Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11]C)[C:5]([O:9]C)=[CH:6][C:7]=1[CH3:8].Br>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:6][C:7]=1[CH3:8])[OH:9]
Reactant: COc1cc(C)c(C)cc1OC
Agent: Br
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(O)cc1C
Reaction time: 4.5 h

Procedure:
53 g of 4,5-dimethylveratrol (prepared by the method of Bruce, et al., J. Chem. Soc., 1956, 3824-29) was mixed with 200 ml of 48% hydrobromic acid. The mixture was stirred at reflux temperature, in a nitrogen atmosphere, for 4.5 hours. The crude mixture was heated with 200 ml of toluene. The toluene phase was separated and cooled, to give 4,5-dimethylcatechol (6A), as a solid, mp: 86°-87° C.
Reaction SMILES: C(C(C(=O)O)[C@@H](C(N[C@@H](C(O)=O)C)=O)NC(OCC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.CN1CCOCC1.ClC(OCC)=O.N[CH:46]([CH:51]([CH3:53])[CH3:52])[C:47]([OH:50])([CH3:49])[CH3:48]>OP(O)=O.O[Mo](O)(=O)=O.C(OCC)(=O)C.CCCCCC.O1CCCC1>[OH:50][C:47]([CH3:49])([C:46](=[O:12])[CH:51]([CH3:53])[CH3:52])[CH3:48]
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Reactant: CC(C)C(N)C(C)(C)O
Agent: O=[Mo](=O)(O)O
Agent: CCOC(=O)Cl
Agent: O=[PH](O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(=O)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 2.14 g. (5.0 mmole) beta-benzyl-N-benzyloxycarbonyl-L-aspartyl-D-alanine in 35 ml. tetrahydrofuran cooled to -15° was added 0.55 ml. (5.0 mmole) N-methylmorpholine and 0.48 ml. (5.0 mmole) ethyl chloroformate. The mixture was stirred at -15° to -10° C. for two minutes and 0.66 g. (5.0 mmole) 3-amino-2-hydroxy-2,4-dimethylpentane was added. The mixture was allowed to warm to room temperature, stirred overnight and worked-up as described in Example 5, Part B, to obtain the diprotected dipeptide amide, Rf 0.27 (TLC, ethyl acetate/hexane, 1:1, phosphomolybdic acid spray, heat) which was used directly in the next step.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=[S:8])[O-:7])[N:3]=[CH:2]1.[K+].P([O-])([O-])([O-])=O.CC(O[CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[C@H:24]([NH2:27])[C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=O.C([O-])(O)=O.[Na+].OP(O)(O)=O>>[NH2:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:30]([OH:32])=[O:31])=[C:20]([CH2:19][S:8][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:7])[CH2:29][S:28][C@H:23]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: [O-]C(=S)c1cscn1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: NC1C(=O)N2C(C(=O)O)=C(CSC(=O)c3cscn3)CS[C@H]12

Procedure:
A solution of 68% potassium thiazole-4-thiocarboxylate (5.4 g., 0.02 mole) in 100 ml. water was washed with 100 ml. of ether and then 200 ml. of pH 6.4 phosphate buffer and 7-aminocephalosporanic acid (5.5 g., 0.02 mole) was added. The mixture was heated at 48° for 4 hours as the pH was kept at 6.4 with NaHCO3 solution. The solution was then cooled and acidified with 40% H3PO4 to pH 5.2. The product was collected by filtration, washed with water and acetone, and air dried overnight to yield 3.0 g. The material was not further purified and IR and NMR spectra were consistent with required structure.
Reaction SMILES: [C:1]1([CH:7]2[N:12](N)[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[N:12]3[C:11]4[C:14]([C:19]5[C:20](=[O:24])[CH2:21][CH2:22][CH2:23][C:18]=53)=[CH:15][CH:16]=[CH:17][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN1c2ccccc2OCC1c1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 110 °C
Yield: 34 %

Procedure:
To a mixture of 3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-ylamine (1.042 g, 4.6 mmol) in toluene (30 mL) is added, with stirring, cyclohexane-1,3-dione (0.538 g, 4.8 mmol). The mixture is heated to 85° C. for 15 min, at which time p-toluenesulfonic acid monohydrate (0.874 g, 4.6 mmol) is added and the temperature increased to 110° C. The mixture is refluxed for 24 h, cooled to room temperature and concentrated. The residue is partitioned between CH2Cl2/1N NaOH and the organic layer is washed with brine and dried over magnesium sulfate. Column chromatography (100 g silica gel) using (acetone/hexane (25/75)) as eluent gave 0.475 g (34%) of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](N)=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.B#B.CCOCC.O>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:16][CH:17]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(C(N)=O)cc2)c([N+](=O)[O-])c1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(Sc2ccc(CO)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
The product from Example 84b (0.5 g, 1.73 mmol) was dissolved in THF (15 mL) and cooled in an ice bath. To the cold solution under nitrogen was added diborane as a 1.0M solution in THF (3.6 mL, 3.6 mmol) and the resulting mixture allowed to warm to room temperature and stir overnight. The crude product was isolated by extractive workup (ether/water) and dried with MgSO4, filtered and concentrated under vacuum giving the crude title compound. Purification by flash chromatography on silica gel gave the alcohol as a bright yellow solid (0.392 g, 82%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].C([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])C>C(Cl)Cl>[NH:22]1[C:23]2[C:24](=[CH:18][CH:5]=[CH:6][CH:7]=2)[C:26]([CH2:2][C:3]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:19])=[CH:25]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c[nH]c2ccccc12)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reaction time: 0.25 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (75 mg, 0.298 mmol) and indole-3-acetyl chloride (57.8 mg, 0.298 mmol) were combined in CH2Cl2 (2 ml) and the pH adjusted to 9.0 with triethylamine (TEA) 41 μml, 0.298 mmol). After stirring 15 min., a second portion of indole-3-acetyl chloride (44 mg, 0.175 mmol) and TEA (30μ, 0.215 mmol) were added and the reaction stirred an additional 15 min. The completed reaction was diluted with CH2Cl2, washed with H2O (lX) and brine (1X), dried over MgSO4, filtered and stripped to dryness in vacuo. The residue was chromatographed on silica gel (5% MeOH in CH2Cl2) to give the title compound as a pinkish solid from Et2O:(m.p. 264°-265° ).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH:18]=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[CH2:18][NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: Nc1cccnc1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cnn(C)c2)cn2ncc(CNc3cccnc3)c12
Reaction time: 24 h

Procedure:
A solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (10.0 mg, 0.039 mmol), 3-aminopyridine (5.5 mg, 0.059 mmol), and acetic acid (50 μl) in 1,2-dichloroethane (1 ml) was stirred for 2 d. Sodium triacetoxyborohydride (24.8 mg, 0.117 mmol) was added and the mixture was stirred for 1 d. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was filtered with isoElute and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give N-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]methyl}pyridin-3-amine 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H); 8.21 (s, 1H); 8.00 (d, 1H); 7.96 (s, 1H), 7.80 (s, 1H), 7.69 (d, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 6.81 (s, 1H), 6.08 (t, 1H), 4.47 (s, 2H), 3.98 (s, 3H), 3.82 (s, 3H) LRMS (ESI) calculated for C18H19N6O [M+H]+, 335.2; found 335.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:27])[NH:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)=[CH:14][C:13]=1[N+:28]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:27])[NH:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)=[CH:14][C:13]=1[NH2:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNc1ccc(C(=O)Nc2cc(Cl)ccn2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNc1ccc(C(=O)Nc2cc(Cl)ccn2)cc1N

Procedure:
Prepared analogously to example 1b by hydrogenation of {3-[4-(4-chloro-pyridin-2-ylcarbamoyl)-2-nitro-phenylamino]-propyl}-carbamic acid tert.-butyl ester using Pt/charcoal 5% in methanol and THF.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:18][C:13]1[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)c1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc(-n2nc(O)c3ccccc3c2=O)cc1
Temperature: 125 °C
Yield: 44.5 %

Procedure:
4-Isopropyl phenyl hydrazine hydrochloride (2.77 g, 14.6 mmol) was added in one portion to a stirred mixture of phthalic anhydride (2.0 g, 13 mmol) in acetic acid (25 ml) at room temperature. The reaction mixture was heated to 125° C. for 2 hours, and then allowed to cool to room temperature. The resultant suspension was poured into H2O (100 ml), NaHCO3 solution (1M) was added and the resulting solid was removed by filtration. The mother liquor was acidified with conc. HCl The resulting solid was collected by filtration and dried in vacuum to give the title compound (1.62 g, 45% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.80 (1H, s), 8.30 (1H, d), 7.92–8.01 (3H, m), 7.92 (2H, d), 7.35 (2H, d), 2.96 (1H, m), 1.25 (6H, d); MS (ESI+)=345.12 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].I[CH:13]([CH2:15][CH3:16])[CH3:14]>C(#N)C>[CH:13]([N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)I
Reactant: c1ccc2[nH]nnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(C)n1nc2ccccc2n1
Yield: 34 %

Procedure:
To a stirred solution of 96.0 grams of benzotriazole in 800 milliliters of acetonitrile at 50° C. is added 33.6 grams of sodium hydroxide pels. After most of the sodium hydroxide has reacted with the benzotriazole, 190 grams of 2-iodobutane is added in one portion and the resulting solution is refluxed for 15 hours. The acetonitrile is then evaporated and 300 milliliters of concentrated hydrochloric acid is added to the residual oil followed by the addition of 800 milliliters of benzene. The precipitated sodium iodide is removed by filtration. The acid layer is separated from the benzene layer and then washed three more times with 300 milliliters of benzene. The benzene washings are combined, dried over MgSO4 and evaporated to yield 48 grams (34%) of the 2-sec-butyl-2H-benzotriazole as an oil. The material is purified by distillation, b.p. 0.25 mm Hg=63° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([O:18][CH3:22])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C)Nc1ccc(C(=O)NC(C)(C)C)c(F)c1
Temperature: 55 °C
Yield: 29.3 %

Procedure:
The title compound was prepared according to General Method 5. A solution of 2-(4-(tert-butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid (1.0 g, 3.3 mmol) and K2CO3 (1.38 g, 10 mmol) in DMF (10 mL) was stirred at RT for 10 minutes. Methyl iodide (710 mg, 5 mmol) was added and heated at 55° C. for 4 h. The solvent was removed and reaction mixture was poured in water, extracted with ethyl acetate (100 mL, 2 times), dried over Na2SO4, concentrated and purified with column chromatography to obtain 300 mg of methyl 2-(4-(tert-butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoate
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Yield: 61 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 4-trifluoromethylphenacyl bromide to obtain methyl 4-[4-(4-trifluoromethylphenyl)-2-thiazoly]benzoate. The product was recrystallized from ethanol. Yield: 61%. Colorless prisms. Melting point: 156 to 158° C.
Reaction SMILES: C([O:8][C:9](=[O:29])[C@H:10]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[NH:14][C:15](=[O:22])[C@H:16]([CH3:21])[NH:17][C:18](=[O:20])[CH3:19])C1C=CC=CC=1>C(O)C.[Pd]>[C:18]([NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:29])=[O:8])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH3:23])=[O:22])[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O

Procedure:
Acetylalanylalanylleucine benzyl ester (2 mmole) is dissolved in denaturated ethyl alcohol (0.5 gal. benzene added to 100 gal. of absolute ethanol) (15 ml) and hydrogenated over 10% palladium/charcoal (0.1 gm) at 40 psi for 1/2 hour. The solution was filtered through Celite and evaporated in vacuo. The residue is triturated with diethyl ether to give crystalline acetylalanylalanylleucine, m.p. 185°-186°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[N:10][OH:11].C(O)(C)C.[OH-].[K+]>O>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10][O:11][C:2]=2[CH:7]=1
Reactant: COc1ccc(C(=NO)c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(-c2noc3cc(F)ccc23)cc1
Yield: 71.5 %

Procedure:
Combine (2,4-difluoro-phenyl)-(4-methoxy-phenyl)-methanone oxime (277.5 g, 1.05 mol), water (200 mL) and isopropyl alcohol (1140 mL) and heat (˜75-80° C.) under a nitrogen atmosphere. Add 45% potassium hydroxide (591.5 g), in one portion, followed by water (75 mL). Immediate exotherm to 82° C. Continue heating for 5.3 hours. Cool reaction mixture to room temperature overnight. Cool reaction mixture in an ice bath, filter and wash (2×250 mL) filter cake with a cold mixture of isopropyl alcohol and water (20:80). Let filter cake dry to the air to give the title compound (182.7 g, 73% Yield): 1H NMR (CDCl3, 200 MHz) δ 3.9 (s, 3H), 7.1 (m, 3H), 7.3 (m, 1H), 7.85 (m, 3H). Purity by LC/MS (APCl)=100% area, [M+H]+=244 m/e.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[CH:12][C:13]=2[Cl:15])[NH:8][C@@H:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6]1)([OH:3])=O.O[C:25]1[C:33]2N=N[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.NC1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(N(CC)CC)C>[C:29]1([NH:30][C:1]([CH2:4][C@@H:5]2[C:14]3[C:9](=[CH:10][C:11]([Cl:16])=[CH:12][C:13]=3[Cl:15])[NH:8][C@@H:7]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:6]2)=[O:3])[CH:33]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H](CC(=O)O)c2c(Cl)cc(Cl)cc2N1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Product: CC(C)(C)OC(=O)[C@H]1C[C@H](CC(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.3 %

Procedure:
Trans-4-carboxymethyl-2-tertiarybutyloxycarbonyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (0.25 g, 0.000696M) was dissolved in dry THF with dry triethylamine (0.29 ml, 3 molar equivalents), hydroxybenzotriazole (0.141 g, 1.5 molar equivalents), aniline (0.0925 ml, 1.5 molar equivalents) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.2 g, 1.5 molar equivalents) and the reaction mixture was stirred at room temperature for 14 h. The solvents were removed in vacuo and the residue was dissolved in ethyl acetate (100 ml) and washed successively with 0.5 normal citric acid solution (3×50 ml), saturated sodium hydrogen carbonate solution (3×50 ml) and brine (1×50 ml), dried (Na2SO4), filtered and evaporated under vacuum. The residue obtained was purified by chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give the title compound (0.14 g) as a colourless oil; δ (250 MHz, DMSO) 1.48 (9H, s, (CH3)3C), 1.69 (1H, ddd, J=13.0, 12.4 and 4.0 Hz, CHACHBHCCHD), 2.47 (2H, m, CHACHBHCCHDCHEHFCONHPh), 2.73 (1H, dd, J=16.5 and 2.5 Hz, CHACHBHCCHDCHEHFCONHPh), 3.73 (1H, m, CHACHBHCCHDCHEHFCONHPh), 3.98 (1H, dd, J=12.4 and 3.3 Hz, CHACHBHCCHDCHEHFCONHPh), 4.72 (1H, br, s, ArNHCHA), 6.50 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.15 (2H, m, p-proton and PhNH), 7.33 (2H, t, J=7.5 Hz, m protons), 7.50 (2H, d, J=7.5 Hz, o protons); m/e (FAB) 379 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[C:10]#[C:11][CH3:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.O>[CH3:21][O:22]/[N:23]=[C:9](/[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])\[C:10]#[C:11][CH3:12]
Reactant: CON
Reactant: CC#CC(=O)c1ccc(F)cc1F
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CC#C/C(=N\OC)c1ccc(F)cc1F
Reaction time: 0.03 h

Procedure:
1-(2,4-Difluorophenyl)but-2-yn-1-one (3.95 g, 21.93 mmol, prepared as described in WO 2000008002, Intermediate #39) was dissolved in MeOH (60 mL) then pyridine (6 mL) and O-methylhydroxylamine hydrochloride (3.66 g, 43.9 mmol) were added. The mixture was stirred for about 2 min until a solution was obtained then sodium sulfate (6.23 g, 43.9 mmol) was added. The mixture was stirred overnight at ambient temperature then the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were extracted with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to an oil. The material was purified by flash chromatography silica gel with heptane/ethyl acetate (85:15) as an eluent to give the title compound: (2.29 g, 50%): LC/MS (Table 1, Method g) Rt=2.58 min; MS m/z: 210.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13].[C:20](Cl)(=[O:22])[CH3:21].[K+].[Br-]>C(O)C>[C:20]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Nc1c(C(=O)c2ccccn2)[nH]c2cc(Cl)ccc12
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2ccccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(pyridine-2-carbonyl)indole (Example 125) and acetyl chloride. m.p.: 211-212° C. (ethanol) 1H-NMR (DMSO-d6) δ: 12.02 (1H, br s), 10.34 (1H, br s), 8.82 (1H, d, J=4.4 Hz), 8.15-8.07 (2H, m), 7.85 (1H, d, J=8.8 Hz), 7.75-7.70 (1H, m), 7.63 (1H, d, J=1.8 Hz), 7.07 (1H, dd, J=1.8, 8.8 Hz), 2.02 (3H, s) IR (KBr) ν: 3450, 1690, 1620, 1580, 1570, 1480, 1350, 1240, 1180, 1160, 1030, 760 cm−1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12]Cl)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20].ClC1C=CC=CC=1Cl.[Sn](Cl)(Cl)(Cl)Cl>O=[Pt]=O.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:27]=1[O:28][CH3:29])[C:19]([NH:21][CH2:22][CH:23]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=2)[CH2:11][CH2:12][NH:24]1)=[O:20]
Reactant: COc1ccc(CCCl)cc1OC
Reactant: COc1cc(C(=O)NCC#N)cc(OC)c1OC
Agent: O=[Pt]=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(cc1OC)C(CNC(=O)c1cc(OC)c(OC)c(OC)c1)NCC2
Reaction time: 8 h

Procedure:
A mixture of 2.0 g. of 1-(3,4-dimethoxyphenyl)-2-chloroethane and 2.5 g of 3,4,5-trimethoxybenzamidoacetonitrile (obtainable from aminoacetonitrile and 3,4,5-trimethoxybenzoyl chloride) is allowed to stand overnight at 20° in 100 ml. of o-dichlorobenzene and with 2.6 g. of tin tetrachloride; the mixture is thereafter heated for 3 hours to 110°. The solution is concentrated by evaporation, and the residue is shaken with chloroform and sodium hydroxide solution. The chloroform solution is evaporated, and the thus-obtained crude 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline is dissolved in 30 ml. of methanol and hydrogenated with 200 mg. of PtO2 at 20° and under normal pressure. After filtration, evaporation, and purification by chromatography on silica gel, 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is obtained; hydrochloride, m.p. 234°-236°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([O:18]C)=[O:17])[C:6]=2[N:7]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([OH:18])=[O:17])[C:6]=2[N:7]=1
Reactant: CCOCCn1nc(C(=O)OC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOCCn1nc(C(=O)O)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester of Step 7 (4.3 g, 11 mmol) was dissolved in dioxan (50 mL) and the solution treated with a 1M aqueous solution of sodium hydroxide (22.0 mL, 22.0 mmol). The reaction mixture was then stirred for 18 hours at room temperature. The reaction mixture was evaporated to dryness, the residue dissolved in water (100 mL) and washed with dichloromethane (50 mL). The aqueous phase was then acidified with 1M citric acid solution to pH 4-5 and a yellow precipitate formed. The mixture was stirred for 15 minutes before being filtered and the solid product dried in vacuo over phosphorus pentoxide to yield the title product, 3.75 g.