Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([OH:11])=[C:9]([C:12]([OH:14])=O)[CH:8]=[N:7][C:6]=12.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([OH:11])=[C:9]([C:12]([N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)=[O:14])[CH:8]=[N:7][C:6]=12
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cnc2c(Br)cnn2c1O)N1CCC(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
3-Bromo-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (6.3 g, 24.5 mmol) obtained in step 1 and 4-phenylpiperidine (7.9 g, 49.0 mmol) were suspended in methylene chloride (120 mL), triethylamine (13.7 ml, 98.1 mmol) and 50% 1-propylphosphonic acid anhydride cyclic trimer-ethyl acetate solution (6.0 g, 49.0 mmol) were added at 0° C., and the mixture was stirred at 0° C. for 2 hr. 4-Phenylpiperidine (7.9 g, 49.0 mmol), triethylamine (13.7 mL, 98.1 mmol) and 50% 1-propylphosphonic acid anhydride cyclic trimer-ethyl acetate solution (6.0 g, 49.0 mmol) were added to the reaction mixture, and the mixture was further stirred at 0° C. for 2 hr. 2 mol/L Hydrochloric acid (100 mL) was added to the reaction mixture, the organic layer and the aqueous layer were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2 mol/L Hydrochloric acid (100 mL) was added to the residue, and the mixture was stirred at 30° C. for 2 hr. The precipitate was collected by filtration, and washed with water (100 mL) to give the title compound (7.7 g, 78%).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:28]1[N:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]2=[N:30][C:29]=1[CH:37]=O>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:23][CH2:24]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:37][C:29]3[N:30]=[C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]4[N:28]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1nc2ncccn2n1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Solvent: CO
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)C(Cc4nc5ncccn5n4)C(=O)O3)cc2F)CC1
Reaction time: 1 h

Procedure:
A solution of 1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with [1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (296 mg, 2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at room temperature. The reaction was stirred for 1 hour and then was concentrated to an oil. The oil was purified by flash chromatography (50 g SiO2, 70% ethyl acetate, 6% methanol, 0.5% acetic acid, 23.5% hexanes) to give the desired product as an oil. It was further purified by crystallization from ethyl acetate/hexanes to give a white powder (142 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 1.11–1.18 (m, 2 H), 1.31–1.52 (m, 10 H), 1.75–1.80 (m, 2 H), 2.16 (t, J=8.84 Hz, 1 H), 2.34 (d, J=17.68 Hz, 1 H), 2.46 (t, J=7.83 Hz, 2 H), 2.59 (d, J=17.94 Hz, 1 H), 3.94 (d, J=3.79 Hz, 2 H), 6.62–6.70 (m, 2 H), 6.97 (t, J=7.83 Hz, 1 H), 7.02–7.04 (m, 1 H), 6.82–6.85 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:1][C:2]2[CH:3]=[C:4]([N:9]([CH3:25])[C:10]3[N:15]=[C:14]4[S:16][C:17]([NH:19][C:20]([CH:22]5[CH2:23][CH2:24]5)=[O:21])=[N:18][C:13]4=[CH:12][CH:11]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.1 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-tert-butyl-4-isocyanatobenzene (72 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (31 mg, 17%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15](=O)[C:16](O)=[O:17]>>[OH:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[NH:8][C:16](=[O:17])[C:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)=[N:1]2
Reactant: O=C(O)C(=O)c1cccs1
Reactant: Nc1ccc(O)cc1N
Product: O=c1[nH]c2ccc(O)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with 3,4-diaminophenol (which is prepared by treating 3,4-dinitrophenol with H2NNH2.H2O, Pd/C refluxed in MeOH), and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-hydroxy-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:36][CH2:37][C:38]#[N:39])[CH:3]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:36][CH2:37][C:38]#[N:39])[CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OCC#N)nccc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCOc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the light brown crude oil from Step 2 was added DCM (3 ml) and TFA (1 ml) and the mixture stirred at room temperature for 30 min affording PMB deprotection. The mixture was dried under reduced pressure and purified using basic, then acidic conditions, respectively affording product (16 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ=12.91 (br. s., 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (d, J=1.9 Hz, 1H), 8.14 (d, J=5.2 Hz, 1H), 7.86 (dd, J=1.9, 8.9 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.34 (dd, J=1.9, 8.1 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 5.16 (d, J=1.0 Hz, 2H). m/z (ESI) 457.0 (M+H)+
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[OH:25])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:14]2[CH:13]=[CH:12][C:11]([OH:25])=[C:10]([CH:15]=2)[CH2:9][P:4](=[O:3])([OH:5])[OH:8])=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1O)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc(O)c(CP(=O)(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.8 %

Procedure:
To a solution of [5-(4-ethylbenzyl)-2-hydroxybenzyl]phosphonic acid diethylester (0.40 g) in dichloromethane (7.8 mL) was added bromotrimethylsilane (0.8 mL) at 0° C., and the reaction mixture was stirred for 17 hr at room temperature. Methanol (1.1 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate-n-hexane to give the title compound (0.29 g) as a colorless crystal.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]=[S:12]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:31]2[N:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])=[CH:33][N:32]=2)[C:15]=1C)[O-:13])=O>C(#N)C.CO>[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[C:34]1[CH:33]=[N:32][C:31]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])[CH:18]=3)[C:14]([S:12]([CH3:1])(=[NH:11])=[O:13])=[CH:15]2)=[N:36][CH:35]=1
Reactant: Cc1c(S([O-])=NC(=O)C(F)(F)F)c2ccc(C(=O)N3CCOCC3)cc2n1-c1ncc(-c2ccccc2F)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CS(=N)(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 1 h

Procedure:
Potassium carbonate (0.143 g, 1.04 mmol) was added at room temperature to a stirred suspension of 287a) (0.3 g, 0.52 mmol) in acetonitrile/methanol (1:1, 9.6 mL) and the mixture was stirred for 1 h. The solvents were evaporated and the residue was purified by column chromatography [alumina; dichloromethane with 1% methanol] and washed with ether. Pink solid. Yield: 0.12 g (48% of theory)
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26]1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:27]1[CH:28]=[CH:29][O:25][CH:26]=1
Reactant: O=Cc1ccoc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccoc1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a stirred and cooled (0° C.) solution of carbon tetrabromide (34.5 g, 104.1 mmol) in CH2Cl2 (70 mL) was added triphenylphosphine (54.6 g, 208.1 mmol) in five equal portions over a period of 5 nm. The resulting dark red solution was stirred for a further 10 min, and a solution of 3-furaldehyde (9) (5 g, 52.0 mmol) in CH2Cl2 (25 mL) was added slowly. The resulting black solution was allowed to warm to r.t. After 5.5 h the mixture was poured into ice-cold pentane and stirred vigourously. The mixture was filtered and the collected solid washed extensively with diethyl ether-ethyl acetate mixture. The combined solutions were washed with saturated aqueous Na2S2O3 (×1), water (×1), 1 M aqueous NaOH, saturated brine (×1), dried (MgSO4), filtered and concentrated. The residue was partially purified by silicagel chromatography (SGC) with hexane as eluent. Appropriate fractions were combined, concentrated and purified by vacuum distillation (150° C./0.5 mm Hg) to afford the dibromo-furan 10 (7.26 g, 55%) as a yellow oil. 1H NMR (400 MHz; CDCl3) δ 6.79 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H) and 7.83 (m, 1H).
Reaction SMILES: [Mg].[C-:2]1([CH:7]=O)[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:9]1[CH:13]=CC=[CH:10]1.[Fe+2:14].C(Br)C=C.C[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[C-:2]1([CH:7]=[CH:13][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:20]1[CH:21]=[CH:22][CH:23]=[CH:24]1.[Fe+2:14]
Reactant: O=C[c-]1cccc1
Reactant: CCCCCC
Agent: [Fe+2]
Agent: [Mg]
Agent: c1cc[cH-]c1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC=C[c-]1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
72 mg (3.0 mmole) of magnesium metal was placed in a 50 ml round bottom flask. 214 mg (1.0 mmole) of ferrocenaldehyde and 181.5 mg (1.5 mmole) of allyl bromide were dissolved in 15 ml of THF. The resulting mixture was poured into the round bottom flask containing the magnesium metal, while stirring at room temperature for two hours. After two-hour stirring, the cover of the flask was opened, and the liquid portion of the reaction mixture was introduced into a silica gel column, which had been wetted with n-hexane. All the liquid migrated into the silica gel, and the column was placed still for 24 hours. Next, the column was eluted with n-hexane. After evaporating the solvent from the eluate collected, 200 mg (0.84 mmole) of a purified title product was obtained with a yield of 84%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:5]([CH:6]=[CH2:7])[CH:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>[Pd].CO>[CH2:6]([CH:5]1[CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]1[CH2:2][OH:1])[CH3:7]
Reactant: C=CC1C(CO)C1C(=O)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1C(CC)C1CO
Reaction time: 8 h
Yield: 75 %

Procedure:
A suspension of a mixture of ethyl (1SR,2SR,3RS)-2-hydroxymethyl-3-vinylcyclopropane carboxylate (500 mg, 2.94 mmol) and 5% palladium on carbon (70-mg) in methanol (25 mL) was stirred under hydrogen atmosphere overnight. The catalyst was then filtered off through celite and the solvent was removed under vacuo. The residue was purified by column chromatography using ethyl acetate and hexane 1:2 as eluent to give 380 mg (80% yield) of ethyl (1SR,2SR,3RS)-3-ethyl-2-hydroxymethylcyclopropane carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Reactant: OCCOC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCOC1CCOCC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 4-chloro-6-cyano-7-hydroxyquinoline (400 mg, 1.95 mmol), (prepared as described for the starting material in Example 1), 4-(2-hydroxyethoxy)tetrahydropyran (371 mg, 2.54 mmol) and triphenylphosphine (820 mg, 3.12 mmol) in methylene choride (15 ml) was added diethyl azodicarboxylate (492 μl, 3.12 mmol) in portions. After stirring for 30 minutes, triphenylphosphine (512 mg, 1.95 mmol), 4-(2-hydroxyethoxy)-tetrahydropyran (142 mg, 0.98 mmol) and diethyl azodicarboxylate (308 μl, 1.95 mmol) were added. The volatiles were removed under vacuum and the residue was purified by column chrolatography eluting with methylene chloride/ethyl actetate/methanol (60/40/0 followed by 50/50/0, 40/60/0, 60/39/1, 60/38/2 and 50/46/4) to give 4-chloro-6-cyano-7-(2-(tetrahydropyran-4-yloxy)ethoxy)quinoline (519 mg, 65%).
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([SH:13])[CH2:11][SH:12].[CH2:14]([O:16][C:17](=[O:26])[C@@H:18]([O:22][C:23](=[O:25])[CH3:24])[CH2:19][CH:20]=O)[CH3:15]>ClCCl>[CH2:14]([O:16][C:17](=[O:26])[C@@H:18]([O:22][C:23](=[O:25])[CH3:24])[CH2:19][CH:20]1[S:13][CH2:10][CH2:11][S:12]1)[CH3:15]
Reactant: CCOC(=O)[C@H](CC=O)OC(C)=O
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)[C@H](CC1SCCS1)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 145 %

Procedure:
Boron trifluoride etherate (1.15 g, 81 mmol) was added to a stirred solution of 1,2-ethanedithiol (0.34 g, 3.65 mmol) and (S)-2-acetoxy-4-oxobutanoic acid ethyl ester (0.46 g, 2.4 mmol) in dichloromethane (20 ml) at 0°. The mixture was stirred at room temperature overnight and ice/water added. The organic layer was separated, dried (MgSO4) and the solvent evaporated to give the sub-title compound (0.92 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][N:8]=1>O1CCOCC1>[N+:16]([C:10]1[C:9]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][CH:7]=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(N2CCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 89.6 %

Procedure:
2.2 g (0.03 mol) of pyrrolidine were added over 10 minutes to a solution containing 3 g (0.015 mol) of 2-chloro-3,5-dinitropyridine in 30 ml of dioxane, at 40° C. The reaction medium was maintained at 60° C. until the reagents disappeared. The reaction medium was then poured into a water/ice mixture with vigorous stirring and the precipitate was filtered off by suction, washed with water and then dried to constant weight to give 3.2 g of 3,5-dinitro-2-pyrrolidin-1-ylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].C(N(CC)C(C)C)(C)C.[CH3:23][O:24][CH2:25]Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH2:23][O:24][CH3:25])[NH2:8]
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(CCO)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCc1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(2-chloro-4-nitrophenyl)-ethanol (2.9 g) in dichloromethane (20 ml) were added N,N-diisopropyl-ethylamine (3.0 ml) and chloromethyl methyl ether (1.2 ml) under ice-cooling, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (20 ml), 3% platinum sulfide on activated carbon (wet) (842 mg) was added, and the mixture was stirred for 10 hours under a hydrogen atmosphere. After the catalyst was removed by filtration, the solvent was removed under reduced pressure to give 3-chloro-4-[2-(methoxy-methoxy)ethyl]aniline (2.0 g).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:22]([CH3:37])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>CO>[CH3:26][C:24]1[CH:25]=[C:20]([O:19][CH:14]([C:11]2[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])=[O:8])=[CH:13][CH:12]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:21]=[C:22]([CH3:37])[C:23]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)s2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.3 %

Procedure:
A solution of 3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (Isomer 1) (91 mg, 0.166 mmol) in methanol (1.66 mL) is treated with 5N NaOH (0.166 mL) and shaken at rt for 2 h. The reaction is neutralized with 1N HCl (0.170 mL), and extracted into ethyl acetate (2×). The combined organic layers are dried and concentrated, giving the title compound (142 mg). MS (ES): 534.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13]>>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:10]([CH3:9])=[CH:11][C:12]([CH3:13])=[N:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)c2ccc(N)nc2n1

Procedure:
Preparation of the compounds having the formula: ##STR3## wherein R' is CH3, OH or CF3 is carried out by (a) condensing 2,6-diaminopyridine with 2,4-pentanedione to yield 7-amino-2,4-dimethyl-1,8-naphthyridine, (b) acetylating the naphthyridine to form the corresponding 7-acetamido naphthyridine, (c) methylating the 7-acetamido compound of step (b) to form a 1,2,4-trimethyl product, (d) hydrogenating the step (c) product to yield 7-acetamido-1,2,4-trimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine, (e) hydrolyzing the product of step (d) under basic conditions and (f) condensing the product of step (e) with a β-diketone of the formula R'COCH2CO2H5 wherein R' is CH3, CH3 or OC2H5.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:21][CH2:20]2)([OH:18])[CH2:15]1)([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.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[CH:1]([N:14]1[CH2:17][C:16]([CH:19]2[CH2:20][CH2:21]2)([O:18][CH3:24])[CH2:15]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
Reactant: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
334 mg of 1-benzhydryl-3-cyclopropylazetidin-3-ol was dissolved in dimethylformamide, and 72 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 30 minutes. 112 μl of methyl iodide was added thereto, and the mixture was further stirred at room temperature for 2 hours. To the reaction solution was added water and the mixture was subjected to extraction with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 280 mg of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[C:23](O)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][C:4]=1[C:23](=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(C)=O

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 56 using 4-(4-methoxyphenoxy)-5-methyl-7-nitroindane instead of ethyl N-[7-(4-methoxyphenoxy)-6-methylindan-4-yl]malonamate and using acetic acid instead of 4-fluorophenylacetic acid.
Reaction SMILES: [ClH:1].NC(=O)[C@@H](N[C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])C1C=CC=CC=1.Cl.[NH2:35][C@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([O:39][CH3:40])=[O:38]>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:35][C@H:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:37]([O:39][CH3:40])=[O:38])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Product: COC(=O)[C@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 51.1 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (R)-methyl 2-amino-2-phenylacetate, hydrochloride salt (Aldrich, 30 mg, 0.10 mmol) in a manner similar to that which is described in Step C of Example 1 to give (R)-methyl 2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate, hydrochloride salt (25 mg, 51% yield). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 9.03 (d, 1H, J=7.0 Hz), 7.96 (d, 1H, J=7.0 Hz), 7.77-7.88 (m, 3H), 7.42 (m, 7H), 6.71 (d, 1H, J=7.5 Hz), 6.12 (s, 1H), 5.44 (d, 1H, J=7.0 Hz), 3.63 (s, 3H), 3.44-3.38 (m, 2H); MS(ESI+) m/z 453.29 (M+H)+.