Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6]C(CO)[O:8][C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:52]([CH3:56])([CH3:55])[C:53]#[N:54]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:55]([CH:52]([CH3:56])[C:53]#[N:54])[O:8][C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19]
Reactant: OCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Reactant: CC(C)(O)C#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C#N)C1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (0.5 g, 1.69 mmol) in toluene (10 mL) was added triphenylphosphine (0.66 g, 2.54 mmol), diethyl azodicarboxylate (0.44 g, 2.54 mmol), and 2-hydroxy-2-methylpropanenitrile (0.21 g, 2.53 mmol) and the reaction mixture was allowed to stir at room temperature for 48 h. The solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9-3:7) provided 0.22 g (43%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]propanenitrile. To a solution of the nitrile in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran (8 mL) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was quenched with 1.0 N aqueous hydrogen chloride (100 mL) and then neutralized with 1.0 N aqueous sodium hydroxide (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:dichloromethane 1:9) provided 0.1 g (19%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a white solid, hydrochloride salt. mp 211-213° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][N:13]=[N+:14]=[N-:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(CCCN=[N+]=[N-])OCC
Temperature: 25 °C
Yield: 98.3 %

Procedure:
(3-Bromopropyl)phosphonic acid diethyl ester (300 mg, 1.15 mmol) and sodium azide (150 mg, 2.3 mmol) were dissolved in acetone (10 ml) and the solution was refluxed for 12 hours under nitrogen atmosphere, then cooled to room temperature, filtered, and dried under vacuum to afford (3-azidopropyl)phosphonic acid diethyl ester (250 mg, 98% yield) as a colorless liquid.
Reaction SMILES: CN(C1C=CC=CN=1)C.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[NH2:22])([O-:12])=[O:11].[C:23]([O:27][C:28](OC([O-])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([O:27][C:28]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[C:16]([NH2:22])=[N:17]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(N)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
Dimethylaminopyridine (4 g, 36 mmol) was added to a solution of 5-nitro-1H-indazol-3-ylamine (32.2 g, 181 mmol), tert-butyldicarbonate (39.4 g, 181 mmol) and triethylamine (25 mL, 181 mmol) in THF (1 L) at room temperature under nitrogen. After stirring for 30 minutes, the reaction mixture was concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase washed with brine, dried (MgSO4), and concentrated to an orange solid. Recrystallisation from ethyl acetate provided the title product as a yellow solid (25 g, 50%). 1H NMR (400 MHz, DMSO) 1.60 (9H, s), 6.75 (2H, brs), 8.10 (1H, d), 8.36 (1H, d), 8.96 (1H, s); MS (ES−) m/e=277.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25][C:26](=[O:28])[CH3:27])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[C-:31]#[N:32].[Na+]>CS(C)=O>[C:31]([C:2]1[O:3][C:4]2[C:24]([O:25][C:26](=[O:28])[CH3:27])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)#[N:32]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(=O)c2c(C#N)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (25 mg, 0.05 mmol) and sodium cyanide (15 mg, 0.38 mmol) in dry DMSO (1 mL) under nitrogen at room temperature was stirred for 3.5 hours (monitored by tlc), quenched with saturated ammonium chloride solution and diluted with ethylacetate (20 mL). The organic layer was separated, dried over magnesium sulfate and the solvent distilled to afford the crude material which was purified over silica gel column (eluent—Hexane:diethyl-ether 1:1 to 0:100) to afford the desired product as pale cream solid (13 mg, 65%); 1H NMR (300 MHz, CDCl3) δ: 7.29 (d, 1H, J=8.71 Hz), 7.19 (s, 2H, benzoyl Hs), 6.06 (d, 1H, J=8.77 Hz), 5.82 (b, 1H, OH), 3.99 (s, 3H, OMe), 3.96 (s, 3H, OMe), 3.88 (s, 6H, 2×OMe).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[O:15]=[C:16]1[C:21]2=[CH:22][NH:23][C:24]([CH:25]=O)=[C:20]2[CH2:19][CH2:18][NH:17]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:25][C:24]2[NH:23][CH:22]=[C:21]3[C:20]=2[CH2:19][CH2:18][NH:17][C:16]3=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C
Yield: 82.8 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (63 mg, 0.3 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 89 mg (82%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15]C2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][N:31]1[C:35]([C:36]2[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=2)N)=[N:34][N:33]=[N:32]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([C:35]3[N:31]([CH3:30])[N:32]=[N:33][N:34]=3)[CH:37]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Cn1nnnc1-c1cccc(N)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: Cn1nnnc1-c1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1-methyl-1H-tetrazol-5-yl)aniline in step 1. MS: 409.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].NC1C=CC([F:41])=CN=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([F:41])=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: Nc1ccc(F)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(F)cn1

Procedure:
The product from Example 11, Part D (100 mg, 0.3 mmol) and 2-amino-5-fluoropyridine (110 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using 2; 1 THF/CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (120 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.13 (m, 1H), 7.92 (d, J=3 Hz, 1H), 7.65 (d, J=8, 1H), 7.43 (m, 2H), 7.30 (m, 2H), 7.17 (t, J=9 Hz, 1H), 7.00 (t, J=9 Hz, 2H), 5.25 (d, J=15 Hz, 1H), 4.69 (m, 1H), 4.23 (d, J=15 Hz, 1H), 2.57 (m, 2H), 1.97 (m, 2H). MS: m/z (MH+) 426.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][C:12]1[NH:13][C:14]([NH2:23])=[C:15]2[C:19]([N:20]=1)=[N:18][C:17]([O:21][CH3:22])=[N:16]2)[CH3:10].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:18]1[C:17]([O:21][CH3:22])=[N:16][C:15]2[C:19]1=[N:20][C:12]([O:11][CH:9]([CH3:8])[CH3:10])=[N:13][C:14]=2[NH2:23]
Reactant: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Reactant: ClCCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-[(1-methylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-5-chloropentane.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][NH:7][CH:8]=1.C([O:17][C:18](=[O:23])[C:19](Br)([CH3:21])[CH3:20])C>O1CCCC1>[CH3:20][C:19]([CH3:21])([N:7]1[CH:8]=[C:4]([CH3:3])[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6]1)[C:18]([OH:23])=[O:17]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cn(C(C)(C)C(=O)O)nc1-c1ccccc1

Procedure:
Sodium hydride (25.0 g. of 57% dispersion in oil, 0.6 mole) was added to a stirred solution of 4-methyl-3-phenylpyrazole (79.0 g., 0.5 mole) in tetrahydrofuran. Ethyl-2-bromoisobutyrate (136.0 g., 0.7 mole) was added and the solution was refluxed for 4 hours. The solvent was removed by evaporation and the residual ester mixture was hydrolyzed by refluxing with methanolic sodium hydroxide solution (40 g. sodium hydroxide in 600 ml. of 30% methanol-water). After cooling, the alkaline reaction solution was extracted with ether and the aqueous phase was acidified with concentrated hydrochloric acid. The solution was extracted with chloroform, and the chloroform layer was evaporated to give a crude acid mixture in which α,α,4-trimethyl-3-phenylpyrazole-1-acetic acid was the major isomer.
Reaction SMILES: [NH2:1][OH:2].C([O-])([O-])=O.[K+].[K+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(Cl)Cl>[C:10]([NH:1][OH:2])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: NO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 135.7 %

Procedure:
A solution of crude amino alcohol 1f (223 g, 1.19 mol) in 1 L of CH2Cl2 was treated with a 1 L aqueous solution of K2CO3 (200 g, 1.45 mol) and cooled in a ice bath. The mixture is stirred vigorously while benzyl chloroformate (225 g, 1.3 mol) is added slowly. After the addition is complete the mixture is stirred an additional 30 min. The organic layer is separated and washed with water, brine and concentrated to give 390 g of crude product. This is recrystallized from hexane to give 270 g of N-CBZ amino alcohol 1g.
Reaction SMILES: [O:1]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[C:18]([C:26]([O:28][CH3:29])=[O:27])[CH:17]=1)[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1>[Rh].C1COCC1>[O:1]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:17]1)[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]1
Reactant: COC(=O)c1ccc(Oc2ccc(C(=O)OC)c(C(=O)OC)c2)cc1C(=O)OC
Agent: [Rh]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(OC2CCC(C(=O)OC)C(C(=O)OC)C2)CC1C(=O)OC
Temperature: 120 °C

Procedure:
A 1-L stainless steel autoclave was charged with 100 g of oxydi(3,4-dicarbomethoxybenzene), 3.00 g of 5% rhodium on alumina, and 750 mL of THF. With stirring, the reactor was purged several times with hydrogen and then charged to approximately 2000 psi of hydrogen. The reaction mixture was heated to 120° C., and the mixture was allowed to stir for 20 h. The reactor was cooled and vented, and the crude reaction mixture removed. The solution was filtered to remove catalyst and then concentrated using a rotary evaporator. The oily residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried (MgSO4), and concentrated to a clear lightly colored oil using a rotary evaporator. Gas chromatographic analysis of the crude product reveals a mixture of tetramethyl oxydi(cyclohexane-3,4-dicarboxylate) (major), dimethyl cyclohexanedicarboxylate (minor), and dimethyl 4-hydroxycyclohexanedicarboxylate (minor).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[C:12]([CH3:21])([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14]>>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([C:12]([CH3:21])([CH3:20])[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)c1cn[nH]c1
Product: CCOC(=O)c1cnn(C(C)(C)C(=O)O)c1
Yield: 83.1 %

Procedure:
By a reaction in the same manner as in Example 10a and using ethyl 1H-pyrazole-4-carboxylate (1.40 g, 10.0 mmol) and tert-butyl 2-bromo-2-methylpropanate (6.70 g, 30.0 mmol), the title compound (1.88 g, 83%) was obtained as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]2[CH2:14][CH2:13][C:6]3([CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(CCN)cc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Product: CCc1ccc(CCN2CCC3(CCC(O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 1, step 4 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 2-(4-ethylphenyl)-ethylamine [CAS Reg. No. 64353-29-3]. MS (m/e): 302.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][C:31]([O:33]CC)=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[OH-].[Li+].CO.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][C:31]([OH:33])=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CCOC(=O)C[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
Prepared analogously to Example 19b from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2S)-2-(ethoxycarbonylmethyl)pyrrolidin-1-ylcarbonyl]benzamide and lithium hydroxide in tetrahydrofuran. Yield: 63%; Rf value: 0.32 (Reversed phase RP 8: methanol/5% sodium chloride solution=6:4); C23H22Cl2N4O4 (489.357); mass spectrum: (M−H)-=487/489/451 (chlorine isotope).
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH2:26]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:22]2[C:21](=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=2)[NH:26][CH:5]=1)=[O:17]
Reactant: Cc1ccncc1N
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3c(C)ccnc3c2=O)cc1C
Yield: 16.1 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (2.01 mmol) 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester, 0.22 g (2.01 mmol) of 4-Methyl-pyridin-3-ylamine, and 30 mL of diphenyl ether to yield 94.4 mg of 3-(3,4-Dimethyl-benzoyl)-8-methyl-1H-[1,5]naphthyridin-4-one as a brown solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31](ON1C(=O)CCC1=O)([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32]>CN(C=O)C>[C:31]([C:2]([NH2:1])([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:32]
Reactant: COc1ccc(C(N)c2cc(C(C)C(=O)O)ccc2OC)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(N)(C(=O)OCC2c3ccccc3-c3ccccc32)c2cc(C(C)C(=O)O)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 3-(α-amino-4-methoxybenzyl)-4-methoxyphenylpropionic acid (1.0 g, 3.17 mmol) prepared in Example 4 was dissolved in 5 ml of DMF containing triethylamine (0.88 ml). To the solution, 1.28 g of Fmoc-OSu was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and 5% citric acid and ether were added to the residue. The resulting power was recrystallized from methanol and ether.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](O[C:12](=[O:13])[CH:2]21)=[O:10].[NH3:14]>O>[CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](=[O:10])[NH:14][C:12](=[O:13])[CH:2]21
Reactant: N
Reactant: O=C1OC(=O)C2C3CCC(CC3)C12
Solvent: O
Product: O=C1NC(=O)C2C3CCC(CC3)C12

Procedure:
A solution of bicyclo[2.2.2]octane-2,3-dicarboxylic anhydride (3 g; 16.6 mmol) in tetrahydrofurn (9 ml) was dropwise added to a mixture of 29% aqueous ammonia (6 g; 83 mmol) and water (18 ml) while ice-cooling, and the resultant mixture was heated. After removal of the solvent by distillation under an ordinary pressure, acetic anhydride (10 ml) was added thereto, followed by refluxing for 30 minutes. The solvent was removed by distillation under reduced pressure, and the residue was combined with toluene (24 ml) and heated to dissolve. After cooling, the precipitated crystals were collected by filtration to give the objective compound. M.P., 199°-200° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(Cl)cc2Cl)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 28.3 %

Procedure:
Sodium hydride (60%, 0.12 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxymethylphenyl) 1-methyl-1H-1,2,4-triazole (1.00 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C. and stirred for 20 minutes. The reaction solution is added dropwise with a solution of 2,3,5-trichloropyridine (0.60 g) in 1,2-dimethoxyethane (20 ml) at -5° C. for 10 minutes with stirring. The reaction mixture is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.40 g of desired compound (melting point: 153.0°-155.0° C.).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:28])[F:29])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CNC4)cc3N21

Procedure:
A solution of 3-(4(S)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 6), Rt=8.78 min., 0.270 g, 0.59 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(S)-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (Example #53-1, Enantiomer 1, SFC (Table 1, Method 7), Rt=6.44 min, 0.275 g, 99%). LC/MS (Table 1, Method 5) Rt=2.070 min.; MS m/z: 356 [M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][N:8]([CH3:34])[C:9](=[O:33])[CH2:10][CH:11]([C:13]1[C:14]([CH:30]2[CH2:32][CH2:31]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)O.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][N:8]([CH3:34])[C:9](=[O:33])/[CH:10]=[CH:11]/[C:13]1[C:14]([CH:30]2[CH2:31][CH2:32]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: CON(C)C(=O)CC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 79.9 %

Procedure:
A dichloromethane (10 ml) solution of methanesulfonyl chloride (1.44 g, 12.6 mmol) was added to a dichloromethane (40 ml) solution of N-methoxy-N-methyl-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3-hydroxypropanamide (3.30 g, 8.38 mmol) and triethylamine (1.27 g, 12.6 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for 3 hours before treatment with triethylamine (1.27 g, 12.6 mmol). The mixture was heated to reflux for 3 hours, quenched with saturated NaHCO3 aq solution, and extracted with dichloromethane. The organic layer was washed with saturated NaCl aq solution, dried over magnesium sulfate, and then concentrated. The residue was purified by column chromatography (hexane:ethyl acetate=3:1) to give N-methoxy-N-methyl-(E)-3-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}propenamide (2.52 g, 80% yield). mp=141° C. Rf =0.52 (hexane:ethyl acetate=2:1) IR (CHCl3): 3000, 1650, 1610, 1515, 1490, 1415, 1385, 1220, 1090, 1025, 840, 760 cm-1.