Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH2:36]([N:38]([C:46]([CH3:50])([CH3:49])[CH:47]=O)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:37].N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:50][C:46]([N:38]([CH2:36][CH3:37])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=O
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 3-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (236 mg, 0.5 mmol, 1 equiv) and tert-butyl ethyl(2-methyl-1-oxopropan-2-yl)carbamate (2.15 g, 10 mmol, 20 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4 A molecular sieves. The resulting mixture was stirred for 2 h at 110° C. The solids was filtered out, the filtrate was diluted with 200 mL of ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified on silica gel column (ethyl acetate/MeOH 10/1) to give 60 mg (19%) of tert-butyl 5-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:14]=[C:13]([O:15][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1
Agent: [Br-]
Product: CC(C)c1cc(OCc2ccc(C(=O)O)cc2)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenyl)-6-isopropyl-pyrimidin-4-ol (which was obtained in Intermediate 6) and methyl 4-(bromomethyl)benzoate bromide according to Method A and Method B; LC retention time 4.11 min; MS: m/z (ESI) 415 (M−H).
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=C(NC(=O)C)C=CC=3)CC2)=CC=1OCC.Cl.Cl.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[N:39][C:38]([NH:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:37][N:36]=1)=[O:34].[CH2:48]([O:50][C:51]1[CH:56]=[C:55]([CH:57]=O)[CH:54]=[C:53]([O:59][CH2:60][CH3:61])[C:52]=1[C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[CH3:49]>>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[N:39][C:38]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:57][C:55]3[CH:54]=[C:53]([O:59][CH2:60][CH3:61])[C:52]([C:62]4[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=4)=[C:51]([O:50][CH2:48][CH3:49])[CH:56]=3)[CH2:44][CH2:43]2)=[CH:37][N:36]=1)=[O:34]
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: COC(=O)c1cnc(NC2CCNCC2)cn1
Agent: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)ccc1Cl
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cnc(C(=O)OC)cn3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile (example 38/step 3) from 5-(piperidin-4-ylamino)-pyrazine-2-carboxylic acid methyl ester dihydrochloride (intermediate B14) and 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (intermediate E22) in a yield of 5.8 mg (7%). MS (ISP): 509.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]([F:45])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:39][CH2:40][CH2:41][CH2:42]Br)[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[CH2:1]=[C:2]1[C:12]([N:13]2[CH2:14][CH2:15][N:16]([CH2:42][CH2:41][CH2:40][CH2:39][C:25]3([C:23](=[O:24])[NH:22][CH2:21][C:20]([F:45])([F:19])[F:44])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[O:32][C:33]4[C:38]3=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:17][CH2:18]2)=[CH:11][CH:10]=[CH:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1C
Product: C=C1C(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)=CC=CC1C(=O)OCC

Procedure:
The procedure of step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 53 and the compound prepared in step (a) of Example 96 were used as the starting compounds. Thus, ethyl 2-methyly-3-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-xanthen-9-yl]butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:26]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:29][C:30]([OH:32])=[O:31].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1/[CH:26]=[CH:29]/[C:30]([OH:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (4.0 g, 9.336 mmol), malonic acid (2.137 g, 20.539 mmol), pyridine (4.3 ml) and piperidine (184 μl, 1.867 mmol) was refluxed for 1 hour under argon atmosphere. The reaction mixture was cooled to room temperature, adjusted to pH 1 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (4.26 g, 97.0%) as a white solid.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17].[CH3:19][C:20]([CH3:22])=O>>[CH2:15]([C:5]1[C:6]([CH2:22][CH:20]=[CH2:19])=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])[CH:16]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccccc1O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCc1ccc(O)c(O)c1CC=C
Temperature: 177.5 °C

Procedure:
To a solution of pyrocatechol (Compound A) (1 g, 0.009 mol) and dry acetone (10 mL) was added dry K2CO3 (2.646 g, 0.0189 mol) in portions for 30 minutes. The stirring was continued for another hour. Allyl bromide (1.6 mL, 0.0189 mol) was added to the mixture for 30 minutes and the mixture was refluxed for 5 hours. After completion of the reaction, the solid was filtered and filtrate was concentrated and extracted with chloroform (3×50 mL), washed with brine (1×50 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude material was heated at 175-180° C. for 2 hours. The reaction mixture was purified by column chromatography (silica gel: 60-120 mesh) using petroleum ether with increasing concentration of chloroform. Elution of 60% and 75% chloroform in petroleum ether yielded pure compounds corresponding to Compound No. 2 and Compound No. 3 as liquids respectively.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][CH:14]=2)[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:67]=[N+:68]=[N-:69])=[CH:15][CH:14]=2)[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2ccc(C)nc2n1-c1ccc(CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2ccc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.7 %

Procedure:
A mixture of 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 4, 217 mg, 0.77 mmol) in THF (20 mL) was added diethyl azodicarboxylate (DEAD) (0.3 mL, 1.5 mmol), triphenylphosphine (380 mg, 1.5 mmol) and diphenylphosphoryl azide (DPPA) (0.4 mL, 1.5 mmol). The mixture was stirred at room temperature for 4.5 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 70 mg (30%) of the title compound as a brown oil:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:24]([CH3:34])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30]CC)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([CH3:34])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCOC(=O)C(=O)C(C)Br
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1C
Yield: 78.2 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (1.97 g, 6.4 mmol), butyl 3-bromo-2-oxobutanoate obtained in Example (106a) (10 g, 42.3 mmol), sodium bicarbonate (1.26 g, 15 mmol) and THF (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 2.09 g of the title compound as a yellow oily substance (73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N+:19]([O-:20])=[O:18])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]=O
Reactant: COc1cccc(NC(C)=O)c1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1cccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
N-(3-methoxyphenyl)acetamide (14.23 g, 0.086 mol) was dissolved in acetonitrile (200 mL) and cooled to 0° C. Solid nitronium tetrafluoroborate (14.79 g, 0.106 mol) was added in four portions. The temperature rose to about 5° C. during each addition and was allowed to cool down to 0°0 C. between additions. After the last addition of nitronium tetrafluoroborate, water (200 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure to give approximately 200 mL of a dark oil. The dark oil was dissolved in dichloromethane (200 mL) and washed with water (6×150 mL). The organic layer was concentrated under reduced pressure and dried to obtain 16.1 g of a dark red oil. The red oil was purified by flash chromatography (silica gel, 25% ethyl acetate/hexane) to give 4.53 g (27%) of the crude product. The crude product was triturated with 25% ethyl acetate/hexane to give 3.0 g (17%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8](SC)=[CH:7][CH:6]=2.Cl[C:29]1C=C(C=CC=1)C(OO)=O.C([O-])(O)=O.[Na+].[O-:44][S:45]([O-:48])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:45]([CH3:29])(=[O:48])=[O:44])=[CH:7][CH:6]=2
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(SC)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of methyl 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.45 g, 6.26 mmol) and 3-chloroperoxybenzoic acid (2.376 g, 13.77 mmol) in dichloromethane (50 mL) was stirred overnight. Saturated aqueous NaHCO3 and Na2S2O3 were added slowly, and the mixture was stirred for 30 min. The mixture was extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography (ISCO, 10-60% ethyl acetate/hexanes) to give methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.59 g, 98% yield). MS (m/z) 424.1 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].CN(C)C(Cl)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:27][CH3:28])=[C:18]([CH:20]2[O:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])[CH:19]=1.[Na].ClC1C=CC(OC)=C(C2OC(=O)N(C(=O)N(C)C)C2=O)C=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:27][CH3:28])=[C:18]([CH:20]2[O:24][C:23](=[O:25])[N:22]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:21]2=[O:26])[CH:19]=1
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Reactant: CCOC(=O)Cl
Agent: CN(C)C(=O)Cl
Agent: COc1ccc(Cl)cc1C1OC(=O)N(C(=O)N(C)C)C1=O
Agent: [Na]
Product: CCOC(=O)N1C(=O)OC(c2cc(Cl)ccc2OC)C1=O

Procedure:
By the same method, but replacing ethyl chloroformate with an equivalent amount of dimethylcarbamoyl chloride, sodium 5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione is converted to 5-(5-chloro-2-methoxyphenyl)-3-dimethylcarbamoyloxazoldine-2,4-dione.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:8]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]2=[O:25])#[CH:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[C:2][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[CH:12][CH:11]=3)[C:6](=[O:25])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: C#Cc1ccc2c(c1)c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3ccnc(C(F)(F)F)c3)cc2c1=O
Yield: 45.1 %

Procedure:
Compound R (20 mg, 0.06 mmol), 4-bromo-2-(trifluoromethyl)pyridine (16.2 mg, 0.07 mmol), CuI (1.1 mg, 0.006 mmol), triethylamine (25 μL, 0.18 mmol), PdCl2(PPh3)2 (2.7 mg, 0.003 mmol), and DMF (600 μL) were added to a small microwave vial. The vial was capped and placed in microwave reactor at 150° C. for fifteen minutes. The reaction was filtered over Celite®, washed very well with a 5% MeOH in DCM solution and concentrated to dryness. Purification by reverse phase HPLC afforded 13 mg (45%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=4.96 Hz, 1H), 8.52-8.5 (m, 2H), 8.17 (s, 1H), 7.93 (d, J=5.04 Hz, 1H), 7.87 (dd, J=8.8 Hz, 1H), 7.81-7.77 (m, 2H), 7.55 (t, J=8.64, 8.68 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 4.24 (q, J=7.04, 7.08 Hz, 2H), 1.28 (t, J=7.12, 7.08 Hz, 3H); ES-MS [M+1]+: 481.2.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][N:4]1[C@H:9]([C:10]([NH:12][C:13]2[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[ClH:21]>O>[CH3:1][CH2:2][CH2:3][NH+:4]1[C@H:9]([C:10]([NH:12][C:13]2[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH2:11].[Cl-:21]
Reactant: Cl
Reactant: CCCN1CCCC[C@H]1C(=O)Nc1c(C)cccc1C
Solvent: O
Product: CCC[NH+]1CCCC[C@H]1C(=O)Nc1c(C)cccc1C
Product: [Cl-]
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
About 2 g of Ropivacaine base was dissolved in a mixture of 2.6 mL of concentrated hydrochloride acid and 40 mL of water. The solution was heated to about 85° C. and stirred for about 30 min to get a clear solution and cooled to about 5° C. and continued stirring for about 2 hr. A precipitated solid was recovered and filtered, then washed with acetone and dried under vacuum at about 35° C. for about 6 hr. Results: wt 2.0 g, yield 88.5 %; water content: 5.5%. The x-ray diffraction pattern of the material obtained is shown in FIG. 1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 54 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-methylbenzoic acid (1.00 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.52 g) described in Preparation Example 96, the title compound (1.04 g) was obtained.
Reaction SMILES: C([NH:4][C:5](C(O)=O)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14](=[O:22])[CH:13]=1)[C:6]([O:8]CC)=[O:7])(=[O:3])C.[ClH:26]>>[OH2:3].[ClH:26].[NH2:4][CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14](=[O:22])[CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1cc(=O)[nH]c2ccccc12)(NC(C)=O)C(=O)O
Agent: Cl
Product: NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O
Product: O

Procedure:
To 5 g of ethy 2-acetamido-2-carboxy-3-(2-quinolon-4-yl)propionate was added 150 ml of 20%-hydrochloric acid and the mixture was refluxed for 9 hours. The reaction mixture was concentrated under a reduced pressure, the residue was recrystallized from ethanon-water to obtain 3.2 g of 2-amino-3-(2-quinolon-4-yl)propionic acid hydrochloride hydrate in the form of folorless prism-like crystals.
Reaction SMILES: C[O:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[NH:8][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14]2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:23]>C(Cl)Cl.CO>[BrH:23].[OH:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[NH:8][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14]2)=[CH:5][CH:4]=1
Reactant: BrB(Br)Br
Reactant: CCCN1CCCC(c2ccc(OC)c3[nH]c(=O)[nH]c23)C1
Solvent: ClCCl
Solvent: CO
Product: Br
Product: CCCN1CCCC(c2ccc(O)c3[nH]c(=O)[nH]c23)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 g of the product of Step C in 100 ml of methylene chloride was cooled to 0°/+5° C. and over 5 minutes, 24 ml of an M solution of boron tribromide in methylene chloride were added dropwise. After stirring for 4 hours at ambient temperature and then cooling to 0° C., 50 ml of methanol were added slowly and the solvents were eliminated under reduced pressure. The residue was taken up in methanol and filtered to obtain 1.05 g of the expected product. 0.75 g of this product were purified by chromatography on silica (eluent: methylene chloride-methanol-triethylamine 8-1-1) to obtain 0.36 g of pure product which was crystallized from methanol.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].C[O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=O.[CH3:15]C(C)=O.O>C(O)(=O)C>[CH3:13][O:12][CH:10]([C:9](=[O:8])[CH2:14][C:2](=[O:4])[CH3:1])[CH3:15]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)OC
Reactant: CC(C)=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(C)C(=O)CC(C)=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
In a 300 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 29.0 g (258 mmol) of potassium t-butoxide, and the flask was purged with argon. Then, 120 mL of methylcyclohexanone was placed in the flask. Subsequently, 15.0 g (127 mmol) of methyl 2-methoxypropionate (prepared by the method of Reference Example 1) was dropped under cooling with ice, and further 7.40 g (127 mmol) of acetone was slowly dropped. The mixture was cooled to 10° C. and stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 1,200 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with methylcyclohexane. The methylcyclohexane extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (66° C., 1.38 kPa) to give 9.63 g (yield: 53%) of 2-methoxy-3,5-hexanedione as colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (300 mg, 1.80 mmol) in 3.6 mL of dry N,N-dimethylformamide was added sodium hydride (94 mg, 55%, 2.1 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methyl iodide (0.17 mL, 2.7 mmol) was added with additional stirring for 30 min. After the reaction mixture was quenched with saturated NH4Cl aqueous solution at 0° C., the solution was extracted with ether. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain the title compound as a slightly yellow powder (298 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH:34]3[C:46]4[NH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:38]=4[CH2:37][CH2:36][NH:35]3)=[CH:28][C:27]=2[O:26]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH:34]3[C:46]4[NH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:38]=4[CH2:37][CH2:36][N:35]3[C:14]([C:12]3[O:13][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=4)=[CH:10][CH:11]=3)=[O:16])=[CH:28][C:27]=2[O:26]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: O=C(O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)o1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-(3-trifluoromethylphenyl)furoic acid (256 mg, 1 mmol) in DCM (20 mL, anhydrous) was added oxalyl chloride (165 mg, 1.3 mmol), followed by two drops of DMF. The mixture was stirred at room temperature for 1 h. A solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (292 mg, 1 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and triethylamine (0.4 mL) in DCM (10 mL, anhydrous) was added and the mixture was stirred at room temperature for 16 h, washed sequentially with aqueous NaHCO3, brine (2×), 1N HCl and brine (2×) and dried with MgSO4. After evaporation of the solvent, a white solid was obtained.