Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:30][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:25][C@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH2:23]3)[C:7]=2[C:6]=1[CH3:31])=[O:4].Cl>[OH-].[Na+].CO>[C:27]([NH:26][C@H:24]1[CH2:25][C@H:22]([O:21][C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[C:6]([CH3:31])=[C:5]([C:3]([OH:4])=[O:2])[S:30][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:23]1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@H](NC(C)=O)C3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.800 g 4-[2-(trans-3-acetylamino-cyclobutoxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (cpd.35.1) in 17 ml sodium hydroxide solution (1M) and 30 ml MeOH was stirred at rt overnight. The reaction mixture was neutralized with aq. HCl (1M) and concentrated. The residue was filtered and the filtercake was washed with diethyl ether.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[C:5](=[C:8]1[CH2:12][CH2:11][C:10]2([CH:17]([CH3:18])[CH2:16][C:15]([O:19]C(C)C)=[CH:14][C:13]2=O)[CH2:9]1)([CH3:7])[CH3:6].Cl>CCOCC>[C:5](=[C:8]1[CH2:12][CH2:11][C:10]2([CH:17]([CH3:18])[CH2:16][C:15](=[O:19])[CH:14]=[C:13]2[CH2:2][CH3:3])[CH2:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)=C1CCC2(C1)C(=O)C=C(OC(C)C)CC2C
Reactant: CCBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCC1=CC(=O)CC(C)C12CCC(=C(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A Grignard solution was prepared from magnesium (1.17 g, 0.048 g-atom) and ethyl bromide (5.2 g, 0.048 mol) in anhydrous ether (50 mL) under nitrogen. 2-Isopropylidene-8-isopropoxy-10-methylspiro[4.5]dec-7-en-6-one (4 g, 0.015 mol), prepared according to Example 2, in anhydrous ether (20 mL) was added dropwise at room temperature and the mixture then heated at reflux for 4 hours. The solution was cautiously added to 2 N hydrochloric acid (200 mL) and stirred for 1 hour at room temperature. The mixture was extracted with ether and the ether extracts washed with saturated sodium bicarbonate, brine, and dried (Na2SO4). Kugelrohr distillation afforded
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][O:16][C:17]2[C:18]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:19]=4[C:20](I)=[N:21][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:38]([B-](F)(F)F)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][O:16][C:17]2[C:18]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:19]=4[C:20]([CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[N:21][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: F[B-](F)(F)Cc1ccccc1
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1OCc1c2ccccc2cc2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1nc(Cc2ccccc2)c2c(-c3ccccc3)noc2c1OCc1c2ccccc2cc2ccccc12
Yield: 59 %

Procedure:
A flask was charged with ethyl 7-(anthracen-9-ylmethoxy)-4-iodo-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (200 mg, 0.33 mmol), potassium benzyltrifluoroborate (80 mg, 0.4 mmol), PdCl2(dppf) (27 mg, 0.033 mmol) and cesium carbonate (326 mg, 1.0 mmol). The flask was evacuated and refilled with nitrogen. THF (4 mL) and water (0.4 mL) were added and the mixture was refluxed for 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 0.5M hydrochloric acid. The aqueous layer was extracted with additional EtOAc and the organic layer was dried over MgSO4. After evaporation of solvent, the crude residue was purified by flash chromatography (0-30% EtOAc/hexanes) to give 110 mg of the title compound. MS: (+) m/z 565.38 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:29][O:30][C:31]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=2[CH:33]=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:29][O:30][C:31]2[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=2/[CH:33]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COc1cccc(C=O)c1OCC1CCCCC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CCCCC1
Yield: 47.1 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (350 mg, 1.072 mmol) with 2-cyclohexylmethoxy-3-methoxybenzaldehyde (372 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 281 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.03-1.10 (m, 2H), 1.18-1.25 (m, 3H), 1.68-1.79 (m, 6H), 3.60-3.68 (m, 2H), 3.77 (s, 3H), 6.81-6.88 (m, 2H), 6.91-6.96 (m, 3H), 7.40-7.46 (m, 5H), 7.98 (d, J=6.3 Hz, 1H), 8.14 (d, J=15.0 Hz, 1H); ESI-MS (m/z) 557.44 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:3][C:4]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=2[CH:6]=[O:7])=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c(C=O)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
0.85 g of sodium hydride was added in portions to a stirred solution of 5.00 g of 2-hydroxy-5-methoxybenzaldehyde in 90 mL of N,N'-dimethylformamide under nitrogen. To the resulting milky, green mixture was added 5.74 g of 1,4-dichloro-2-nitrobenzene. The reaction was placed in an oil bath and stirred at 90° C. for 16 hours. The reaction was then evaporated in vacuo, and the residue partitioned between 75 mL of chloroform and 75 mL of 1N NaOH. The layers were separated and the aqueous layer was extracted With 75 mL of chloroform. The chloroform extracts were combined and washed with water (2×75 mL) and brine (75 mL), dried over magnesium sulfate, and evaporated in vacuo. The semi-solid residue was triturated with diethyl ether. The precipitated product was collected by filtration, washed with ether, and dried in vacuo to yield 5.96 g (64.8%) of product as a yellow solid. Melting Point: 127°-128° C.
Reaction SMILES: [Na+:1].C([O:5][C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][C:39]=1[O:40]C(=O)C)[C:9]([NH:11][CH2:12][C:13]1[CH2:20][S:19][CH:18]2[N:15]([CH2:16][CH:17]2[NH:21][C:22](=[O:33])[C:23]([C:27]2[N:28]=[C:29]([NH2:32])[S:30][CH:31]=2)=[N:24][O:25][CH3:26])[C:14]=1[C:34]([O-:36])=[O:35])=[O:10])(=O)C.CC#N>C([O-])(O)=O.[Na+].CO>[Na+:1].[OH:5][C:6]1[CH:7]=[C:8]([CH:37]=[CH:38][C:39]=1[OH:40])[C:9]([NH:11][CH2:12][C:13]1[CH2:20][S:19][CH:18]2[N:15]([CH2:16][CH:17]2[NH:21][C:22](=[O:33])[C:23]([C:27]2[N:28]=[C:29]([NH2:32])[S:30][CH:31]=2)=[N:24][O:25][CH3:26])[C:14]=1[C:34]([O-:36])=[O:35])=[O:10]
Reactant: CON=C(C(=O)NC1CN2C(C(=O)[O-])=C(CNC(=O)c3ccc(OC(C)=O)c(OC(C)=O)c3)CSC12)c1csc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CON=C(C(=O)NC1CN2C(C(=O)[O-])=C(CNC(=O)c3ccc(O)c(O)c3)CSC12)c1csc(N)n1
Yield: 60 %

Procedure:
By following the procedures and conditions described in Example 29, 20 mg (0.031 mmol) of [6R-[6 alpha,7 beta(Z)]]-3-[[[3,4-bis(acetyloxy)benzoyl]amino]methyl]-7-[[2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt (Example 30) in 1 mL of saturated aqueous NaHCO3 and 500 μL of methanol gave 10 mg (60%) of a white solid after chromatography (reverse phase, 0-20% CH3CN) and lyophilization.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH2:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][C:21](=[O:23])[CH3:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Reaction time: 1 h

Procedure:
To a solution of 2-(6-fluoro-1H-indol-3-yl)-ethylamine (0.88 g) and NEt3 (2.27 ml) in CH2Cl2 (8 ml) was added acetic acid anhydride (0.43 ml) and stirring was continued at 22° C. for 1 h. The mixture was washed with 1 N aqueous HCl, the organic layer was dried and evaporated. The residue was chromatographed on silica using CH2Cl2/MeOH (25:1) to give the title compound as a pale yellow oil. MS: 219.1 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH2:14]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C(F)(F)F)cc1
Reaction time: 12 h
Yield: 51.3 %

Procedure:
4-(Trifluoromethyl)phenol (1.50 g, 9.25 mmol), allyl bromide (14.55 9, 12.03 mmol), Cs2CO3 (3.62 g, 11.10 mmol), and water (15 drops) were combined in DMF (40 mL) and the mixture stirred for 12 h. The reaction mixture was then concentrated under reduced pressure, diluted with water, and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 0.96 g (51%) of thetitle compound as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.59 (d, 2H), 5.32 (d, 1H), 5.43 (d, 1 H), 6.05 (m, 1H), 6.97 (d, 2H), 7.53 (d, 2H).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[C@H:21]([NH2:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35][C:36](=[O:38])[CH3:37])[CH3:31])=[O:11])=CC=1)([O-])=O.[H][H]>[Pd].O>[C:36]([NH:35][C:34]([O:33][CH2:32][C@@:13]1([CH3:31])[C@H:12]([C:10]([OH:11])=[O:9])[N:16]2[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[C@H:21]([NH2:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:15]2[S:14]1)=[O:39])(=[O:38])[CH3:37]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 62.8 %

Procedure:
To a prehydrogenated suspension of 10% palladium on carbon (0.59 gm), water-washed ethyl acetate (6.0 ml) and water (3.0 ml) was added (2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-6-[(R)-2-amino-2-phenylacetamido]-2-methylpenam-3-carboxylic acid p-nitrobenzyl ester (0.59 gm. 1.06 mmol). The mixture was shaken at 50 psi hydrogen pressure for 3 hours at 25° and then filtered through Dicalite-coated paper. The aqueous phase was separated, concentrated at reduced pressure to remove volatile solvent and gases, frozen and lyophilized. There was obtained 0.30 gm of the title compound as an amorphous solid. The purity was estimated from its nmr spectrum to be 60-70%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(=O)=O.CC(C)=O.[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:27]O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.ClCCCl.O.C(N(CC)CC)C.CS(C)=O>[CH2:29]([NH:36][CH2:27][C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: OC[C@@H]1CCCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CNC[C@@H]2CCCCN2Cc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A solution of dimethyl sulfoxide (0.219 ml) in dichloromethane (1.1 ml) was added dropwise to a solution of oxalyl chloride (0.133 ml) in dichloromethane (2.7 ml) under cooling below −60° C. with dry ice-acetone. After 5 minutes, the mixture was allowed to −10° C., and a solution of (2S)-1-benzyl-2-(hydroxymethyl)piperidine (156.5 mg) in dichloromethane (1.6 ml) was added to the mixture. The whole mixture was then cooled below −60° C. and was stirred for 20 minutes at the same temperature. After addition of triethylamine (0.64 ml) followed by stirring at room temperature, the reaction mixture was poured into water and extracted with 1,2-dichloroethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. Benzylamine (0.33 ml) was added to the solution of the syrup obtained above procedure in 1,2-dichloroethane (2.5 ml) with ice-cooling. After the whole was stirred for 30 minutes at the same temperature, sodium triacetoxyborohydride (0.323 g) was added to this mixture. The reaction mixture was allowed to room temperature and was stirred for 3 hours. The mixture was poured into aqueous saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography using a mixture of dichloromethane and methanol (20:1) as an eluent to give N-benzyl-[(2S)-1-benzylpiperidin-2-ylmethyl]amine (168.5 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](NN)[N:5]=[C:4]([C:11]#[N:12])[C:3]=1[Cl:13].S(Cl)([Cl:17])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:17])[N:5]=[C:4]([C:11]#[N:12])[C:3]=1[Cl:13]
Reactant: N#Cc1nc(NN)c(F)c(N)c1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1nc(Cl)c(F)c(N)c1Cl
Temperature: 25 °C
Reaction time: 40 h
Yield: 76 %

Procedure:
To a suspension of 4-amino-3-chloro-5-fluoro-6-hydrazinylpicolinonitrile (9.04 g, 44.8 mmol) in CH2Cl2 (150 mL) was added sulfuryl chloride (7.20 mL, 89 mmol). The mixture was stirred at room temperature for 40 h. The solvent was removed under reduced pressure, and the residue was partitioned with saturated aqueous sodium bicarbonate (NaHCO3) and EtOAc. The organic phase was separated, dried over Na2SO4, and filtered. The solution was concentrated and the residue was purified by silica gel chromatography to give the product (7.01 g, 76%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.55 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 143.26 (d, J=259.2 Hz, C5), 142.69 (d, J=14.0 Hz, C4), 135.53 (d, J=17.6 Hz. C6), 126.07 (d, J=4.4 Hz, C2), 120.14 (d, J=4.3 Hz, C3), 114.36 (s, CN); 19F NMR (376 MHz, DMSO-d6) δ −132.30 (s); ESIMS m/z 203 ([M+H]+), 206.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].C1CCC(N=C=NC2CCCCC2)CC1.ClCCl.[C:44](O)(=[O:46])[CH3:45]>CN(C)C1C=CN=CC=1.CCCCCC>[C:44]([O:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6])(=[O:46])[CH3:45]
Reactant: COc1ccc(OC)c2c(OC)c(C(O)CCC(C)C)cc(OC)c12
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(OC)c2c(OC)c(C(CCC(C)C)OC(C)=O)cc(OC)c12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
In a 25 ml two-neck flask 1 mmole of 2-(1-hydroxy-4-methylpentyl)-1,4,5,8-tetramethoxynaphthalene, 226 mg (1.1 mmole) of DCC and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were introduced and then 3 ml of dry dichloromethane was added thereto. After adding 1 mmole of acetic acid at 0° C. under nitrogen gas, the reaction mixture was stirred for 30 minutes and then subsequently stirred at normal temperature for further 3 hours. To the reaction mixture was added 20 ml of n-hexane. The mixture was stirred for further 10 minutes and then filtered to remove the insoluble materials. The filtrate was dried over anhydrous magnesium sulfate to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 2.5×20 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 20:1 to 5:1, to obtain the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[O:18][C:19]=1[CH3:20].CCOCC>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[O:18][C:19]=2[CH3:20])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of cis-3-allylcyclohexanol are dissolved in 30 ml of dimethylformamide, and 750 mg of sodium hydride (60% strength suspension in paraffin oil) are added. After 30 minutes, 6.7 g of 4-iodomethyl-5-methyl-2-(3-methylphenyl)oxazole, dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture is stirred at room temperature for 1 hour. 200 ml of methy tert-buthyl ether are then added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 1.56 g of 4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazole as an oil. C21H27NO2 (325.45), MS (ESI): 326 (M+H+), Rf(n-heptane:ethylacetate=2:1)=0.28.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[CH:3]1([N:2]([CH3:1])[S:12]([CH:11]=[CH2:10])(=[O:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Product: C=CS(=O)(=O)N(C)C1CCCCC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of N-methylcyclohexylamine (0.048 mol) and TEA (0.053 mol) in DCM (200 mL) was cooled in an ice bath to 5° C., and then a solution of 2-chloro-ethanesulfonyl chloride (0.048 mol, 97%) in DCM (20 mL) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature and then was washed with H2O. The organic layer was separated, dried (MgSO4), and filtered, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CCC(=O)O)ccc1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 8.0 g. (0.025 mole) of ethyl 5-(ρ-chlorobenzoyl)-1-methylpyrrole-2-propionate in 15 ml. ethanol and 30 ml. 1N sodium hydroxide is refluxed for one hour. The ethanol is then evaporated, and the remaining solution is poured into dilute hydrochloric acid. The remaining solution is poured into dilute hydrochloric acid. The resulting white precipitate is filtered off and purified by recrystallization from isopropyl alcohol, 5-(ρ-chlorobenzoyl)-1-methylpyrrole-2-propionic acid, M.P. 188°-191° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([NH2:14])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].N.O>C(O)C.CCOCC>[C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1cc(SC2=CCCCC2)ccc1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Nc1ccc(SC2=CCCCC2)cc1N

Procedure:
To a suspension of 3.5 g (0.014 mole) of 5-(1-cyclohexen-1-ylthio)-2-nitrobenzene-amine in 125 ml of absolute ethanol under N2 there is added a solution of 8.4 g of Na2S2O4, 8.4 ml of concentrated aqueous ammonia and 52.5 ml of water. The mixture is refluxed for 15 minutes and an additional 0.8 g of Na2S2O4 is added. After an additional 15 minutes reflux period TLC (silica, Et2O) shows no starting material present. The ethanol is removed in vacuo; the aqueous residue is taken to pH 12 with 50% aqueous NaOH and then extracted with CH2Cl2. The organic extracts are combined, dried (MgSO4) and evaporated to give an oil which is used immediately in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:21][CH:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:47])[CH2:43][C:44](O)=[O:45].C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Si:23]([O:22][CH:20]1[CH2:21][N:18]([C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:30]=[CH:31][C:2]([NH:1][C:44](=[O:45])[CH2:43][C:42]([NH:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][CH3:33])=[O:47])=[CH:3][C:4]=3[F:32])[CH:13]=2)=[O:17])[CH2:19]1)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O[Si](C)(C)C(C)(C)C)C4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A mixture of (7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)methanone 274 (145.2 mg, 0.31 mmol), 27 (77 mg, 0.367 mmol), and EDC (70.3 mg, 0.367 mmol) in DMF (4.4 mL) was stirred overnight at room temperature. The crude mixture was diluted with EtOAc, extracted with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure affording crude 275 (178.4 mg, 0.269 mmol, 87% yield) that was used in the next step without further purification. MS (m/z): (M+1) 665.1 (100%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C@@H:20]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH2:15]2)=[CH:10][CH:9]=1)C.[OH-].[Na+].[ClH:36]>C(O)C>[ClH:36].[C:22]1([C@H:20]([NH:19][C@H:16]2[CH2:17][CH2:18][C@@H:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:33])=[O:3])=[O:32])=[CH:13][CH:12]=3)[CH2:15]2)[CH3:21])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CNC(=O)c1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(C(=O)NCC(=O)O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
N-{4-[(1R,3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}cyclopentyl]benzoyl}glycine ethyl ester (139 mg, 0.31 mmol) was dissolved in ethanol (2 mL), followed by addition of 1N aqueous sodium hydroxide (2 mL), and the mixture was stirred for 4 hours at room temperature. 1N hydrochloric acid was added dropwise to the reaction mixture to make the reaction solution acidic, and the solvent was distilled off under reduced pressure. Diisopropyl ether and water were added to the reaction mixture, followed by ultrasonic wave treatment, and then the solid generated was collected by filtration to give the title compound (52 mg, 37%).