Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:36][CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[CH2:29]([N:36]([CH3:37])[C:23]([C:20]1[N:19]=[C:18]([C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[O:22][N:21]=1)=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CN(Cc1ccccc1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Yield: 82.9 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with N-benzyl-N-methylamine (0.98 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (100:0) gradually changing to dichloromethane:ethyl acetate (95:5) to afford the title compound (296 mg).
Reaction SMILES: C([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C1C=CC=CC=1>C(O)C.C(O)(=O)C.[C].[Pd]>[NH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOP(=O)(CN)OCC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A 250-mL pressure tank reactor was purged, flushed and maintained with a hydrogen atmosphere, then, was added a solution of diethyl (benzylamino)methylphosphonate (3.5 g, 13.62 mmol, 1.00 equiv) in ethanol (180 mL), acetic acid (10 mL) and Palladium carbon (0.2 g, 0.10 equiv). The resulting solution was stirred for 24 h at 50° C. under 20 atm pressure. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 2.0 g (crude) of the title compound as brown oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[CH:13]=1)=[CH2:11].[H][H]>CO.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[CH:13]=1)[CH3:11]
Reactant: C=C(C(=O)c1ccc(O)cc1O)c1ccc(O)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)c1ccc(O)cc1O)c1ccc(O)c(O)c1

Procedure:
The title compound was obtained by catalytic hydrogenation of 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-2-propene obtained as in Example 3 or Example 4. To a solution of 1-(2,4-dihydroxyphenyl)-2-(3′,4′-dihydroxyphenyl)-1-oxo-2-propene in methanol was added palladium on carbon, and hydrogen gas was bubbled vigorously through the solution for ten minutes. Removal of the catalyst and evaporation of the solvent afforded the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[N:7][CH:6]=[N:5]1.Cl[C:12]1[C:13]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[N:19][N:20]=2)[N:17]=1>CN(C=O)C>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:10][CH2:9][C:8]3[N:4]([CH3:3])[N:5]=[CH:6][N:7]=3)[C:13]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: Cn1ncnc1CO
Reactant: Fc1ccc(-c2nnc3cc(N4CCCC4)c(Cl)nn23)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccc(F)cc3F)nnc2cc1N1CCCC1
Reaction time: 18 h
Yield: 30 %

Procedure:
Sodium hydride (60% dispersion in oil, 16 mg, 0.41 mmol) was added to a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210) (38 mg, 0.33 mmol) in dry DMF (2 ml) at room temperature. After 1 h at room temperature a solution of 6-chloro-3-(2,4-difluorophenyl)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (102 mg, 0.30 mmol) was added and the reaction stirred for 18 hours. The residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (2×100 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 0-2% ethyl acetate-methanol to afford the title pyridazine (42 mg, 30%). 1H NMR (250 MHz, CDCl3) 1.73-1.78 (4H, m), 3.51-3.55 (4H, m), 3.93 (3H, s), 5.40 (2H, s), 6.65 (1H, s), 6.95-7.03 (2H, m), 7.92-7.94 (1H, m), 8.04 (1H, s), MS (ES+) 413 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(=[O:17])=[O:16])=[O:13])[N:4]=1.ClCCl.[C:33](OC(=O)C)(=[O:35])C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[C:22]([NH:24][CH:33]=[O:35])[CH:21]=[CH:20][C:19]=2[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C(=O)N(C)C)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(NC=O)ccc2C(=O)N(C)C)n1

Procedure:
A solution of 1.9 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-5-amino-2-dimethylaminocarbonylbenzenesulfonamide and 10 ml of dichloromethane is added dropwise to the mixed anhydride, prepared in situ from 0.5 ml of formic acid and 1.0 ml of acetic anhydride in accordance with standard methods. After the end of reaction, the reaction mixture is concentrated and the residue is washed with water and ethyl acetate, to give 1.8 g of desired product; purity>92% (HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: CCI
Reactant: O=C(O)c1occc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1occc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 3-bromofuran-2-carboxylic acid (23.5 g), iodoethane (11.8 mL) and potassium carbonate (25.6 g) in DMF (200 mL) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with diethylether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in hexane, passed through a silica gel (NH) layer, and the eluate was concentrated under reduced pressure to give the title compound (23.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25](Br)[CH2:26][CH2:27][CH3:28])[CH3:21].O>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:26][CH2:27][CH3:28])[CH3:21]
Reactant: CCCC(Br)CC(=O)OCC
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 5-benzyloxyindole (5.00 g, 22.4 mmol) in DMF (20 mL) was added dropwise to a stirred solution of sodium hydride (0.91 g, 38.1 mmol) in DMF (50 mL) at 0° C. and stirred for 20 minutes. Ethyl-β-bromocaproate (5.59 g, 26.9 mmol) in DMF (20 mL) was added and the reaction was stirred at room temperature overnight. The reaction was then poured into cold H2O (150 mL) and extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40% ethyl acetate in hexane) to give the title compound as oil (40% yield). 1H NNR (CDCl3) δ 7.47 (d, 2H, J=7.2 Hz), 7.38 (t, 2H, J=7.1 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.12 (dd, 2H, J=2.4, 13.7 Hz), 6.94 (dd, 1H, J=2.4, 10.2 Hz), 6.44 (d, 1H, J=3.1 Hz), 5.09 (s, 2H), 4.79 (m, 1H), 3.98 (q, 2H, J=7.1 Hz), 2.80 (m, 2H), 1.90 (m, 2H), 1.25 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.86 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (745 mg, 2.3 mmol), benzoic acid (337 mg, 2.76 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.31 g, 3.45 mmol) in dichloromethane (10 mL) and triethyl-amine (0.8 mL, 5.75 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (984 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H28N2O3 (M+H)+: 429.54, observed: 429.1.
Reaction SMILES: [ClH:1].O1CCOC[CH2:3]1.[CH3:8][O:9][C:10](=[O:32])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1>>[ClH:1].[NH:22]1[CH2:23][CH2:24][CH:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]([O:9][CH2:8][CH3:3])=[O:32])[CH2:20][CH2:21]1
Reactant: COC(=O)CCc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CCOC(=O)CCc1ccccc1C1CCNCC1
Reaction time: 8 h
Yield: 98 %

Procedure:
4 M HCl/dioxane (2.2 mL, 8.97 mmol) was added to neat tert-butyl 4-(2-(3-methoxy-3-oxopropyl)phenyl)piperidine-1-carboxylate at 23° C. and was stirred overnight. The reaction mixture was concentrated to yield methyl 3-(2-(piperidin-4-yl)phenyl)propanoate hydrochloride (24, 250 mg, 98% yield). LC/MS RT (5 min method)=1.14 min. Mass observed: 248.16 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and iPr2NEt (6.67 g, 51.6 mmol) were added to a DMF (50 mL) solution of 3-[(tert-butoxycarbonyl)amino]pyrrolidine (4.81 g, 25.8 mmol). The reaction mixture was stirred at 70° C. for 15 hours, and the solvent was removed under reduced pressure. The objective 3-[(tert-butoxycarbonyl)amino]-1-(4-chlorobenzyl)pyrrolidine (6.43 g, 80%) was obtained as an off-white solid by recrystallization (acetonitrile, 50 mL). 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); the purity was determined by RPLC/MS (98%). ESI/MS m/e 311.0 (M++H, C16H24ClN2O2).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35](O)=[O:36])[CH:30]=[CH2:31].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(OCC)(=O)C>[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35]([NH:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12)=[O:36])[CH:30]=[CH2:31]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: C=CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 ml) was added BSA (1.1 ml, 4.5 mmoles), and the mixture was stirred for 30 minutes at room temperature to become a clear solution. A mixture of (Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVd) (1.40 g, 3.0 mmoles) and phosphorus pentachloride (690 mg, 3.3 mmoles) in methylene chloride (20 ml) was stirred for 15 minutes at room temperature and poured in one portion into the solution of the trimethylsilylated Compound V. The mixture was stirred for 20 minutes at room temperature and diluted with ethyl acetate (200 ml), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wakogel, C-200, 30 g). The column was eluted with chloroform and the fractions containing the desired product were combined. Evaporation under reduced pressure afforded the title compound (VId) as an amorphous powder, yield 2.32 g (89%). Mp. 100°-115° C. (dec.).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11][C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:23]>O>[Br:23][CH2:3][CH2:2][CH:1]=[C:4]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Br
Reactant: OC1(C2CC2)c2ccccc2Sc2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: BrCCC=C1c2ccccc2Sc2ccccc21
Reaction time: 0.5 h

Procedure:
To the above crude alcohol (25.2 g) was added glacial acetic acid (120 ml). The mixture was cooled on an ice-bath and a mixture of glacial acetic acid (60 ml) and 47% hydrobromic acid (30 ml) was added. The mixture was stirred for 30 minutes, poured into water (600 ml) and extracted with diethyl ether (3×200 ml). The combined organic phases were washed with water, dried (Na2SO4) and the solvent was evaporated in vacuo to give 19.5 g of crude 9-(3-bromo-1-propylidene)-9H-thioxanthene. Rf =0.35 (SiO2 ; THF/heptane=1:9).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH2:10]([Sn](CCCC)(CCCC)CCCC)[CH:11]=[CH2:12]>CN(C=O)C.CCOC(C)=O.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>[CH2:12]([C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)[CH:11]=[CH2:10]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloropyridine-3-carbonitrile (7.0 g, 50 mmol), allyl tri-n-butyltin (18.2 g, 55.0 mmol) and Pd(PPh3)2Cl2 (1 g) in 80 mL DMF was stirred at 90° C. for 3 hours. The mixture was cooled down and diluted with 1 L of EtOAc, washed with water (100 mL×2) and brine (100 mL), then concentrated. The residue was purified by column chromatography (PE:EtOAc=10:1) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=4)=[C:16]([C:17]#[N:18])[C:9]=23)[CH:7]=1.C(N(CC)CC)C.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>CN(C)C=O>[C:17]([C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])[NH:14][C:15]=1[C:19]1[CH2:20][CH2:21][N:22]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:23][CH:24]=1)#[N:18]
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNCC3)c(C#N)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)N(C)C)CC3)c(C#N)c12
Temperature: 70 °C

Procedure:
To a suspension of Example 248E (125 mg, 0.359 mmol) in N,N-dimethylformamide (6 mL) was added triethylamine (0.30 mL, 2.153 mmol) and 2-chloro-N,N-dimethylacetamide (56 mg, 0.466 mmol) and the mixture was heated at 70° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and sodium bicarbonate and the organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (5-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.77-2.80 (m, 2H), 2.86 (t, J=5.65 Hz, 2H), 2.95 (s, 3H), 3.11 (s, 3H), 3.37 (q, J=2.75 Hz, 2H), 3.77 (s, 3H), 6.65-6.67 (m, 1H), 7.04-7.12 (m, 3H), 7.15-7.21 (m, 1H), 8.34 (d, J=4.88 Hz, 1H). MS (DCI/NH3) m/z 434 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCNCC(=O)OCC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of diester 58 (3.88 g, 20.2 mmol) in dry acetonitrile (40 mL) at 0° C., under Argon, was added slowly benzyl chloroformate (3.17 mL, 1.1 equiv.). The solution was stirred at 0° C. for 1 h after which it was poured into water (50 mL) The phases were separated and the aqueous layer was extracted with dichloromethane (3×50 mL) the combined organic extracts were washed with 5% HCl, water, brine and dried over anhydrous sodium sulfate. Evaporation of the solvents was followed by distillation to afford compound 70 as a colorless oil (5.4 g, 80%).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][C:28]=1[C:37](O)=[O:38].FC(F)(F)C(O)=O>ClCCl>[CH2:19]([N:18]([C:37]([C:28]1[CH:29]=[N:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)=[O:38])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and quinoxaline-2-carboxylic acid as starting materials and by an operation similar to that of Example 312-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]OC(=O)C(N)CCC.Cl.CN(C)C>C(Cl)Cl.C(Cl)CCl>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: CCCC(N)C(=O)OC
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)Cc1cccc(Oc2ccccc2)c1
Yield: 131.8 %

Procedure:
A mixture of (3-Phenoxy-phenyl)-acetic acid (10.00 g, 0.0438 mol), 2-amino-pentanoic acid methyl ester (7.34 g, 0.0438 mol.), HBOT (6.20 g, 0.046 mol), EDC. HCl (12.59 g, 0.067 mol) and a trimethylamine (30.45 ml, 0.22 mol) in methylene chloride (150 ml) was stirred at room temperature overnight. The mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with 1N HCl, then brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide 13.99 g of (3-phenoxy-phenyl)-acetic acid methyl ester as a thick oil, LC-MS M+1=342.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[CH:11][C:10]2[N:9]([CH3:13])[C:8](=[O:14])[C@@H:7]([CH2:15][CH3:16])[N:6]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:5]=2[N:4]=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:26]=1[O:36][CH3:37]>C(O)C.O>[F:22][C:19]1([F:23])[CH2:20][CH2:21][C@@H:17]([N:6]2[C:5]3[N:4]=[C:3]([NH:24][C:25]4[CH:35]=[CH:34][C:28]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:26]=4[O:36][CH3:37])[N:12]=[CH:11][C:10]=3[N:9]([CH3:13])[C:8](=[O:14])[C@H:7]2[CH2:15][CH3:16])[CH2:18]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1[C@@H]1CCC(F)(F)C1
Reactant: CCNC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(Nc2ncc3c(n2)N([C@@H]2CCC(F)(F)C2)[C@H](CC)C(=O)N3C)c(OC)c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
Concentrated hydrochloric acid (42 μl) was added to a mixture of (R)-2-chloro-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (80 mg, 0.24 mmol) and 4-amino-N-ethyl-3-methoxybenzamide (70.47 mg, 0.36 mmol) in ethanol (1.2 mL) and water (4.8 mL). The reaction mixture was heated to 95° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with dichloromethane, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (89 mg, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][C:9]([OH:11])=O)[CH:3]=1.[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(OC(C)C)(C)C>>[O:16]([CH2:20][CH2:21][NH:22][C:9](=[O:11])[CH2:8][O:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)[N+:17]([O-:19])=[O:18]
Reactant: NCCO[N+](=O)[O-]
Reactant: Cc1cc(OCC(=O)O)no1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: Cc1cc(OCC(=O)NCCO[N+](=O)[O-])no1
Yield: 36.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.40 g of 5-methyl-3-isoxazolyloxyacetic acid and 0.43 g of nitroxyethylamine nitrate, 0.23 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).