Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:35])[CH2:23][C:24]=1[CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])[CH:20]([NH:36]C(OC(C)(C)C)=O)[C:19]2=[O:44])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].O>C(#N)C>[NH2:36][CH:20]1[C:19](=[O:44])[N:18]2[CH:21]1[S:22](=[O:35])[CH2:23][C:24]([CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2S(=O)C1)Sc1nnc(C)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2S(=O)C1)Sc1nnc(C)s1
Temperature: 40 °C
Reaction time: 0.58 h
Yield: 93.7 %

Procedure:
A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (4.45 g) in acetonitrile (150 cc) is heated to 40° C. A solution of p-toluenesulphonic acid (monohydrate) (2.59 g) in acetonitrile (75 cc) is added dropwise in the course of 5 minutes. The mixture is stirred at 40° C. for 35 minutes and then poured into a saturated aqueous solution of sodium bicarbonate (200 cc). Distilled water (500 cc) is added and extraction is carried out with methylene chloride (500 cc). The organic phase is washed with distilled water (500 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 7-amino-2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (3.53 g) in the form of a hard brown foam.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][O:37][C:38]1[N:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:41]3[CH:42]=[N:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](CN)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and (6-methoxypyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.92 min, m/z=488.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccccc1
Product: Cc1c2n(c3c(-c4ccccc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (62 mg, 82%), MS (ISP) m/z=302.6 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([CH3:39])=[C:24]([NH:28]C(=O)OCC4C=CC=CC=4)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2]>O1CCCC1.CO.[Pd]>[NH2:28][C:24]1[C:23]([CH3:39])=[C:22]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Temperature: 25 °C
Yield: 102.3 %

Procedure:
A mixture of benzyl 3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.226 g, 0.431 mmol) and Pd/C (60 mg, 0.056 mmol) in tetrahydrofuran (12 mL) and methanol (18 mL) was stirred at room temperature under H2, provided with a H2 balloon, for 1.5 hr. The catalyst was removed by suction filtration, and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (80 mL) and dried over anhydrous MgSO4. Removal of the solvent under vacuum provided the desired product (0.172 g, 0.441 mmol, 102% yield) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1)[CH3:22]
Reactant: C=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: C=CCCC(C)Nc1c(C)noc1-c1ccc(-c2ccccc2CC(=O)OCC)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-pent-4-enyl)-amine and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH:14]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C1CCC1
Product: O=C(O)c1ccc(NC(=O)C2CCC2)cc1[N+](=O)[O-]

Procedure:
4-Cyclobutanecarbonylamino-2-nitro-benzoic acid was prepared as described in Example 3 from 10.9 g (0.06 mol) of 4-amino-2-nitro-benzoic acid and 7.83 g (0.066 mol) of cyclobutanecarboxylic acid chloride.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][N:2]=[C:3]2[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCC(=NO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C1CCC(=NOS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
To a solution of ethyl 4-(hydroxyimino)cyclohexanecarboxylate (1.85 g) in pyridine (10 mL) was added 4-methylbenzenesulfonyl chloride (2.28 g) over 5-10 min at −20° C. The reaction mixture was stirred for several hours while allowing to gradually warm to 0° C. The reaction mixture was added to ice water, and the precipitate was collected by filtration, and washed with ice water to give the title compound (2.54 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.N[NH:14][C@@H:15]([CH2:20][OH:21])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[OH:21][CH2:20][C@H:15]([NH:14][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CC(C)C[C@H](CO)NN
Product: CC(C)C[C@H](CO)NC(=O)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and (R)-aminoleucinol. MS (M+H, 266.1)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)[C:5]=2[O:4][CH2:3][CH2:2]1.O.NN>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH2:14])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc2c1OCCO2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCOc1cccc2c1OCCO2

Procedure:
Cleavage of the phthalimide group of the compound obtained in Step B is carried out in ethanol in the presence of an aqueous 98% hydrazine hydrate solution (2 eq. per 1.5 g of product). It is preferable to add the latter after 10 minutes' refluxing. When the reaction is complete, the alcohol is removed under reduced pressure. The dry residue is taken up in dichloromethane in the cold in order to precipitate the phthalic hydrazide that has formed. The latter may then be removed by filtration and the recovered and concentrated filtrate is washed several times to obtain the pule product by thin-layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([CH:23]=[CH:24][C:25]=2[F:26])[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([NH:22][S:36]([C:30]3[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])[CH:23]=[CH:24][C:25]=2[F:26])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.357 mL, 2.64 mmol) the title compound of Step A was obtained as a light yellow solid (857 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 7.64-7.72 (m, 1H), 7.49-7.56 (m, 1H), 7.21-7.32 (m, 3H), 6.55 (d, J=5.3 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O[C:5](=O)[C:4]=1[C:16]([O:18][CH3:19])=[O:17].[C:20]1([N:26]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH2:31]C3=O)=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[C:5]=2[C:4]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1c(SC)cc(-c2ccccc2)oc1=O
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccccc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.9 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-phenyl-2H-pyran-3-carboxylate (276 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 7 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 234 mg (55%) of methyl 8-(methylthio)-2,6-diphenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:30][O:31][C:32](=[O:69])[NH:33][CH:34]([C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:46][CH:47]=[C:48]([C:50]2[CH:59]=[CH:58][C:57]3[C:52](=[CH:53][CH:54]=[C:55](B4OC(C)(C)C(C)(C)O4)[CH:56]=3)[CH:51]=2)[N:49]=1)=[O:39])[CH:35]([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:55]3[CH:54]=[CH:53][C:52]4[C:57](=[CH:58][CH:59]=[C:50]([C:48]5[N:49]=[C:45]([CH:41]6[CH2:42][CH2:43][CH2:44][N:40]6[C:38](=[O:39])[CH:34]([NH:33][C:32]([O:31][CH3:30])=[O:69])[CH:35]([CH3:37])[CH3:36])[NH:46][CH:47]=5)[CH:51]=4)[CH:56]=3)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC(=O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)c[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(=O)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Temperature: 120 °C
Yield: 5 %

Procedure:
(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (46.0 mg, 0.1 mmol), [2-Methyl-1-(2-{4-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (54 mg, 0.1 mmol), and Pd[PPh3]4 (11.5 mg, 0.01 mmol) were dissolved in DME (2 mL) under an atmosphere of argon. Saturated, aqueous sodium bicarbonate solution (0.3 mL) was added and the reaction was heated under microwave conditions at 120° C. for 20 minutes. The solids were discarded and the volatiles were removed in vacuo. The crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (4.0 mg) as a TFA salt.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N:13]=[O:14]
Reactant: CCCn1c(=O)cc(N)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-amino-3-propyl-1,3-dihydropyrimidine-2,4-dione (5.6 g) in a mixture of 50% acetic acid/water (160 ml) at 70° C. was added sodium nitrite (4.5 g) in portions over a period of 15 minutes. The mixture was stirred at 70° C. for 45 minutes, then the reaction mixture concentrated to a low volume under reduced pressure. The solid was filtered off, and washed with water, to provide 6-amino-5-nitroso-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (11).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(O)c2ccc(Cl)cc2n1
Reactant: COC(=O)CBr
Product: COC(=O)COc1cc(C(=O)OC)nc2cc(Cl)ccc12

Procedure:
The purified methyl 7-chloro-4-hydroxy-2-quinoline-carboxylate was alkylated with methyl bromoacetate as described in example 2 to produce methyl 7-chloro-4-methoxycarbonylmethyloxy-2-quinolinecarboxylate as a white solid having a melting point of 153.5°-154.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: COCCn1cc(-c2ccccc2)n(C(=O)c2ccccc2)c1=O

Procedure:
Approximately 21.8 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 14.5 g. of benzoyl chloride and 20 g. of tri-n-butylamine are refluxed together in 60 ml. of xylene for sixteen hours. The solvent is distilled off under reduced pressure and the remaining viscous oil is dissolved in 300 ml. of benzene. The benzene solution is washed with water (2×100 ml.), dried over sodium sulfate, and the solvent removed to give a semisolid. Recrystallization from ether gives the title compound as a pale yellow solid; m.p. 114°-117° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:10]([O:30][CH3:31])=[CH:11][C:12]2[C:21]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:20]=3[CH2:19][CH:18]3[C:13]=2[C:14]=1[CH2:15][N:16]([CH3:29])[CH2:17]3.C1(C)C=CC=CC=1.[OH-].C1([N+](C)(C)C)C=CC=CC=1>CN(C)C=O>[CH3:31][O:30][C:10]1[C:9]([O:8][CH3:2])=[C:14]2[CH2:15][N:16]([CH3:29])[CH2:17][CH:18]3[CH2:19][C:20]4[CH:25]=[C:24]5[O:26][CH2:27][O:28][C:23]5=[CH:22][C:21]=4[C:12](=[C:13]23)[CH:11]=1
Reactant: COc1cc2c3c(c1O)CN(C)CC3Cc1cc3c(cc1-2)OCO3
Reactant: O=C(O)C(F)(F)F
Agent: C[N+](C)(C)c1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c3c(c1OC)CN(C)CC3Cc1cc3c(cc1-2)OCO3

Procedure:
10.65 g. (±)-5,6,6a,7-tetrahydro-3-hydroxy-2-methoxy-9,10-methylenedioxy-5-methyl-4H-dibenz(de,g)isoquinoline trifluoroacetate (see Example 1) are dissolved in 500 ml. of a mixture of toluene and dimethyl formamide (9:1) in a manner analogous to that described in Example 7 and methylated with phenyltrimethyl ammonium hydroxide. When the methylation is finished (monitoring with TLC), the reaction mixture is evaporated in a vacuum. After partitioning the residue between water and methylene chloride, working up the organic phase and crystallising from methanol/chloroform, there is obtained (±)-5,6,6a,7-tetrahydro-2,3-dimethoxy-9,10-methylenedioxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of cream-coloured crystals; m.p. 169°-172° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:18][C:16]([F:17])([F:19])[C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1

Procedure:
Procedure G′: 4-(6-Trifluoromethyl-pyridin-3-yl)-benzoic acid methyl ester (0.57 g, 2 mmol) is dissolved in tetrahydrofuran/water (9:1)(25 ml), lithium hydroxide monohydrate (0.9 g, 2.2 mmol) is added and the mixture is heated under reflux overnight. The mixture is concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is acidified and the resulting precipitate is collected by filtration to give the 4-(6-trifluoromethyl-pyridin-3-yl)-benzoic acid. MS (FIA)267 (MH−)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2].C(N(CC)CC)C.[C:40]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:46]([C:43]1[CH:44]=[CH:45][C:40]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:41][CH:42]=1)=[O:47])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)N(Cc1ccccc1)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
A sample of 2-benzylamino-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (490 mg, 1.10 mmol) was dissolved in 10 mL of methylene chloride followed by addition of triethylamine (0.31 mL, 2.21 mmol) and biphenyl-4-carbonyl chloride (287 mg, 1.33 mmol). The reaction was allowed to stir at room temperature for 12 hours then partitioned between additional methylene chloride (50 mL) and 0.1 N HCl (50 mL). The organic phase was dried over sodium chloride, then concentrated under reduced pressure to yield 687 mg (100%) of an oil. HPLC RT1=7.65 min; 1H NMR (400 MHz, CDCl3) δ 7.60-7.20 (m, 14H), 6.77-6.46 (m, 4H), 4.91-4.45 (m, 2H), 4.19-3.66 (m, 7H), 2.78-2.12 (m, 2H), 1.49 (s, 6H), 1.25-1.22 (m, 6H).
Reaction SMILES: [CH2:1]1[C:10]2[CH:5]([CH2:6][CH2:7][CH:8]3C=[CH:13][CH:12]=[CH:11][C:9]3=2)[NH:4][CH2:3][CH2:2]1.[CH3:15][OH:16]>>[OH:16][C:15]1[C:8]2[CH2:7][CH2:6][C@H:5]3[C@H:10]([CH2:1][CH2:2][CH2:3][N:4]3[CH2:12][CH2:11][C:9]3[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CO
Reactant: C1=CC2=C3CCCNC3CCC2C=C1
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCCN1CCc1ccccc1
Yield: 46 %

Procedure:
Cis-(−)-7-hydroxy4-phenethyl-1,2,3,4,4a,5,6, 10b)-octahydrobenzo[f]quinoline (hereinafter, “cis-(−)-25”) was prepared in 46% yield from 34 mg (0.11 mmole) of cis-(−-24 by the method described for trans-9 in Example 3. The melting point observed was 196° C. and [α]D (20° C.) was −6.0 (c 0.20, MeOH).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:12][C:9]3[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=3[CH3:11])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: COc1ccc2c(c1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(CCC(=O)O)c1C
Yield: 76.5 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 82 mg 6-methoxy-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 95° C. for overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 130 mg (76%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([O:18]C)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[Li+].[OH-].Cl>C(OCC)(=O)C>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2c(NC(C)(C)C)nccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1nccc2c(C(=O)O)cccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
Methyl 1-(t-butylamino)isoquinoline-5-carboxylate (1.6 g, 6.20 mmol) obtained in Step (5) above was stirred in a solution of tetrahydrofuran (16 mL) and distilled water (16 mL). The reaction solution was added with LiOH (0.57 g, 13.6 mmol) and stirred for about 12 hours at 80° C. The reaction mixture was cooled to room temperature and adjusted to have a pH value in a range of 1˜2 by adding 1N aqueous HCl. The reaction mixture was diluted with ethyl acetate, and washed with distilled water. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.6 g, 40%).