 (2H, s), 4.31 (1H, m), 3.2-2.96 (2H, m); m/z (ESI, 60V) 445 (MH+).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH3:39])[CH:32]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH3:39])[CH:32]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:18][CH2:19]1
Reactant: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3c2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@@H](N)CC4)c3c2)ccc1O

Procedure:
Following general procedure A-2, tert-butyl cis-4-[3-(cyclopropanecarbonyl)-6-(4-hydroxy-3-methoxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (43 mg, 0.100 mmol) was reacted with TFA (2 mL) to afford the desired product (20 mg, 56%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.26 (s, 1H), 8.39 (d, J=1.7 Hz, 1H), 8.10 (dd, J=8.8, 1.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.27 (d, J=2.1 Hz, 1H), 7.18 (dd, J=8.2, 2.1 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 4.74 (s, 1H), 3.96 (s, 3H), 3.12-3.02 (m, 1H), 2.98-2.84 (m, 1H), 2.17 (d, J=9.9 Hz, 2H), 2.10-1.93 (m, 4H), 1.93-1.73 (m, 2H), 1.31-1.20 (m, 2H), 1.16-1.08 (m, 2H); ESI MS m/z 432 [C26H29N3O3+H]+; HPLC 98.4% (AUC), tR=9.93 min.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C@@H:13]([CH3:20])[C:14](N(OC)C)=[O:15])[CH2:11][O:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[CH2:1]([N:8]1[C@@H:12]([C@@H:13]([CH3:20])[CH:14]=[O:15])[CH2:11][O:10][C:9]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](C)[C@H]1COC(=O)N1Cc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](C=O)[C@H]1COC(=O)N1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 105.3 %

Procedure:
To a solution of (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)-N-methoxy-N-methylpropanamide from Step 6 (1.5 g, 5.13 mmol) in THF (30 mL) was added dropwise DIBAL-H (1M solution in hexane; 11.29 mL) at −78° C. The mixture was stirred for 90 min at −78° C., diluted slowly with Rochelle's salt solution (1M solution in water; ˜20 mL) and stirred vigrously for ˜15 min. The aqueous layer was separated and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated sodium bicarbonate solution and brine, filtered through a mixture of celite/silica gel. The filtrate was concentrated under reduced pressure providing crude (R)-2-((S)-3-benzyl-2-oxooxazolidin-4-yl)propanal (1.26 g) as a colorless oil, which was directly used without further purification. MS m/z 234.2 (M+H)+; Rt-0.60 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=1.[C:22]([O:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28])(=[O:24])[CH3:23]>>[C:22]([O:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH:10]=[C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[C:13]=2[CH:14]=1)=[O:19])=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: NNC(=O)c1ccc2occ(-c3cc(F)ccc3F)c2c1
Product: CC(=O)OC(C)(C)C(=O)NNC(=O)c1ccc2occ(-c3cc(F)ccc3F)c2c1
Yield: 85 %

Procedure:
In the same manner as in Reference Example 129 and using 3-(2,5-difluorophenyl)-1-benzofuran-5-carbohydrazide instead of 3-bromo-1-benzofuran-5-carbohydrazide and 2-chloro-1,1-dimethyl-2-oxoethyl acetate instead of (1S)-2-chloro-1-methyl-2-oxoethyl acetate, the title compound (yield 85%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:13][C:14]([CH3:20])=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:13][C:14]([CH3:20])=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1
Reactant: COc1c(-c2nc(C(=O)O)c(C)s2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(N)cccc1-c1nc(C(=O)O)c(C)s1
Reaction time: 24 h
Yield: 92.7 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-5-methyl-thiazole-4-carboxylic acid 47a (300 mg, 1.02 mmol) was dissolved in 15 mL of methanol followed by addition of 30 mg of palladium on carbon. The reaction mixture was stirred for 24 hours under hydrogen atmosphere. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon and the filtrate was concentrated under reduced pressure to obtain the title compound 2-(2-methoxy-3-amino-phenyl)-5-methyl-thiazole-4-carboxylic acid 47b (250 mg, yield 92%) as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([S:37]CC[Si](C)(C)C)=[CH:33][C:32]=2[O:44][CH3:45])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][C:32]=2[O:44][CH3:45])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(SCC[Si](C)(C)C)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: COc1cc(S)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of tetrabutylammoniumfluoride (1.0 M in THF, 9.3 mL) was added to a solution of 3-[2-methoxy-4-(2-trimethylsilanyl-ethylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.380 g, 0.9275 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 30 minutes. A solution of 10% KHSO4/Na2SO4 was added and the resulting mixture was extracted 3 times with EtOAc. The combined organic extracts were washed with water and brine; and then dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude material was purified via flash chromatography (hexane/EtOAc/AcOH, 80/20/0.1) to give 0.178 g (62% yield) of 3-(4-mercapto-2-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>C(OCC)C.C(Cl)Cl.C1(C)C=CC=CC=1>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:18])=[CH:12][CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: NCCCO
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc(NC(=O)NCCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.5 %

Procedure:
A solution of 3-amino-1-propanol (0.180 mL, 2.36 mmol) in diethylether (15 mL) was cooled at 0° C. and treated dropwise with 1-tert-butyl-4-isocyanatobenzene (0.400 mL, 2.25 mmol). The reaction mixture was allowed to slowly warm to room temperature. After 16 h the reaction was found to be complete by TLC (100% ethyl acetate) The reaction mixture was diluted with 10 mL portions of CH2Cl2 and Et2O and washed with 15 mL portions of H2O, 0.5N HCl and brine and dried over Na2SO4. The organic phase was filtered and concentrated to yield a colorless viscous oil which was dissolved in PhCH3, concentrated and placed under high vac overnight to yield the title compound (600 mg, 110%) as a colorless viscous oil: MS (ESI+) for C14H22N2O2 m/z 251.0 (M+H)+; (ESI−) for C14H22N2O2 m/z 249.3 (M−H)−; HPLC purity 98% (ret. time, 3.43 min).