Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]#[CH:36].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]#[C:36][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1ccc(C(F)(F)F)cc1Cl
Yield: 20.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.044 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.012 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.52 (t, J=9.0 Hz, 1H), 7.56-7.75 (m, 6H), 7.83 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 12.78 (s, 1H); MS (m/z): 522.00 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21](=[O:23])[CH3:22].[O:24]=[C:25]1[NH:34][C:33]2[N:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=O)[CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26]1>>[C:21]([C:10]1[C:9]([Cl:8])=[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:31]3[N:32]=[C:33]4[C:28]([CH2:27][CH2:26][C:25](=[O:24])[NH:34]4)=[CH:29][CH:30]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1)(=[O:23])[CH3:22]
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CC(=O)c1cccc(N2CCNCC2)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cccc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl

Procedure:
In a manner similar to that of other examples above, 1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 138–139° C. MS: APCI: M+1: 457.2 (Exact Mass: 456.19).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[N:20][C:14]3[N:15]=[C:16]([NH2:19])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Na+].F[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:34]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[N:20][C:14]3[N:15]=[C:16]([NH:19][C:25]4[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:34])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: COc1cc(OC)cc(-c2cnc3nc(N)ncc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a solution of 6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-amine (400 mg, 1.42 mmol) in THF (20 mL) at 0° C. was added sodium hydride (102 mg, 4.25 mmol). The solution was stirred for 20 mins, followed by the addition of 2-fluoro-1-methyl-3-nitrobenzene (440 mg, 2.84 mmol). The reaction mixture was stirred at RT overnight, quenched by water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:1) to afford 6-(3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)pyrido[2,3-d]pyrimidin-2-amine (310 mg, 51%) as a brown solid. MS (ES+) C22H19N5O4 requires: 417. found: 418 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH:6]=[CH:5]2.C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:18][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[C:8]2=[O:12]
Reactant: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (201 mg, 0.000679 mol), ethanol (10 mL, 0.2 mol), ammonium chloride (363.03 mg, 0.0067868 mol) and water (10 mL, 0.6 mol) was heated at 85° C. Iron (152 mg, 0.00271 mol) was added in three portions, 2 minutes apart and the reaction was stirred at that temperature for 1 hour. The mixture was poured onto dichloromethane (150 mL) and the layers were separated. The organic layer was washed with brine, dried, and the solvent was removed under reduced pressure to afford the product as a light yellow solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH:3]([OH:5])[CH3:4].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>C(Cl)Cl>[S:7]([CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CC(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCC(C)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a mixture of 1,3-butandiol (1.0 g, 11.1 mmol), Et3 3N (1.6 mL, 11.5 mmol) in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of TsCl(2.12 g, 11.1 mmol) in CH2Cl3 (5 mL). The resulting mixture was stirred at 0° C. and warmed gradually to room temperature, then kept at room temperature for overnight. It was transferred into a separatory funnel and washed with H2O (3×20 mL). The organic layer was dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was purified on column chromatography (silical gel, 30% ethyl acetate/hexane), thereby affording a colorless oil (1.3 g, 48%). 1H NMR (CDCl3) d 1.07 (d, J=6.0 Hz, 3 H, CH3), 1.52-1.76 (m, 2 H, CH2), 2.33 (s, 3 H, CH3), 3.84 (br s, 1 H, OH), 4.08-4.20 (m, 2 H, CH2), 7.25 (d, J=8.4 Hz, 2 H, aromatic), 7.77 (d, J=8.1 Hz, 2 H, 5 aromatic). 13C NMR (CDCl3) d 21.60 (q, CH3), 23.58 (q, CH3), 37.86 (t, CH2), 64.10 (d, CH), 67.79 (t, CH2OTs), 127.85 (d, aromatic) 129.84 (d, aromatic), 144.78 (s, aromatic), 152.23 (s, aromatic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[I:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[I:30])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccccc1I
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1I

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-iodophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 635.7.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([F:8])[O:7][C:4]1(F)F.[C:11](=O)([O-:13])[OH:12].[K+]>O>[CH3:4][O:7][C:3]([F:8])([C:2]([F:10])([F:9])[F:1])[C:11]([OH:13])=[O:12]
Reactant: FC(F)(F)C1(F)OC1(F)F
Reactant: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COC(F)(C(=O)O)C(F)(F)F

Procedure:
2-Methoxytetrafluoropropionic acid is prepared by the method described in J. Org. Chem 31 2312, (1966) from hexafluoropropene oxide. 5.25 g of this acid are treated with 3.5 g of potassium hydrogencarbonate in 10 ml of water. After reaction, the water is evaporated off at reduced pressure and the solid residue is extracted with 20 ml of methyl formate. After evaporation of the organic solution, the salt K[CH3OCF(CF3)CO2 ] is obtained. 4.26 g of this salt are dissolved in 15 ml of acetonitrile and 300 mg of anhydrous magnesium chloride are added. The precipitate of KCl is removed by centrifuging and the supernatant solution is mixed with 15 g of poly(ethylene oxide) with a mass of 9×105 g/mole in 200 ml of acetonitrile. The solution is degassed and cast on a glass plate. After evaporation and drying, a film 70 μm in thickness is obtained, whose conductivity at 80° C. is 2×10-3 (Ω cm)-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:25][CH:22]4[CH2:24][CH2:23]4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1nc(NC2CC2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 120 °C
Yield: 5.3 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (650 mg, 2.14 mmol), cyclopropylamine (650 mg, 11.4 mmol), and Hunig's base (2 mL, 11.4 mmol) in 1,4-dioxane (5 mL) was heated for 2 hours at 120° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 15% CH3CN/H2O to 45% CH3CN/H2O) to afford the title compound (32 mg) as a yellow solid. LC-MS (ES) m/z=282 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.46-0.49 (m, 2H), 0.73 (t, J=6.8 Hz, 2H), 2.62-2.67 (m, 1H), 5.37 (s, 2H), 6.0 (s, 2H), 6.38 (s, 1H), 7.02 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[N:37]=[CH:38][N:39]3[CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:41][C:40]=23)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:42]3[S:41][C:40]4=[C:36]([S:33]([C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)(=[O:35])=[O:34])[N:37]=[CH:38][N:39]4[CH:43]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)c3ccncc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)c5ccncc5)c4s3)[C@H](C)[C@H]12
Yield: 55.1 %

Procedure:
The procedure of Example 1a) was repeated, except that 503 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 808 mg of 7-(pyridin-4-yl)sulfonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 466 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)sulfonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:10]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[N:10]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1C
Yield: 89.3 %

Procedure:
This compound was prepared according to general method D from 2 methyl 2-(4-(2,4-dimethylphenyl)-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.073 g; 0.185 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h to afford 0.063 g (88%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([CH:17]=O)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC3C(=CC(CO)=CC=3)N=2)C=CC=CC=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:17][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Agent: O=[Mn]=O
Agent: OCc1ccc2ccc(-c3ccccc3)nc2c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Additionally, 2-phenylquinoline-7-carbaldehyde could be prepared as follows: To a solution of (2-phenylquinolin-7-yl)methanol (75 mg, 0.319 mmol) in chloroform (1 mL) was added MnO2 (277 mg, 3.19 mmol). The mixture was stirred at rt for 20 h and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (1% MeOH in dichloromethane) to afford the title compound. 1H-NMR (CDCl3, 400 MHz) δ 7.50-7.59 (m, 3H), 7.95 (d, J=8.8 Hz, 1H), 8.04 (dd, J=2.4, 8.8 Hz, 2H), 8.19-8.22 (m, 2H), 8.31 (d, J=8.8 Hz, 1H), 8.69 (s, 1H), 10.26 (s, 1H). MS (ES+): m/z 234 [MH+]. HPLC: tR=3.59 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[OH:10]O>C(O)(=O)C.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:8]=[N+:7]([O-:10])[C:6]([CH3:9])=[CH:5][CH:4]=1
Reactant: OO
Reactant: COc1ccc(C)nc1
Agent: O=[Mn]=O
Solvent: CC(=O)O
Product: COc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 5-methoxy-2-picoline from Step 1 (6.7 g) was treated with 30% H2O2 (6.12 mL) in acetic acid (40 mL) at 100° C. overnight. After cooling to r.t., excess MnO2 was added and the slurry was stirred for 2 hours. Filtration and concentration in vacuo gave 7.0 g of the title N-oxide.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[O:18]1[CH2:20][CH:19]1[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:19]([OH:18])[CH2:20][NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:12]=1
Reactant: Cn1cnc2ccc(-c3cccc(N)c3)cc21
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Solvent: CCO
Product: Cn1cnc2ccc(-c3cccc(NCC(O)CN4CCc5ccccc5C4)c3)cc21
Temperature: 120 °C
Yield: 29.4 %

Procedure:
To a solution of 3-(1-methyl-1H-benzo[d]imidazol-6-yl)aniline (300 mg, 1.34 mmol) in EtOH (3 mL) were added 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (250 mg, 1.32 mmol). The reaction mixture was heated at 120° C. under microwave conditions for 30 min. After cooling, the resulting solution was concentrated in vacuo and purified via column chromatography to yield the title compound (160 mg, 28.9%) LCMS (m/z): 413.2 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)c1
Yield: 89 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.19-3.32 (m, 4H), 3.61-3.90 (m, 4H), 3.79 (s, 3H), 4.17 (s, 3H), 6.44-6.58 (m, 4H), 7.00-7.65 (m, 3H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[C:20]2[C:15](=[CH:16][N:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)C(OCC)=O)C.[OH-].[Na+]>CO>[C:21]1([CH:11]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:5][C:4]([OH:27])=[O:3])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(c1ccccc1)c1c[nH]c2cnccc12
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a RT solution of 2-[phenyl-(1H-pyrrolo[2,3-c]pyridin-3-yl)-methyl]-malonic acid diethyl ester (0.33 g) in MeOH (30 mL) was added NaOH (2 M in water, 10 ml). The mixture was refluxed for 5h, cooled to RT, and concentrated. The residue was acidified by addition of HCl (1 M) and extracted with EtOAc. The combined extracts were refluxed for 10 h, cooled to RT, and concentrated. The residue was partitioned between water and EtOAc and extracted 3 times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated, affording crude 3-Phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propionic acid (224 mg, 94% yield), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:38][C:39]1([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42][CH2:41][CH2:40]1)(=O)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:38][C:39]1([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42][CH2:41][CH2:40]1)[CH:6]=[C:5]2[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)c(=O)c3ccc(Br)cc23)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 59.5 %

Procedure:
A solution of tert-butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate (Example 27b, 0.171 g) dissolved in DMF (5 mL) was treated with cesium carbonate (0.264 g) and [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl methanesulfonate [Archiv der Pharmazie (Weinheim, Germany), 2005, 338 (11), 522-7] (0.187 g) under nitrogen. The resulting mixture was stirred at 70° C. for 7 h. The reaction was diluted with water (300 mL), and extracted with diethyl ether (300 mL×3). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 6-12% ethyl acetate/isohexane) to afford the subtitle compound (0.153 g).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:16])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])C>O.CO>[C:10]1([NH:9][C:7](=[O:8])[C:6]([OH:16])=[O:5])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A solution of KOH (1.68 g, 30 mmol) in water (25 mL) and MeOH (25 mL) was added to Intermediate 1 (5.8 g, 30 mmol), and the resulting mixture was stirred for 18 hours at room temperature. The reaction was diluted with water, then extracted with EtOAc. The aqueous layer was cooled in an ice bath, acidified with 1N HCl, extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo to provide 3.8 g (77%) of a colorless solid. 1H NMR (DMSO-d6) δ: 7.1–7.8 (m, 6H), 10.5 (s, 1H); MS ES+m/e 166.0 (p+1), ES−m/e 164.1 (p−1). Anal. Calcd for C8H7NO3: C, 58.18; H, 4.27; N, 8.48. Found: C, 57.99; H, 4.25; N, 8.46.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:10](=[O:39])[CH2:11][N:12]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:10]([OH:39])[CH2:11][N:12]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])[CH3:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)N(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)N(CC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 62.5 %

Procedure:
(3S)-1-[N-[3-[[(t-Butyloxy)carbonyl]amino]-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, t-butyl ester (1.75 g, 2.75 mmol) was dissolved in ethanol (15 ml), and stirred in an ice bath. Sodium borohydride (150 mg, 3.95 mmol) was added and the solution was stirred at room temperature for 90 minutes. It was then evaporated, taken into ethyl acetate and washed with 10% aqueous potassium hydrogen sulfate solution. The ethyl acetate solution after evaporation was chromatographed over silica gel (100 g) using the solvent system ethyl acetate:hexane-4:6 to obtain 1.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:31][N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][N:30]=4)=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
After a mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (800 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for 5 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-(4-fluorophenyl)-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (700 mg, yield: 93%). This was recrystallized from ethanol-water. Melting point: 162–163° C.