Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Temperature: -18 °C
Yield: 38 %

Procedure:
1.64 g of ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 3 g of tributylstannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 42 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to approx. -18° C. and filtered. After the filter residue has been dried, 0.74 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate is obtained (38% of theory).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([C:24]([NH2:26])=[O:25])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=O)C.Cl.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([C:24]([NH2:26])=[O:25])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C1CN(c2cccc(N)c2)CCN1Cc1ccccc1

Procedure:
To 4-[3-(acetylamino)phenyl]-1-(phenylmethyl)-2-piperazinecarboxamide (14.0g, 39.9 mmol) in methanol (115 mL) add 6N aqueous hydrochloric acid (28 mL). Stir the reaction at reflux. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction adjust the pH to 12 with 4N aqueous NaOH to obtain a white precipitate. Filter the precipitate to obtain the title compound.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(Cl)Cl>[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([CH2:31][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:29][CH:30]=3)=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:15])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CO)cc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Under ice-cooling, 628 mg (5.5 mmol) of methanesulfonyl chloride was added dropwise to a solution of 1.83 g (5 mmol) of 1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester and 1.52 g (15 mmol) of triethylamine in methylene chloride. After the mixture was stirred at room temperature for 1 hour, 5 ml of morpholine was added thereto and the mixture was stirred overnight. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1 g (57%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=N1.Br[CH2:25]C1C=CC(C2OC3C=CC=CC=3N=2)=CC=1OC.N1C=CN=C1>>[N:10]1([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:15]3[O:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:4][C:3]=2[O:2][CH3:1])[CH:14]=[CH:13][N:12]=[CH:25]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Agent: c1c[nH]cn1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnc1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and imidazole (70 mg, 1.0 mmol) afforded the desired 2-[4-(1H-imidazol-1-ylmethyl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.57–7.86 (m, 6H), 7.26–7.40 (m, 4H), 5.53 (s, 2H), 4.02 (s, 3H). MS (ESI) 306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18](O)=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1[CH3:31])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH2:73][NH2:74])[CH2:67][CH2:66]1>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([NH:74][CH2:73][CH2:72][CH2:71][N:68]4[CH2:69][CH2:70][O:65][CH2:66][CH2:67]4)=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1[CH3:31])=[O:25]
Reactant: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)ccc1F
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)NCCCN4CCOCC4)c[nH]3)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Example 28) (150 mg, 0.36 mmol) in 10 ml of anhydrous DMF were added HATU (163 mg, 0.43 mmol) and N,N-diisopropylethylamine (102 mg, 0.79 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-morpholinopropylamine (104 mg, 0.72 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 10% methanol in chloroform to give 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 110 mg, 56%.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>C1COCC1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:8])[CH2:21][O:22]1
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(Cl)cc2Cl)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and the reaction mixture was stirred for 10 min. after which the solution of 1-(2,4-dichlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:25])=[C:19]([CH:20]=[CH:21][C:22]=1[CH3:23])[O:24][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Cc1ccc(O)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A solution of 3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-dimethyl-phenol (340 mg, 1.0 mmol, 1.0 eq) and Cs2CO3 (489 mg, 1.5 mmol, 1.5 eq) in 2-butanone (20 mL) was stirred at room temperature for 30 min. Ethyl 2-bromoacetate (167 mg, 1.0 mmol, 1.0 eq) was added and the reaction mixture was stirred at for 3 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the organic extract dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as a gummy solid (300 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1Br
Yield: 46 %

Procedure:
2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4-dichlorobenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 138°-141° C., yield 46%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1>>[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([I:11])=[N:6]2)[CH2:15][CH2:14]1
Reactant: OC1CCC(F)(F)CC1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2C1CCC(F)(F)CC1
Yield: 17 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 4,4-difluorocyclohexanol in 17% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.94-2.17 (4H, m), 2.34-2.52 (4H, m), 4.67-4.73 (1H, m), 7.02 (1H, dd, J=2.4, 8.4 Hz), 7.11 (1H, td, J=2.4, 9.2 Hz), 7.67 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[CH2:18][CH2:17][CH2:16]2.I[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([CH2:36][N:12]([CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[CH2:18][CH2:17][CH2:16]2)=[O:38])[CH3:41]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCc4ccc5ccccc5c4)ccc32)cc1
Reactant: CCOC(=O)CI
Product: CCOC(=O)CN(Cc1ccc2ccccc2c1)c1ccc2c(c1)CCCN2C(=O)CCc1ccc(C#N)cc1

Procedure:
Prepared from 6-[(naphthalin-2-ylmethyl)-amino]-1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline (see Example 14(2)) and ethyl iodoacetate
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:6]([O:8]C)=[O:7].[OH-].[K+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:6]([OH:8])=[O:7]
Reactant: COCCC(C(=O)OC)n1cccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCC(C(=O)O)n1cccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of 0.045 g (0.23 mmol) of methyl 4-methoxy-2-(1H-pyrazol-1-yl)butanoate from step A above in 2 mL of methanol was added a solution of 0.032 g (0.57 mmol) of potassium hydroxide in 0.5 mL of water. The mixture was stirred at ambient temperature for 1.5 h then acidified with a 2 N hydrochloric acid solution until a pH of 4 was achieved. The mixture was evaporated to remove all volatiles then extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound (0.040 g, 95%). LC-MS: m/z (ES) 185 (MH)+.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25](O)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl>C1COCC1>[CH2:25]([CH:2]([CH2:1][CH2:7][CH2:8][CH3:9])[C:3]([OH:4])=[O:16])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous THF (50 mL). Octanoic acid (15.12 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) was dissolved in the solution. When the catalyst was fully dissolved, EDC HCl (18.32 g, 95.6 mmol) was added into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was stripped of THF via rotoevaporation and redissolved into chloroform. The organic layer was washed 2× with sodium bicarbonate buffer and 2× with deionized water to remove unreacted starting materials. The chloroform was removed to yield a clear viscous liquid. NMR analysis supported full conversion of hydroxyl groups to the octanoic esters.
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[OH:26][C@H:27]([C@H:32]([NH:36][C:37](=[O:98])[C@H:38]([NH:60][C:61](=[O:97])[C@H:62]([NH:67][C:68](=[O:96])[CH2:69][C@@H:70](O)/[CH:71]=[CH:72]/[CH2:73][CH2:74][S:75][C:76]([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[CH2:63][CH:64]([CH3:66])[CH3:65])[CH2:39][S:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)Cl.C1COCC1>[OH:26][C@@H:27]1[CH2:28][C:29](=[O:31])[O:30][C@H:70](/[CH:71]=[CH:72]/[CH2:73][CH2:74][S:75][C:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:69][C:68](=[O:96])[NH:67][C@H:62]([CH2:63][CH:64]([CH3:65])[CH3:66])[C:61](=[O:97])[NH:60][C@H:38]([CH2:39][S:40][C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:37](=[O:98])[NH:36][C@@H:32]1[CH:33]([CH3:34])[CH3:35]
Reactant: CC(C)C[C@@H](NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(C)C)[C@@H](O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@H]1NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)C[C@@H](O)[C@@H](C(C)C)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC1=O
Yield: 46.7 %

Procedure:
To a solution of 2-methyl-6-nitrobenzoic anhydride (MNBA) (32.7 mg, 0.095 mmol) and DMAP (22.5 mg, 0.184 mmol) in CH2Cl2 (20 mL) was added dropwise a solution of acid 5C (76 mg, 0.075 mmol) in CH2Cl2/THF (2:1, 66 mL) over 3 hours. After a further 12 h the reaction was quenched by the addition of 1M HCl (30 mL). The organic phase was separated (extracting with CH2Cl2) and washed with sat NaHCO3 (30 mL), followed by brine (30 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography on silica gel (eluent 40% EtOAc/Hexane) gave 6C (35 mg, 0.035 mmol, 47%) as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH:13]([CH3:21])[C:14](=O)[C:15]([O:17][CH2:18]C)=[O:16]>O1CCCC1>[CH3:21][C:13]1[N:7]2[C:6]([C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[CH:9]=[CH:8]2)=[N:11][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: Nc1nccc2ncccc12
Reactant: CCOC(=O)C(=O)C(C)Br
Solvent: C1CCOC1
Product: COC(=O)c1nc2c3cccnc3ccn2c1C
Yield: 63.5 %

Procedure:
A solution of 1,6-naphthyridin-5-amine (700 mg, 4.83 mmol) in tetrahydrofuran (25 mL) was added ethyl 3-bromo-2-oxobutanoate (1.51 g, 7.24 mmol). The mixture was stirred at reflux for 36 h. Then the mixture was concentrated under reduced pressure, and purified by column chromatography to give 740 mg of the product as a yellow solid. MS (ESI): m/z 256.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1O.[NH3:11]>[Pd].[Mn].[Ag]>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[CH:3]1[NH2:11]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: N
Agent: [Ag]
Agent: [Mn]
Agent: [Pd]
Product: CC1CCC(C)C(N)C1C
Yield: 95.7 %

Procedure:
A mixture of 550 g of 2,3,6-trimethylphenol and 510 g of ammonia and 50 g of catalyst which contains 5.0% by weight of palladium, 1.0% by weight of manganese and 5.0% by weight of silver on aluminum oxide in powder form is hydrogenated at 220° C. and under a hydrogen pressure of 200 bar in a 3 l rolling autoclave. The mixture is cooled and filtered and the filtrate is distilled. 546 g of 2,3,6-trimethylcyclohexylamine, boiling point=78°-81° C./22 mbar, are obtained, corresponding to a yield of 96%.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:16](C)([C:22](OCC)=O)[C:17]([O:19]CC)=[O:18]>C(O)(=O)C.O>[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH:16]([CH3:22])[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1F
Yield: 77 %

Procedure:
Concentrated sulfuric acid (7.5 mL) was added to compound (4) obtained above (7.09 g, 22.6 mmol) in acetic acid (26 mL) and water (18 mL), and the obtained mixture was heated to reflux for 12 hours. After completion of the reaction, the mixture was cooled and concentrated under reduced pressure, and the residue was extracted with dichloromethane. The extract was washed with saturated saline and water and dried (over sodium sulfate). The solvent was then distilled off under reduced pressure to give 3.72 g (77%) of compound (5) of interest as clear reddish brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N>C1COCC1.O>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-amino-3-methoxy benzoic acid (5.00 g, 29.9 mmol) in THF (50 mL) were added EDCl (6.88 g, 35.9 mmol), HOBt (4.85 g, 35.9 mmol), N-methylmorpholine (3.60 g, 35.9 mmol), and aqueous ammonia (50% v/v, 30 mL). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the product was extracted with ethyl acetate (2×250 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Removal of solvent gave product 2-amino-3-methoxy-benzamide as a light orange solid. Yield: 1.70 g (34%).
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([CH3:11])=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH3:10][C:9]1[C:4]([C:1](=[N:13][OH:14])[CH3:2])=[N:5][CH:6]=[C:7]([CH3:11])[N:8]=1
Reactant: NO
Reactant: CC(=O)c1ncc(C)nc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1ncc(C)nc1C
Yield: 87.1 %

Procedure:
2-Acetyl-3,5-dimethylpyrazine (2.65 g), hydroxylamine hydrochloride (2.5 g) and sodium acetate trihydrate (3.5 g) were refluxed in methanol (50 ml) for 1 hour. The reaction mixture was concentrated, diluted with water (75 ml) and extracted with ethyl acetate. The combined extracts were dried and concentrated to give an oil which was triturated with ether and 60°-80° C. petrol to give 3,5-dimethyl-2-(1-hydroximinoethyl)pyrazine (2.54 g, 87% yield) as a white solid (m.p. 85°-89° C.) and as a 1:1 mixture of (E/Z) isomers.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(C#N)c1
Product: CN(C)/C=C/C(=O)c1cccc(C#N)c1
Temperature: 120 °C

Procedure:
3-Acetylbenzonitrile (0.435 g, 0.00300 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.400 mL, 0.00301 mol) were combined and heated in sealed tube to 120° C. in the microwave for 15 min. The reaction was then allowed to cool to rt giving the 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-benzonitrile as a red-orange crystalline material, LC/MS (M+H)+: 201.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(N)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.17 g, 0.615 mmol) in dry DCM (10 mL) were added tert-butyl 4-aminopiperazine-1-carboxylate 205 (0.19 g, 0.923 mmol), 1-hydroxybenzotriazole (0.125 g, 0.923 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.177 g, 0.923 mmol) and 4-dimethylaminopyridine (0.113 g, 0.923 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 206 (0.25 g, 88%) as a clear thick oil.