Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1([CH:27]2[CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][N:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH:27]([N:22]5[CH:26]=[CH:25][N:24]=[N:23]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 91.8 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.18 mmol) was reacted with 3-(1,2,3-triazol-1-yl) azetidine hydrochloride (72 mg, 0.45 mmol) in 3 ml of dry pyridine in the presence of 68.5 mg (0.45 mmol) of DBU at 80° C. for 16 h. The yellow solution was then evaporated to dryness, water was added to the residue, solid was collected and dried to yield 64 mg (92%) of the desired product. m.p. 315°-316° C. 1H NMR (TFA) δ: 9.26 (s, 1H), 8.75 (d, 1.2Hz, 1H), 8.60 (d, 1.2Hz, 1H), 8.10 (d, 11.8Hz, 1H), 6.35-6.0 (m, 1H), 5.8-5.15 (m, 4H), 4.65-4.3 (m, 1H), 1.9-1.3 (m, 4H). Anal. calcd. for C18H15F2N 5 O3H2O: C, 53.33; H, 4.23; N, 17.28. Found: C, 53.68; H, 4.23; N, 17.28.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1cc(F)c(F)cc1C(=O)c1cccnc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1cc(F)c(F)cc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the general procedures for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-4,5-difluoro-phenyl)-pyridin-3-yl-methanone 1 g (4.27 mmol) and 4-bromo-benzenesulfonyl chloride 1.15 g (4.27 mmol) with stirring in 20 ml pyridine. Purification on silica gel with flash column chromatography yielded light orange solid
Reaction SMILES: O=[C:2]([CH2:8][C:9]([O:11]C)=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[OH:11][C:9]1[N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:20]=[C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:8]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: c1ccccc1
Product: COC(=O)Cc1cc(O)n(-c2ccccc2)n1
Yield: 80 %

Procedure:
The mixture of dimethyl 3-oxopentanedioate (10 mmol, 1.74 g) and phenylhydrazine (10 mmol, 1.08 g) in dry benzene (50 ml) was refluxed for 8 h, then solvent was removed in vacuo and the title compound was separated by recrystallization from i-PrOH (20 ml). Yield: 80%. 1HNMR (500 MHz, DMSO-d6, ppm): 3.49 (2H, s), 3.68 (3H, s), 5.43 (1H, s), 7.12 (1H, t, 7.4 Hz), 7.35 (2H, t, 7.6 Hz), 7.78 (2H, d, 7.9 Hz), 11.1 (1H, bs)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[C@@H:13]([CH3:32])[CH2:12]1)=O)C1C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1>>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH:42][C:27]2[N:26]=[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][NH:17][C@@H:14]4[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]4[CH3:32])[CH:20]=3)[CH:30]=[CH:29][N:28]=2)=[CH:36][CH:35]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NCc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CNCC[C@H]1NCc1cccc(-c2ccnc(NCCc3ccc(Br)cc3)n2)c1

Procedure:
Intermediate 136 was coupled with 2-(4-bromo-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G3. LC-MS showed the product had the expected M+H+ of 481. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.67 (s, 1H) 8.39 (d, 2H) 7.95 (d, 1H)) 7.69 (t, 1H) 7.40 (d, 2H) 7.28 (d, 2H) 4.50 (s, 2H) 4.00 (m, 1H) 3.84 (m, 1H) 3.72 (m, 1H) 3.57 (m, 1H) 3.42 (d, 1H) 3.36 (d, 1H) 3.20 (t, 2H) 3.04 (t, 2H) 2.30 (m, 2H) 1.30 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].OS(O)(=O)=O.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCO
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(Cl)cc1Cl

Procedure:
To a stirred solution of (2E)-3-(2,4-Dichlorophenyl)acrylic acid (10 g, 46 mmol) in ethanol (60 ml) was added conc. H2SO4 (2.5 ml). The mixture was heated to reflux and for 48 H, then allowed to cool, concentrated in vacuo, dissolved in ethyl acetate, washed three times with 4N NaOH, dried over sodium sulfate and concentrated in vacuo to afford ethyl (2E)-3-(2,4-dichlorophenyl)acrylate (10.7 g) as pale brown crystals. 1H NMR δ (ppm)(CDCl3): 8.00 (1 H, d, J=16.1 Hz), 7.55 (1 H, d, J=8.5 Hz), 7.44 (1 H, d, J=1.9 Hz), 7.26 (1 H, dd, J=2.0, 8.4 Hz), 6.41 (1 H, d, J=16.1 Hz), 4.28 (2 H, q, J=7.1 Hz), 1.34 (3 H, t, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([CH2:10][Br:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1Br
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A mixture of 2-bromo-4-methylbenzonitrile (13.3 g, 81.4 mmol), NBS (14.4 g, 84.4 mmol) and BPO (0.20 g) in CCl4 (150 mL) was heated for 4 h at reflux. The reaction mixture was cooled to room temperature and filtered. Then the solid was washed with CCl4 (20 mL×2) and the combined filtrate was washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL). The organic phase was dried over Na2SO4 and concentrated in vacuum afforded the titled compound, 2-bromo-4-(bromomethyl)benzonitrile (18.7 g, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.ClC[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: ClCCc1ccccn1
Agent: Cl
Product: N#Cc1ccnc(-c2cn(Cc3ccccn3)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 2-(chloroethyl)pyridine hydrogen chloride according to the procedure for the preparation of Example 43, part A. [M+H] Calc'd for C15H11N5, 262. Found, 262.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:18](O)(C)C>C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:10]=1)=[O:5])([CH3:18])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1cn(-c2cccc(Cl)c2)cn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)c1cn(-c2cccc(Cl)c2)cn1
Yield: 63 %

Procedure:
A solution of 0.4 g of 1-(3-chlorophenyl)-imidazole-4-carboxylic acid ethyl ester in 40 ml of i-propanol is mixed with 0.5 ml of titanium tetraisopropanolate and refluxed for 8 hours. After concentration of the solution, it is filtered over silica gel and recrystallized from diisopropyl ether. 267 mg (63%) of the title compound with a melting point of 109° C. is obtained from diisopropyl ether.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:35])=[C:9]([C:31]([Cl:34])=[CH:32][CH:33]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:6])=[O:4].[C:36]([NH:44][C:45]1[CH:55]=[CH:54][C:48]([CH:49]=[CH:50][C:51](O)=[O:52])=[CH:47][CH:46]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:35][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:51](=[O:52])[CH:50]=[CH:49][C:48]2[CH:47]=[CH:46][C:45]([NH:44][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)=[CH:55][CH:54]=2)=[CH:33][CH:32]=[C:31]([Cl:34])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: O=C(O)C=Cc1ccc(NC(=O)c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)c5ccncc5)cc4)c3Cl)c2n1
Reaction time: 24 h
Yield: 42.5 %

Procedure:
To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (30 mg) and 4-(isonicotinamido)cinnamic acid (17 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg) and 1-hydroxybenzotriazole (11 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacua. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(isonicotinamido)cinnamoylglycyl]amino]-benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (19 mg) as an amorphous powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:2]1
Reactant: C1CCNC1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCc1c[nH]c2ccccc12)N1CCCC1

Procedure:
681 mg (3.60 mmol) 3-(1H-indol-3-yl)-propionic acid, 0.3 mL (3.60 mmol) pyrrolidine, 1.13 g (3.50 mmol) TBTU and 0.98 mL (7.00 mmol) triethylamine in 5.0 mL DMF were stirred overnight at RT. The mixture was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [C:1]([CH:4]([CH2:15][CH2:16][CH2:17][SH:18])[CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(O)=[O:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[O:2]=[C:1]1[CH:4]([CH2:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:15][CH2:16][CH2:17][S:18]1
Reactant: O=C(O)c1cccc(CC(CCCS)C(=O)O)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc(CC2CCCSC2=O)c1
Yield: 63.9 %

Procedure:
A solution of 3-(2-carboxy-5-mercaptopentyl)benzoic acid (5.12 g, 20 mmol) and 10-camphorsulfonic acid (500 mg) in toluene (30 mL) was refluxed for 6 hours. The liberated water was removed using a Dean-Stork azeotropic adapter. Toluene was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/hexanes, 1:4). Fractions containing the product were collected, evaporated and recrystallized from EtOAc/hexanes to afford 3.2 g of 3-[(2-oxotetrahydro-2H-thiopyran-3-yl)methyl]benzoic acid as a white solid (67% yield): 1H NMR (CDCl3) δ 1.58-1.68 (m, 1 H), 1.90-2.02 (m, 2 H), 2.04-2.13 (m, 1 H), 2.68 (m, 1 H), 2.78-2.86 (m, 1 H), 3.08-3.19 (m, 2 H), 3.37-3.44 (m, 1 H), 7.38-7.48 (m, 2 H), 7.93 (brs, 1 H), 7.94-8.02 (m, 1 H); 13C NMR (CDCl3) δ 22.6, 27.8, 31.1, 36.8, 52.0, 128.8, 129.2, 129.8, 131.3, 135.3, 140.1, 172.6, 203.7. Analysis calculated for C13H14O3S: C, 62.38; H, 5.64; S, 12.81. Found: C, 62.19; H, 5.65; S, 12.59.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[I:23]I>C1C=CC=CC=1>[I:23][C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: II
Reactant: CCOC(=O)Cc1ccc(-c2ccc3occ(C)c3c2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc3oc(I)c(C)c3c2)cc1
Temperature: 62.5 °C

Procedure:
To a solution of 2.8 g. of the product of step B in 50 ml. of benzene is added 2.7 g. of iodine and 2.4 g. of mercuric oxide followed by stirring and heating at 60-65° C. for about three days. The mixture is cooled and evaporated, and the residue is chromatographed on silica gel, eluting with a carbon tetrachloride-dichloromethane mixture, to provide ethyl 4-(2-iodo-3-methylbenzofuran-5-yl)phenylacetate. To this intermediate is added dichloromethane, then dinitrogen tetraoxide. After one hour the mixture is washed with water, then with sodium bisulfite solution and dried. Evaporation provides a residue which is recrystallized from a dichloromethane-hexane mixture to yield ethyl 4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=[O:18])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:21]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 85.4 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.40 g, 2.6 mmol), 3-ethoxy-4-hydroxybenzaldehyde (0.43 g, 2.6 mmol) and cesium carbonate (0.84 g, 2.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 20 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (1×), 0.5N sodium hydroxide solution (1×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(2-ethoxy-4-formylphenoxy)benzonitrile (0.67 g, 86%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=NN=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>O1CCCC1.CO>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[N:10]=[N:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:28][C:27]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1ccccc1-c1nnc(-c2ccccc2Cl)nn1
Reactant: O=CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccccc1-c1cc(-c2ccccc2)c(-c2ccccc2Cl)nn1
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
3,6-Bis(2-chlorophenyl)-1,2,4,5-tetrazine (4.6 g) and phenylacetaldehyde (2.0 g) were dissolved in tetrahydrofuran (60 ml). A solution of potassium hydroxide in methanol (1.5 ml, 1%) was added dropwise to the solution and left to stand for 5 minutes. The solution was evaporated to 20 mls volume and was then diluted with water (50 ml). The precipitated solid was filtered, washed with water and dried to give 5.5 g of desired product, mp 176°-178° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24](=[O:36])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:38])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24](=[O:36])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=3)=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)C(=O)Nc3cccc(C(F)(F)F)c3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1cc(-c2ccc(NC(=O)C(=O)Nc3cccc(C(F)(F)F)c3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.6 %

Procedure:
To methyl 3-methyl-2-(3-(4-(2-oxo-2-(3-(trifluoromethyl)phenylamino)acetamido) phenyl)isoxazole-5-carboxamido)butanoate (100 mg) in THF (2 ml) 1 M aqueous solution of Lithium hydroxide monohydrate (0.375 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to yield 22 mg (22%) of the title compound as white solid. MS (ES+): m/z 519 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 11.24 (s, 1H), 11.13 (s, 1H), 9.01 (d, 1H), 8.35 (dd, 1H), 8.16 (dd, 1H), 8.06 (d, 2H), 7.96 (d, 2H), 7.73 (s, 1H), 7.64 (m, 1H), 7.54 (dd, 1H), 4.28 (m, 1H), 2.23 (m, 1H), 0.98 (d, 6H).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]2)=[N:17][CH:18]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Temperature: 150 °C
Yield: 91.5 %

Procedure:
1.03 g (5 mmol) of 1,1-dimethylethyl 1,4-diazepane-1-carboxylate, 1.19 g (5 mmol) of 2,5-dibromopyridine and 0.7 g (5 mmol) of potassium carbonate suspended in 0.90 ml of dimethyl sulfoxide (DMSO) are introduced into an autoclave. The mixture is heated at 150° C. for 22 hours. The reaction mixture is allowed to cool to room temperature, it is taken up in ethyl acetate, and the organic solution is washed with water and then brine, and dried over sodium sulfate. The filtrate is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 99.5/0.5 mixture of dichloromethane and methanol. 1.63 g of product are obtained in the form of an oil, and are used without further purification in the following step.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CO)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a well stirred solution of 2-hydroxyacetophenone (1.0 g, 7.34 mmol) in dichloromethane (15 mL) is added triethylamine (1.23 mL, 8.81 mmol), 4-dimethylaminopyridine (45 mg, 0.367 mmol) and tert-butyldimethylsilyl chloride (1.16 g, 7.71 mmol) dissolved in dichloromethane (2 mL). The reaction mixture is stirred at room temperature for 1 h, then diluted with dichloromethane (50 mL), washed with 10% citric acid, saturate sodium carbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (20% ethyl acetate in hexanes) to yield the title compound as a yellow oil (1.3 g, 5.19 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.O.[NH2:13][NH2:14]>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:13][NH2:14])=[O:10]
Reactant: COC(=O)Cc1cnccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1cnccn1
Temperature: 120 °C
Yield: 80 %

Procedure:
In a 25 mL sealed tube, methyl 2-(pyrazin-2-yl)acetate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.33 g, 4 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 2-(pyrazin-2-yl)acetohydrazide (0.2 g) which was used without further purification in the following step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[N:27]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)=[O:37])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:29][CH2:28][N:27]([CH2:33][CH2:34][NH:35][C:36](=[O:37])[C:38]2[CH:45]=[CH:44][C:41]([C:42]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:40][CH:39]=2)[CH2:32][CH2:31]1
Reactant: O=Cc1ccc(C(=O)NCCN2CCOCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: O=C(NCCN1CCOCC1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 231 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(2-morpholinylethyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C31H34N6O3: 539.28; found: 539.63.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([SH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)=O>C(O)C.O>[CH2:18]([S:17][C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S)c(C(=O)O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(SCc2ccccc2)c(C(=O)O)c1
Yield: 89 %

Procedure:
To a solution of 4.15 g. (0.030 moles) of potassium carbonate in 50 ml. of water is successively added 100 ml. of ethanol, 5.05 g. (0.030 moles) of 5-methyl-2-mercaptobenzoic acid, and 3.8 g. (0.030 moles) of benzyl chloride. After the evolution of carbon dioxide ceases (about 10 minutes), the mixture is refluxed on a steam bath for one hour. The mixture is cooled, and the major portion of the solvent is evaporated under reduced pressure. The cloudy, white liquid residue is diluted to a volume of about 600 ml. with water. The mixture is filtered, cooled, and acidified with 6 N hydrochloric acid. The white precipitate which forms is separated, filtered, and triturated with about 400 ml. of water. Filtration and drying under high vacuum provides 6.9 g. (89 percent yield) of 2-benzylthio-5-methylbenzoic acid, m.p. 169°-171°C. sint. 167°C.