Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>C(O)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:19](=[N:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccccc1
Temperature: 120 °C
Yield: 59.2 %

Procedure:
A solution of 2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol) in 50 mL of isopropanol was treated with benzaldehyde (0.66 mL, 6.50 mmol) and 10 mg of p-toluenesulfonic acid. The reaction mixture was heated to 120° C. for 3 d. The reaction mixture was cooled, and a precipitate started to form. The reaction mixture was treated with Et2O and then filtered to give N-benzylidene-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.21 g) as a gray solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[O:27]CCBr)[C:17]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:27][C:26]1[CH:25]=[C:24]([CH:33]=[CH:32][CH:31]=1)[O:23][CH2:16][CH2:17][N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: BrCCOc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3cccc(O)c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (294 mg, 1.30 mmol), 2-(3-benzyloxyphenoxy)ethyl bromide (399 mg, 1.3 mmol) and potassium carbonate (449 mg, 3.2 mmol) in two steps as white-off solid (230 mg): mp 163-165° C. 1H NMR (CD3OD) 1.421 (m, 2 H), 1.733 (m, 2 H), 2.135 (s, 3 H), 2.424 (d, J=5.7 Hz, 2 H), 2.9 (m, 2 H), 3.370 (m, 2 H), 3.448 (m, 2 H), 4.147 (t, J=4.8 Hz, 2 H), 6.302 (m, 3 H), 6.937 (m, 5 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]3)[CH:7]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:22]=[C:13]1[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11][C:10]2[C:15](=[CH:16][C:17]([C:18]([F:20])([F:21])[F:19])=[C:8]([N:6]3[CH:7]=[C:3]([CH2:2][O:1][C:35](=[O:36])[NH:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:4]=[CH:5]3)[CH:9]=2)[NH:14]1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(C(F)(F)F)cc2[nH]c1=O
Product: CCOC(=O)c1cc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(C(F)(F)F)cc2[nH]c1=O
Yield: 89.1 %

Procedure:
Using the compound of Example 17 (200 mg, 525 μmol) and phenyl isocyanate (93.9 mg, 0.788 mmol), and through the process similar to Example 18, 234 mg of title compound were obtained as colorless powder. Yield 89%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (20.3% yield). 1H NMR (300 MHz, CDCl3) δ8.04, 7.98, 7.47-7.40, 7.26-7.21, 7.15-7.09, 6.99, 3.95-3.78, 3.58-3.5, 1.54-1.47, 0.78-0.69, 0.48-0.42, 0.11-0.05.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1N
Yield: 55.5 %

Procedure:
A mixture of N-(2-nitro-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (6.0 g), dioxane (150 ml), water (30 ml), sodium hydrosulfite (14.6 g) and sodium hydrogencarbonate (17.6 g) was heated under reflux for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate/n-hexane (1/3) as the eluant to afford the title compound (2.98 g). Rf=0.23 (thin-layer chromatography on a silica gel plate using ethyl acetate/n-hexane (1/3) as the eluant).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([O:21][CH3:22])=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.I[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([O:21][CH3:22])=[C:10]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:11]=1
Reactant: Ic1cnccn1
Reactant: COc1cc(OC)c(C2OCCO2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(OC)c(C2OCCO2)cc1-c1cnccn1
Yield: 59 %

Procedure:
Ex-46C: 2-(5-[1.3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Ex-46B, 2.22 g, 6.60 mmol, containing borolane impurity) was dissolved in DME (60 mL) and 2-iodopyrazine (0.59 mL, 6.0 mmol) was added. 2M aqueous Na2CO3 (17.8 mL, 35.6 mmol) was added and the mixture was purged with nitrogen for 20 min. Tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.60 mmol) was added and the mixture was heated at reflux for 2.5 h. After cooling, water (50 mL) was added and the mixture was extracted with CH2Cl2 (2×30 mL). The organic phase was washed with brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the resulting yellow-orange solids via silica chromatography (50–80% EtOAc/hexanes) provided 1.02 g of 2-(5-[1,3]dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine as a yellow solid (59% yield). 1H-NMR (CDCl3) δ 9.10 (d, J=2 Hz, 1H), 8.61 (m, 1H), 8.39 (d, J=3 Hz, 1H), 8.07 (s, 1H), 6.57 (s, 1H), 6.14 (s, 1H), 4.13–4.18 (m, 2H), 4.01–4.05 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(N)cn2)cc1
Yield: 93.6 %

Procedure:
1-(4-Methoxybenzyl)-4-nitro-1H-pyrazole (2.17 g, 9.30 mmol) was dissolved in ethanol (20 ml). Ammonium chloride (50 mg, 0.93 mmol) and iron (powder, 2.60 g, 46.56 mmol) were added and the mixture was refluxed for 1 h. The reaction mixture was filtered through Celite® and the solvent was evaporated to dryness under reduced pressure. Usual work-up with water and ethyl acetate afforded 1.77 g (94% yield) of the title compound as an oil, which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27][C:28]([CH3:36])([CH3:37])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
210 mg of tert-butyl 2-[[4-[[[2-[(2,4,6-trimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-propanoate are dissolved in 5 ml of dichloromethane and reacted with 1 ml of trifluoroacetic acid. The mixture is stirred at room temperature for 4 h and then concentrated and purified chromatographically (dichloromethane/ethyl acetate 50+1). This gives 187 mg of the title compound as a solid foam.
Reaction SMILES: [ClH:1].[OH:2][C:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1>C(O)C.CO.[Pt]=O>[ClH:1].[OH:2][C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[OH:14])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A solution of 5.64 g (0.01 mole) of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride in 200 ml of absolute ethanol and 50 ml of methanol and 0.5 g of platinum oxide is hydrogenated at about 50 psi for about 1 hour until the infrared showed no evidence of a ketone carbonyl function. The solution is filtered and the filtrate concentrated leaving a residue which is recrystallized from butanone and methanol-butanone to give ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate HCl, M.P. 185°-187° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[NH3:17]>>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4]([NH2:17])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)cnc1-c1cccc(Cl)c1Cl
Product: Nc1cnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
This compound was prepared in an analogous manner to Example 1 Route A, from 2-amino-6-chloro-3-(2,3-dichlorophenyl)pyrazine, by reaction with 0.880 ammonia. Yield 0.195 g, M.p. 169-170° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].Cl>CO>[N:1]1([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)CCc1c[nH]c2cnc(-n3cncn3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1c[nH]c2cnc(-n3cncn3)cc12
Temperature: 50 °C
Yield: 168.4 %

Procedure:
To a solution of ethyl 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propionate (0.43 g, 1.5 mmol) in methanol (20 mL) was added NaOH (4M, 1 mL) and the mixture was heated at 50° C. for 5 hours. After cooling the solution was neutralised (5M, HCl) and the solvents evaporated in vacuo to give 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propionic acid (0.65 g) as a colourless solid. 1H NMR (360 MHz, d6 -DMSO) δ 2.60 (2H, t, J=7.5Hz), 2.98 (2H, t, J=7.4Hz), 7.55 (1H, s), 7.98 (1H, s), 8.23 (1H, s), 8.62 (1H, s), 9.24 (1H, s) and 11.74 (1H, br s). This was used without purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:43])[C:9]1[S:21][C:20]2[CH2:19][C@@H:18]3[C@H:13]([CH2:14][C@@H:15]([C:23]([N:25]([CH2:38][CH2:39][CH3:40])[C:26](=[O:37])OC4C=CC([N+]([O-])=O)=CC=4)=[O:24])[CH2:16][N:17]3[CH3:22])[CH2:12][C:11]=2[C:10]=1[C:41]#[N:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:44][CH2:45][CH2:46][CH2:47][N:48]([CH3:50])[CH3:49]>O1CCCC1>[C:41]([C:10]1[C:11]2[CH2:12][C@@H:13]3[C@@H:18]([CH2:19][C:20]=2[S:21][C:9]=1[N:8]([CH3:43])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[N:17]([CH3:22])[CH2:16][C@H:15]([C:23]([N:25]([C:26](=[O:37])[NH:44][CH2:45][CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[CH2:38][CH2:39][CH3:40])=[O:24])[CH2:14]3)#[N:42]
Reactant: CCCN(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CCCN(C(=O)NCCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Temperature: 25 °C

Procedure:
To a mixture of 4-nitrophenyl N-{[(4aR*,6R*,8aR*)-2-{[(tert-butoxy)carbonyl](methyl)amino}-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]-quinolin-6-yl]carbonyl}-N-propylcarbamate (200 mg) and tetrahydrofuran (3 mL) was added (3-aminopropyl)dimethylamine (0.082 mL) while stirring at room temperature, and then stirred at the same temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give tert-butyl N-[(4aR*,6R*,8aR*)-3-cyano-6-[({[3-(dimethylamino)propyl]carbamoyl}(propyl)amino)carbonyl]-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno-[3,2-g]quinolin-2-yl]-N-methylcarbamate (118 mg).
Reaction SMILES: [C:1]([CH2:4][S:5]/[C:6](=[CH:21]\[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)/[C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)=[O:8])([OH:3])=[O:2].[CH3:31][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(Cl)(Cl)Cl.CO.CCCCCC>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](/[CH:21]=[C:6](\[S:5][CH2:4][C:1]([O:3][CH3:31])=[O:2])/[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[O:8])=[CH:23]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)/C(=C/c2c[nH]c3ccccc23)SCC(=O)O)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CS/C(=C\c1c[nH]c2ccccc12)C(=O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 0.17 h

Procedure:
Compound 107 (50.0 mg) obtained in Example 107 was dissolved in a mixed solvent of chloroform (10 ml) and methanol (5 ml), and a solution (0.5 ml) of trimethylsilyldiazomethane in hexane, followed by stirring for 10 minutes. Acetic acid (20.0 mg) was added to the reaction solution and the mixture was subjected to partitioning between chloroform and a 5% aqueous solution of sodium bicarbonate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from isopropyl ether to give Compound 108 (36.9 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=[O:10].B>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccccc1Br
Agent: B
Solvent: C1CCOC1
Product: OCCc1ccccc1Br
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a cooled to 0° C. solution of 10.0 grams (0.0465 mole) of 2-bromophenylacetic acid in 75 milliliters of dry tetrahydrofuran was added dropwise over a one-half hour period, a solution of 0.070 mole of borane in tetrahydrofuran while the reaction mixture was maintained under a nitrogen atmosphere. After completion of the addition, stirring was continued for one hour at ambient temperature, then cooled and the reaction quenched by adding 100 milliliters of water dropwise to the cooled mixture. Thereafter, the mixture was diluted with 100 milliliters of diethyl ether, sodium chloride was added to the resulting mixture and the organic and aqueous phases were mechanically separated. The organic solution was washed with saturated sodium bicarbonate solution and dried over sodium sulfate to obtain a clear, colorless dried solution. The solution was placed on a rotary evaporator to remove the solvent and to obtain 9.11 grams (98 percent) of the desired 2-(2-bromophenyl)ethanol intermediate as a clear oil. The Rf was 0.5 on silica gel when eluted with one percent methanol in chloroform.
Reaction SMILES: [C:1]([O-:6])(=O)[C:2]([CH3:4])=O.[OH:7][C:8]1C=C([CH:13]=[CH:14][CH:15]=1)C=O>>[OH:6][C:1]1[CH:2]=[CH:4][CH:13]=[CH:14][C:15]=1[CH:8]=[O:7]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(=O)C(=O)[O-]
Product: O=Cc1ccccc1O

Procedure:
The reaction rate was measured as described in Example 1, using as substrates 5 mM pyruvate and 5 mM 3-hydroxybenzaldehyde. The absorbance values at 346 nm decreased linearly at a rate of 0.15 OD/min, which yielded a decrease of hydroxybenzaldehyde concentration 0.3 μmol/min, when using ε=480 M−1cm−1. The corresponding activity was 0.93 U/mg.
Reaction SMILES: C([NH2:4])(=O)C.B(F)(F)F.CCOCC.C([O:18][C:19](=[O:72])[CH2:20][N:21]([CH2:46][C:47]1[CH:71]=[CH:70][C:50]([C:51]([O:53][CH2:54][C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([CH3:69])=[CH:65][CH:64]=3)=[CH:59][CH:58]=2)=O)=O)=[CH:49][CH:48]=1)[C:22](=[O:45])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:44])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[C:40]([F:43])([F:42])[F:41])=[CH:25][CH:24]=1)(C)(C)C.N#N>C(Cl)Cl.C(#N)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([N:21]([CH2:20][C:19]([OH:18])=[O:72])[CH2:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]4[O:53][CH:54]=[C:55]([C:57]5[CH:58]=[CH:59][C:60]([C:63]6[CH:64]=[CH:65][C:66]([CH3:69])=[CH:67][CH:68]=6)=[CH:61][CH:62]=5)[N:4]=4)=[CH:70][CH:71]=3)=[O:45])=[CH:24][CH:25]=2)=[O:44])=[C:33]([C:40]([F:42])([F:43])[F:41])[CH:34]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)OCC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)cc2)c(C(F)(F)F)c1
Reactant: CC(N)=O
Agent: FB(F)F
Agent: N#N
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)co4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To stirring acetamide (292 mg, 4.95 mmol) at 100° C. was added boron trifluoride etherate (16.0 μl, 0.130 mmol). The temperature was raised to 140° C. and a solution of 2-(4′-methyl-[1,1′-biphenyl]-4-yl)-2-oxoethyl 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoate INT-38 (100 mg, 0.124 mmol) in DCM (1 mL) was added drop wise under a stream of N2. After 1 h, the reaction mixture was allowed to cool to room temperature and acetonitrile (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h and the precipitate was collected by filtration and washed with acetonitrile (0.5 mL) and isohexanes (2 mL). The isolated precipitate was further re-slurried from DCM (2 mL) to afford 39 mg (43%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(4-(4′-methyl-[1,1′-biphenyl]-4-yl)oxazol-2-yl)benzyl)benzamido)acetic acid 360 as a white solid. LCMS-ESI (m/z) calculated for C42H34F3N3O6: 733; found 734 [M+H]+, tR=9.18 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 10.34 (s, 1H), 8.78 (s, 1H), 8.10-8.03 (m, 2H), 7.98-7.92 (m, 2H), 7.80-7.73 (m, 2H), 7.68-7.53 (m, 5H), 7.50-7.35 (m, 4H), 7.33-7.27 (d, J=7.8 Hz, 2H), 7.26-7.16 (m, 2H), 4.75 (s, 1H), 4.67 (s, 1H), 4.03 (m, 1H), 3.95 (s, 1H), 3.89-3.79 (m, 5H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH2:9][C:10]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[CH:26]([N-]C(C)C)([CH3:28])[CH3:27].[Li+].C(=O)CC.C(N(CC)CC)C.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:9](=[CH:27][CH2:26][CH3:28])[C:10]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: CN1CCN(C2=Nc3ccccc3N=C(N3CCN(C)CC3)C2)CC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCC=O
Product: CCC=C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Temperature: -30 °C
Yield: 36843.4 %

Procedure:
A suspension of 2,4-bis(4-methyl-1-piperazinyl)-3H-[1,5]benzodiazepine (1.702 g, 5 mmol) in tetrahydrofuran (20 ml) under constant flow of argon was cooled to −30° C. A solution of lithium diisopropylamide (LDA) (2 M, 3.75 ml, 7.5 mmol) was added dropwise. Thus obtained dark brown suspension was allowed to warm to −5° C. until dissolved and then again cooled to −30° C. Propionaldehyd (0.54 ml, 7.5 mmol) was added during 5 min. The resulting clear yellow solution was allowed to warm to −5° C., triethylamine (5.55 ml, 40 mmol) and pyridine (0.040 ml, 0.5 mmol) were added. A solution of trifluoroacetic anhydride (4.2 ml, 30 mmol) in tetrahydrofuran (6 ml) was added dropwise maintaining the temperature at −5° C. The reaction mixture was stirred for another hour. Methanol (5 ml) and while strongly agitated NaOH (1 M, 35 ml) were added dropwise. The reaction mixture was stirred for four hours while slowly warming to room temperature. The solution was made acidic at ph of 1 and extracted with dichloromethane (3×25 ml). The water phase was made alkalic at a pH of 10 and extracted with diethyl ether (15×25 ml). After each extraction water phase was adjusted to pH of 10. The ether phase was dried over anhydrous Na2SO4 and ether was evaporated at reduced pressure to give 1, 701 g (89%) of the title compound as a yellow resin.