Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=1)[CH2:3][C:4]#[N:5].CO>C1COCC1>[NH2:5][CH2:4][CH2:3][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=1)[OH:1]
Reactant: N#CC[C@@H](O)c1cccc(OCC2CCOCC2)c1
Solvent: CO
Solvent: C1CCOC1
Product: NCC[C@@H](O)c1cccc(OCC2CCOCC2)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
BH3-DMS (0.56 g, 7.4 mmol) was added dropwise to a solution of hydroxynitrile (14) (0.65 g, 2.4 mmol) in dry THF (50 mL). The reaction mixture was refluxed 18 h at 65° C. After completion of the reaction (as monitored by TLC) the MeOH (15 mL) was added to the reaction mixture which was stirred at rt for an additional 1 h. The mixture was then concentrated under reduced pressure followed by purification by column chromatography (100-200 silica mesh, 4-6% MeOH in DCM) to give Example 1 as a white solid. Yield (0.75 g, 99%); 1H NMR (400 MHz, DMSO-d6) δ 7.80 (bs, 3H), 7.24 (t, J=8.0 Hz, 1H), 6.89-6.87 (m, 2H), 6.82-6.80 (m, 1H), 5.54 (bs, 1H), 4.65 (bs, 1H), 3.87 (dd, J=11.4, 2.8 Hz, 2H), 3.81 (d, J=6.4 Hz, 2H), 3.37-3.30 (m, 2H), 2.87-2.79 (m, 2H), 2.02-1.96 (m, 1H), 1.88-1.80 (m, 2H), 1.69-1.65 (m, 2H), 1.34-1.27 (m, 2H); RP HPLC tR=1.10 min, 94.5% (AUC); ESI MS m/z 266.27 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:27])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[Br:27][C:16]1[C:15]([C@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[C:24]([CH3:25])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N+:21]2[O-:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(ccc(C)[n+]2[O-])c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (5E) (118 mg, 0.31 mmol) in chloroform (5 mL) was added mCPBA (209 mg, 77%, 0.93 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour before quenched with NaHCO3 solution. The mixture was extracted with DCM (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (52 mg, 37%). LCMS-ESI+ (m/z): 452.1, 454.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[CH3:26][N:27]1[C:31](B(O)O)=[CH:30][CH:29]=[N:28]1>>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([C:31]2[N:27]([CH3:26])[N:28]=[CH:29][CH:30]=2)=[C:3]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:10][C:4]2=[CH:5]1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Reactant: Cn1nccc1B(O)O
Product: Cn1nccc1-c1c2c(cn(C)c1=O)CN(CCc1ccc3ccccc3n1)C2=O

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and 2-methyl-2H-pyrazol-3-ylboronic acid.
Reaction SMILES: C(=[N+]([O-])[CH:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[C:9]1([F:23])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])C1OC=CC=1.[CH:25](=[N:31]/[OH:32])\[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.CC(C)=O>[F:23][C:9]1([C:16]([O:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[O:17])[CH:8]([O:32]/[N:31]=[CH:25]/[C:26]2[O:30][CH:29]=[CH:28][CH:27]=2)[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: O/N=C/c1ccco1
Reactant: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1[N+]([O-])=Cc1ccco1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 51 h
Yield: 55.1 %

Procedure:
In 3 ml of pyridine-acetone (pyridine-acetone=2:1) were dissolved 341 mg (1 mmol) of N-(furfurylidene)-(5-fluoro-5-isobutoxycarbonyl-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-6-yl)amine N-oxide and 133 mg (1.2 mmol) of (E)-furfuraldoxime, and the solution was stirred at room temperature for 51 hours. The reaction solution was treated in the same manner as described in Example 9 to give 188 mg of isobutyl 5-fluoro-6-[(E)-furfurylideneaminooxy]-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(C#N)[CH3:6])C.S(=O)(=O)(O)O.C(O)(=O)C.[OH-].[Na+]>O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:15]3[C:10](=[C:9]([CH:5]([CH3:6])[C:4]([OH:26])=[O:3])[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:12][N:13]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(C#N)c1cccc2c(-c3ccc(Cl)cc3)nccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc2c(-c3ccc(Cl)cc3)nccc12

Procedure:
Ethyl-2-[1-(4-chlorophenyl)isoquinolin-5-yl]-2-cyanopropionate (1.0 g) was heated over an oil bath at 150° C. together with 2 ml of conc. sulfuric acid, 4 ml of acetic acid and 2 ml of water. After the reaction, the reaction mixture was poured into water. The pH of the mixture was adjusted to 4 with a 1 N aqueous solution of sodium hydroxide. The crystals that precipitated were extracted with dichloromethane, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from dichloromethane-hexane to afford 2-[1-(4-chlorophenyl)isoquinolin-5-yl]propionic acid as colorless prisms having a melting point of 199.5° to 202.0° C.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C@@H:13]1[C:18]([CH3:20])([CH3:19])[O:17][C:16]2[CH:21]=[C:22]([C:24]#[N:25])[S:23][C:15]=2[C@H:14]1[N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32])C1C=CC=CC=1>ClCCl>[C:24]([C:22]1[S:23][C:15]2[C@@H:14]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3=[O:32])[C@H:13]([OH:12])[C:18]([CH3:20])([CH3:19])[O:17][C:16]=2[CH:21]=1)#[N:25]
Reactant: CC1(C)Oc2cc(C#N)sc2[C@@H](N2CCCCC2=O)[C@@H]1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)Oc2cc(C#N)sc2[C@@H](N2CCCCC2=O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boron tribromide (1.0 M in dichloromethane, 17.6 mL, 17.6 mmol) was slowly added to a solution of trans-6-benzyloxy-2-cyano-5,6-dihydro-5,5-dimethyl-7-(2-oxopiperidin-1-yl) -7H-thieno[3,2-b]pyran (1.4 g, 3.5 mmol) in dichloromethane (40 mL) at0° C. and stirred for 1h. The solution was poured into ice water. The organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 3% methanol in dichloromethane as the eluant. The product was recrystallized from dichloromethane/hexanes to give a colorless solid, 0.997 g (93%); mp 212°-214° C.; IR(KBr): 2210, 1624, 1558 and 1486 cm-1 ; MS: m/z 307 (MH+); 1H NMR(CDCl3): δ 1.29 (s, 3H), 1.50 (s, 3H), 1.77-1.90 (m, 4H), 2.53 (m, 2H), 3.17 (m, 2H), 3.66 (d, J=5.9 Hz, 1H), 3.80 (dd, J=5.9 Hz, J=9.4 Hz, 1H), 5.85 (d, J=9.4 Hz, 1H), 5.92 (bs, 1H) and 7.07 (s, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].COC1C=CC=CC=1[Mg]Br.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=[O:39])[C:31]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:24][C:23]=2[O:22]1>C1COCC1>[OH:39][C:32]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH3:10])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=2)=[C:31]1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: COc1ccccc1Br
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccccc1[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Reaction time: 0.25 h

Procedure:
To dry magnesium turnings (81 mg, 3,4 mmol) under an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2 O (3 ml). A portion of the resulting 2-methoxyphenyl magnesium bromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound. (100 mg, 68%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].[CH2:14]([C:16]([C:27]1[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=1)([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:17][CH3:18])[CH3:15]>C(#N)C.[Cu]I.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>[CH2:14]([C:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:29]([CH3:41])[CH:28]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#C[Si](C)(C)C)c(C)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
Triethylamine (25.1 mL, 180.09 mmol), ethynyltrimethylsilane (25.5 mL, 180.09 mmol), CuI (1.143 g, 6.00 mmol) and tetrakis(triphenylphosphine)palladium (0) (6.93 g, 6.00 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 25 g, 60.03 mmol) in acetonitrile (300 mL) at room temperature, and the mixture was stirred at 110° C. for 18 hours and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and a 1 N hydrochloric acid aqueous solution was added to adjust the pH to about 7. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=15/1) to give the title compound (16 g, 74%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]2)=[N:24][CH:25]=1>>[OH:31][CH:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=2)[CH2:27]1
Reactant: Nc1ccc(N2CCC(O)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCC(O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C20H17F3N4O3 (m/e) 418, obsd 419 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[N:15]1[C:20](=[O:21])[CH2:19][N:18]([CH2:22][C@H:23]([NH:33]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C@@H:24]2[CH2:28][C@@H:27]([CH:29]([CH3:31])[CH3:30])[C:26](=[O:32])[O:25]2)[C:17]([CH3:47])([CH3:46])[CH2:16]1.C1(S)C=CC=CC=1.C(N(CC)CC)C.[C:62](OC(OC(C)(C)C)=O)([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63].N[C@H]([C@@H]1C[C@@H](C(C)C)C(=O)O1)CN1C(C)(C)CN(C2C=C(F)C=CC=2Cl)C(=O)C1>CN(C)C=O.[Cl-].[Na+].O.C(Cl)Cl>[C:65]([O:64][C:62](=[O:63])[NH:33][C@H:23]([C@@H:24]1[CH2:28][C@@H:27]([CH:29]([CH3:30])[CH3:31])[C:26](=[O:32])[O:25]1)[CH2:22][N:18]1[CH2:19][C:20](=[O:21])[N:15]([C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[Cl:7])[CH2:16][C:17]1([CH3:47])[CH3:46])([CH3:68])([CH3:67])[CH3:66]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)[C@@H]1C[C@@H]([C@@H](N)CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)OC1=O
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 1 h
Yield: 70.3 %

Procedure:
1.1 g of cesium carbonate (3.42 mmol) was added to a solution of 1.70 g of N-{(S)-2-[4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (62e) (2.85 mmol) and 0.87 ml of thiophenol (content: 95%) (8.54 mmol) in N,N-dimethylformamide (15 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for one hour. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 0.99 ml of triethylamine (7.11 mmol) and 620 mg of di-t-butyl dicarbonate (2.84 mmol) were added to a solution of 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one obtained above in methylene chloride (24 ml), and the mixture was stirred at room temperature for 15 hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=3/1) to obtain 1.05 g of the title compound (yield: 70%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:6][CH:5]=[N:4][NH:3]1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:20][N:3]1[C:2](=[O:1])[C:7]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])=[CH:6][CH:5]=[N:4]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nccc(CN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione (255 mg, 1.00 mmol) in dimethylformamide (3 mL) was heated with potassium carbonate (145 mg, 1.05 mmol) and methyl iodide (426 mg, 3.00 mmol) at 70° C. for 2 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was stirred with 4 M hydrogen chloride/1,4-dioxane (10 mL) at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (233 mg, 86% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(Br)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(Br)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-bromophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=3)=[CH:11][C:12](=[O:14])[CH:13]=2)[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[NH:9][C:10]([C:15]4[CH:20]=[C:19]([N:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:18]=[CH:17][N:16]=4)=[CH:11][C:12](=[O:14])[CH:13]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: O=c1cc(-c2cc(Cl)ccn2)[nH]c(-c2cc(Cl)ccn2)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: CN1CCN(c2ccnc(-c3cc(=O)cc(-c4cc(N5CCN(C)CC5)ccn4)[nH]3)c2)CC1

Procedure:
A mixture of 10.89 g (34.2 mmol) of 4,4″-dichloro-1′H-[2,2′;6′,2″]terpyridin-4′-one, 68.6 g (685 mmol, 76.1 ml) of 1-methylpiperazine and 233 mg (1.71 mmol, 0.05 equivalent) of zinc(II) chloride in 200 ml of 2-methyl-2-butanol is boiled under reflux for 24 hours. The mixture is evaporated to dryness on a rotary evaporator. The crude product is recrystallized from ethyl acetate/methanol 33:1 (v/v). It is taken up in 100 ml of water, adjusted to pH=8-9 with 4N sodium hydroxide solution, and light-beige 4,4″-bis(4methylpiperazin-1-yl)-1′H-[2,2′;6′,2″]terpyridin-4′-one is filtered off. 1H-NMR (360 MHz, CDCl3): 8.32 (d, 2H, J=5.9 Hz); 7.18 (dm, 2H); 6.93 (s, 2H); 6.66 (dd, 2H; J=5.9,2.3 Hz); 3.41-3.32 (tm, 8H); 2.55-2.44 (tm, 8H); 2.29 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9](F)=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]2N[C@H](C1C=CC=CC=1)CO.[H-].[Na+].[OH2:33]>C1COCC1>[F:1][C:2]1[C:3]2[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]3[C@H:4]([C:3]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=4)[CH2:5][O:33][C:9]([C:8]=23)=[C:10]([F:13])[C:11]=1[F:12]
Reactant: CCOC(=O)c1cn(N[C@@H](CO)c2ccccc2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)OC[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
To a solution of ethyl (R)-5,6,7,8-tetrafluoro-1,4-dihydro-1-[(2-hydroxy-1-phenylethyl)amino]-4-oxo-3-quinolinecarboxylate (3.10 g, 7.57 mmol) in THF (60 mL) was added NaH (364 mg, 9.10 mmol, 60% in oil) and the mixture was stirred at room temperature for 10 h. The mixture was treated portionwise at 0° C. with water. A precipitate formed and was collected by filtration, washed successively with EtOAc and then dried to give ethyl(R)-8,9,10-trifluoro-2,3-dihydro-7-oxo-3-phenyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (329 mg, 11%) as a solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH:11]1([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[C:29](F)[CH:28]=[CH:27][C:26]=3[N+:32]([O-:34])=[O:33])[CH:22]=2)=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[C:29]([N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)[CH:28]=[CH:27][C:26]=3[N+:32]([O-:34])=[O:33])[CH:22]=2)=[O:16])[CH2:13][CH2:12]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (13) in the portion of Example 1 which is concerned with the preparation of starting materials, 1-(methylsulfonyl)piperazine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[4-(methylsulfonyl)piperazin-1-yl]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.64 (m, 4H), 2.31 (s, 3H), 2.84 (m, 1H), 2.93 (s, 3H), 3.26 (m, 4H), 3.64 (m, 4H), 7.13 (m, 2H), 7.29 (d, 1H), 7.58 (d, 1H), 7.98 (s, 1H), 8.08 (t, 1H), 8.37 (d, 1H), 9.95 (s, 1H); Mass Spectrum: M−H+ 500.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:22][O:23]CC[Si](C)(C)C)[CH:8]=2)[CH:4]=[N:3]1>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:22][OH:23])[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cn(CO)c3ncnc(N4CCOCC4)c23)cn1

Procedure:
A solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C4) (200 mg, 0.48 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the product as a yellow oil, which was used for the next step without additional purification.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:21](O)[CH3:22]>>[CH2:21]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[CH3:22]
Reactant: CCO
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCC(Cc1ccccc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of diethyl benzylmalonate (20.0 g, 80 mmol) in ethanol (500 mL) was added potassium hydroxide (4.7 g, 84 mmol) as pellets. The mixture was stirred at room temperature for 24 h, and concentrated to dryness in vacuo. The residue was dissolved in water (300 mL), transferred to a separatory funnel, and washed with ether (2×150 mL). The aqueous solution was acidified to pH˜2 by adding conc. HCl, and extracted with ether (2×400 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness in vacuo, yielding the title compound as an oil residue (16.9 g, 95%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:42]3[CH2:44][CH2:43]3)=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:42]3[CH2:43][CH2:44]3)=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K33) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (297 mg, 72%).