Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:19][CH:18]=1)=[O:15].C1(O)C=CC=CC=1>ClCCl>[F:32][C:30]([F:31])([F:33])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:14]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:15])=[CH:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C1CC(CNCC2CC2)CCN1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CNCC2CC2)CC1
Reaction time: 8 h

Procedure:
Cyclopropylmethyl-piperidine-4-ylmethyl-amine (0.65 mmol, 110 mg) was dissolve in dichloromethane. 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate (0.65 mmol, 0.208 g) (prepared from the corresponding phenol by conventional methods) was added at −15° C. for 15 min and stired at room temperature overnight and evaporated to dryness. The crude product was purified by preparative HPLC (Method C) (16%, colourless crystals). HPLC-MS m/z=450.1 (M+1), Rt: 2.98 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4](Cl)[CH3:5].[CH:12]1[CH:13]=[CH:14][N+:15]([O-:19])=[C:16]([S-:18])[CH:17]=1.[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]([S:18][C:16]1[CH:17]=[CH:12][CH:13]=[CH:14][N+:15]=1[O-:19])[CH3:5]
Reactant: [O-][n+]1ccccc1[S-]
Reactant: CC(Cl)c1c(F)cccc1F
Agent: [Na+]
Solvent: CCO
Product: CC(Sc1cccc[n+]1[O-])c1c(F)cccc1F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2,6-Difluoro-alpha-methylbenzyl chloride (16.6 g, 0.094 mol) is dissolved in ethanol (40 ml) and warmed to 75° C. A 40 percent solution of sodium omadine (38.5 g, 0.103 mol) is added dropwise over a period of 30 minutes maintaining a reaction temperature of 75° C. throughout. Once the addition is complete, the reaction mixture is kept between 75° C. and 80° C. for 2 hours. Thereafter the mixture is quenched in ice-water and crude product is filtered off. After recrystallization with ethyl acetate pure title product (10.65 g, 42.4%) is obtained; Melting Point 158°-160° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1c2ccccc2CN1C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1c2cc([N+](=O)[O-])ccc2CN1C1CCCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
The compound (50.00 g, 0.23 mol) obtained in step (b) just above was dissolved at 0° C. in concentrated sulfuric acid (413 ml). Potassium nitrate (36.63 g, 0.36 mol) was added to the solution. The mixture was stirred overnight while gradually raising the temperature from 0° C. to room temperature. The reaction solution was poured into ice water (2000 ml), and then extracted with ethyl acetate. The extract was then washed with water, a saturated aqueous NaHCO3 solution, and saturated saline in that order, and then dried over anhydrous MgSO4. The solvent was removed by distillation under the reduced pressure. The precipitated crystals were collected by suction filtration, washed with hexane, and then dried to give 49.78 g (82%) of 2-cyclohexyl-2,3-dihydro-6-nitro-1H-isoindol-1-one as a pale yellow crystalline product.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.Cl[CH2:40][C:41]1[N:45]=[CH:44][O:43][N:42]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:23][CH2:24][N:25]([CH2:40][C:41]3[N:45]=[CH:44][O:43][N:42]=3)[CH2:26][CH2:27]2)=[N:11][CH:10]=1
Reactant: ClCc1ncon1
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCN(Cc3ncon3)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A mixture of 200 mg (0.373 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide (Example 53), 66 mg (0.56 mmol) 3-(chloromethyl)-1,2,4-oxadiazole and 62 mg (0.45 mmol) potassium carbonate in 4 ml acetonitrile was stirred at 45° C. for 1 h and at room temperature over night. The reaction mixture was diluted with 10 ml water and extracted with 3 30-ml portions of dichloromethane. Drying with sodium sulfate and concentration gave 244 mg of the crude product. Flash column chromatography afforded 80 mg (34.7%) of the title compound as a red-brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH2:17][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:19][CH:20]=1)=[O:23]
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN(c2ccc([N+](=O)[O-])cc2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-[N-(4-nitrophenyl)amino]-4H-1,2,4-triazole and methyl 4-bromomethylbenzoate
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].C1C2C(=CC=CC=2)CCC1C([Cl:36])=O>>[CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([Cl:36])=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C1CCc2ccccc2C1
Reactant: CCCN(Cc1ccc(C(=O)O)cc1)C1CCc2ncsc2C1
Product: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1

Procedure:
4-{[Propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amino]-methyl}-benzoyl chloride (42C) is prepared from 42B as described for 23A. The crude product is obtained in almost quantitative yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2].CCN(CC)CC.Cl.[NH2:25][OH:26]>CCO>[CH2:15]([C:5]1[CH:4]=[C:3]([C:1](=[NH:2])[NH:25][OH:26])[CH:8]=[C:7]([CH3:9])[C:6]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:16]
Reactant: CCc1cc(C#N)cc(C)c1CCC(=O)O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Temperature: 25 °C
Yield: 101.6 %

Procedure:
To a solution of 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (10.0 g, 46.0 mmol) in EtOH (80 mL), NEt3 (13.97 g, 138.1 mmol) followed by hydroxylamine hydrochloride (6.40 g, 92.1 mmol) is added. The mixture is refluxed for 7 h before it is cooled to rt. The solvent is removed in vacuo. The residue is dissolved in 2 N aq. HCl and the pH is adjusted to 5 by adding 32% aq. NaOH solution. The precipitate that forms is collected, washed with water and dried under high vacuum at 40° C. for 18 h to give 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid (11.7 g) as a beige crystalline powder; LC-MS: tR=0.60 min, [M+1]+=251.09.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([N+:21]([O-])=O)=[C:19]([CH2:24][C:25]#[N:26])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Fe].C(O)C>[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([NH2:21])=[C:19]([CH2:24][C:25]#[N:26])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccnc(N2CCN(Cc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: N#CCc1ccnc(N2CCN(Cc3ccccc3)CC2)c1N
Reaction time: 0.5 h

Procedure:
43 ml of hydrochloric acid and 35 g of iron powder are added to a suspension, that has been heated at 80° C. for 1 hour, of 59 mmol of the product obtained in Step A in 1.5 1 of absolute ethanol. After 2 hours 30 minutes at 80° C., filtration while hot, and concentration of the reaction mixture under reduced pressure, the residue is taken up in water, rendered basic with a 20% sodium hydroxide solution and extracted with ethyl acetate. The organic phase is subsequently dried, filtered and evaporated, and chromatography of the residue on silica gel (dichloromethane/ethanol: 90/10) enables the expected product to be isolated.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])[CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[Cl:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:30])[C:23]=1[CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)n1nc(-c2cccc(OCc3c(Cl)cccc3Cl)c2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3cccc(OCc4c(Cl)cccc4Cl)c3)c12

Procedure:
1-tert-butyl-3-(3-(2,6-dichlorobenzyloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (19.5 mg, 0.05 mmol) was dissolved in a solution of formic acid (2 mL) and conc. HCl (0.2 mL) and heated to reflux for 30 min. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 386.1, found 386.2.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2Cl)=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].[H-].[Na+:36]>CN(C=O)C.C(O)CC>[Na+:36].[CH2:3]([O:2][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:2])=[O:34])[CH2:30][CH2:31][S:32][CH3:33])=[O:29])=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:9]=1)[CH2:4][CH3:30]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cnccc2Cl)cc1-c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCCO
Solvent: CN(C)C=O
Product: CCCOc1ccncc1C=Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)[O-])c(-c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-(2-(4-chloropyridin-3-yl)ethenyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 1040, (28 mg, 0.06 mmol) was dissolved in DMF (1 mL) with n-propanol (0.1 mL) and treated with NaH (60% in mineral oil, 6.8 mg, 0.17 mmol). After stirring 18 hours at ambient temperature, the reaction was evaporated and lyophilized from water to provide 29 mg of the title compound. MS m/e 505 (M+H)+. 1H NMR (d6-DMSO, 300 MHz) δ 1.03 (m, 3H), 1.24 (m, 2H), 1.6 (m, 3H), 2.0 (m, 7H), 3.71 (m, 2H), 6.94 (m, 1H), 7.3 (m, 9H), 7.74 (m, 1H), 8.33 (m, 1H), 8.52 (m, 1H), 8.67 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][CH2:35]O>>[CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:35][C:34]#[C:33][CH2:32][CH2:31][CH2:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[O:4]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCCCOC1CCCCO1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCCOC3CCCCO3)cc2)CCSC1(C)C
Yield: 64.4 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 3.4 g (9.842 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.34 g (11.81 mmol) of 6-(tetrahydro-2H-pyran-2-yloxy)-2-hexyn-1-ol provided 3.33 g (64%) of methyl-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil. Electrospray Mass Spec: 526.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21](COCC[Si](C)(C)C)[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:9][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3[nH]ccc23)cn1
Reaction time: 16 h
Yield: 26 %

Procedure:
Ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (20 mg, 0.0000452 mol) was stirred in 1 mL TFA for 1 hour. Then excess TFA was removed in vacuo. The residue was stirred for 16 hours in 2 mL MeOH containing 0.5 mL NH4OH. Evaporation of the volatiles was followed by purification by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford ethyl 3-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate, trifluoroacetate salt (5 mg, 26%). 1H NMR (400 MHz, d6-DMSO): δ 12.19 (s, 1H), 8.61 (br s, 1H), 8.34-8.22 (br m, 2H), 7.62 (br s, 1H), 7.51 (br d, 1H), 7.02 (br s, 1H), 3.91 (q, 2H), 2.96 (s, 2H), 1.70 (s, 6H), 1.02 (t, 3H); MS(ES):313(M+1).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:12]=[C:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])[O:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH:2]([C:11]1[CH:12]=[C:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])[O:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:22])[CH3:21]
Reactant: CCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 17 h

Procedure:
A mixture of 4-(1-hydroxynonyl)-2-trimethylsilylfuran (1.65 g, 5.9 mmol), acetic anhydride (2 ml) and pyridine (3 ml) was stirred under argon at approximately 20° for 17 hours. After most of the solvent was removed under high vacuum (less than 40° C.), the residue was dissolved in ether (40 ml) and washed thoroughly with aqueous copper sulfate and water. Drying (magnesium sulfate) and evaporation gave a brown oil, which was flash chromatographed on silica using 5% ethyl ether/petroleum ether. Fractions with Rf 0.32 on evaporation afforded 4-(1-acetoxynonyl)-2-trimethylsilylfuran as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].O>CN(C=O)C>[CH3:19][N:20]([CH3:24])[C:21]([O:18][C:5]1[C:4]([CH3:3])=[CH:13][C:12]2[C:11]([CH3:14])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[C:7]=2[CH:6]=1)=[S:22]
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1OC(=S)N(C)C)C(C)(C)CCC2(C)C

Procedure:
In a round bottom flask there are introduced 1.7 g (57 mmoles) of sodium hydride (80% in oil) and 50 ml of dimethylformamide. There is slowly added a solution of 10.3 g (47 mmoles) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol in 100 ml of DMF and the reaction mixture is stirred until the cessation of gas evolvement. There are then added 8.1 g (66 mmoles) of dimethylthio-carbamoylchloride in 100 ml of DMF and the reaction mixture is stirred for 4 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethylether. The organic phase is decanted, washed with water, dried on MgSO4 and the solvent evaporated. The residue is purified by chromatography on a silica column (eluant: 20/80 mixture of CH2Cl2 /hexane). 13.2 g (92%) of 2-(N,N-dimethylthiocarbamoyloxy)-3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 102-103° C. are recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]([C:23]([O:25]CC)=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]([C:23]([OH:25])=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C[C@H](NS(=O)(=O)c2ccc(Cl)c(Cl)c2)C(=O)O)cc1

Procedure:
5 g of 3,4-dichlorophenylsulphonyl chloride are introduced, with stirring, into a mixture of 3,8 g of ethyl O-methyltyrosinate in 35 ml of CH2 Cl2 and 50 ml of a saturated aqueous potassium carbonate solution. After one night, the solid is removed, the organic phase separated and the aqueous phase reextracted with CH2Cl2. The dried organic phases are concentrated and the residue is chromatographed on a silica column, eluting with a mixture of CH2Cl2 and CH3OH (95/5-V/V). 6.8 g of racemic ethyl N-(3,4-dichlorophenylsulphonyl)-O-methyltyrosinate are obtained, which product melts at 99° C. This ester is hydrolysed in 100 ml of C2H5OH containing 9.5 ml of a 5N aqueous KOH solution to give, after acidification, 5.5 g of the corresponding acid which melts at 183° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[C:14]([Br:28])[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(Br)c2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (418 mg, 1.13 mmol), N-bromosuccinimide (221 mg, 1.24 mmol), silica gel (EM Scientific, 230-400 mesh, 2.51 g) and methylene chloride (70 mL) was stirred at room temperature for 16 h. Solvents were removed in vacuo and the residue was subjected to silica gel chromatography using ethyl acetate/hexanes (2:3) as eluent to afford the title compound. 1H-NMR (CD3COCD3, 500 MHz) δ 10.71 (s, 1H), 7.35-7.28 (m, 6H), 7.21 (s, 1H), 6.75 (d, J=7.5 Hz, 1H), 5.06 (d, 12.5 Hz, 1H), 5.02 (d, J=12.5 Hz, 1H), 4.56-4.51 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J=14.0, 5.0 Hz, 1H), 3.03 (dd, J=14.0, 10.0 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 153.8, 144.4, 137.6, 133.7, 129.8, 128.7, 128.2, 128.0, 127.8, 110.1, 100.9, 66.3, 55.9, 52.0, 37.3; Mass spec. 448.03 (MH+).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:18][C:19]1[C:24]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:23]([CH3:33])[N:22]=[C:21]([O:34][CH2:35][C:36]([N:38]([CH3:45])[CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:37])[N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:3]1([CH2:2][N:42]2[CH2:41][CH2:40][CH:39]([N:38]([CH3:45])[C:36](=[O:37])[CH2:35][O:34][C:21]3[N:20]=[C:19]([CH3:18])[C:24]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[C:23]([CH3:33])[N:22]=3)[CH2:44][CH2:43]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: BrCC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Bromomethyl cyclohexane (25 μL) and diisopropylethylamine (63 μL) were added to a solution of Compound 31 (71 mg) in dimethylformamide (1 mL) and the mixture was stirred at 120° C. for 8 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (hexane:ethyl acetate=1:1) to give 40 mg (46% yield) of the desired product.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:20](=[O:21])[O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of 4-pentylphenol (20.1 g, 0.13 mol) and pyridine (10 ml, 0.13 mol) in 300 ml of methylene chloride was added under nitrogen dropwise over 45 minutes to a solution of 4-nitrophenyl chloroformate (25.28 g, 0.13 mol) in 200 ml of methylene chloride at room temperature. After the addition, the reaction was stirred overnight at room temperature. The reaction was extracted one time with 1N HCl, four times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 36.97 g of a yellow crytstalline solid. Purification of the solid on 450 g of silica gel (230-400 mesh) using 50-60% CH2Cl2 -hexane as the eluent gave 11.58 g (28%) of the title compound as a yellow crystalline solid, mp 67-69° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.O>[C:12]([C:3]1[C:2]([NH:1][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: CCOC(=O)CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cnc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 1-(3-amino-5-(trifluoromethyl)pyridin-2-yl)ethanone (0.87 g, 4.26 mmol, 1 eq.) in DCM (20 ml) were added TEA (0.65 ml, 4.69 mmol, 1.1 eq.) and ethyl 3-chloro-3-oxopropanoate (0.71 ml, 5.54 mmol, 1.3 eq.) at 0° C. The reaction mixture was stirred at RT for 3 h. Then the mixture was diluted with water (50 ml) and extracted with DCM (3×80 ml). The combined organic layers were washed with water (80 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to provide ethyl 3-(2-acetyl-5-(trifluoromethyl)pyridin-3-ylamino)-3-oxopropanoate (1.35 g, 4.24 mmol, 99%) which was used in subsequent reactions without further purification.