Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+]([O-])([O-])=O.[C:34]1([NH:40][C:41]([NH2:43])=[NH2+:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O.O>[NH:40]([C:41]1[N:43]=[C:16]([C:15]2[C:14]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:13][N:12]3[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:8][CH:9]=[CH:10][C:11]=23)[CH:17]=[CH:18][N:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Reactant: NC(=[NH2+])Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 140 °C

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (100 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added N-phenylguanidinium nitrate (252 mg, 1.27 mmol) and potassium carbonate (175 mg, 1.27 mmol). The suspension was heated at 140 ° C. (bath temperature) for 21 hours. The mixture was cooled to room temperature, ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes-ethyl acetate) provided 3-(2-anilino-4-pyrimidinyl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine which was recrystallized from ether/hexanes (90 mg, 76%) to give a white crystalline solid. 1H NMR (CDCl3): δ 8.15 (d, 1 H), 7.69–7.59 (m, 5 H), 7.32–7.27 (m, 3 H), 7.18–7.13 (m, 3H), 7.02 (t, 1 H), 6.49 (d, 1 H), 6.06–6.01 (m, 2 H), 4.01 (m, 1 H), 2.20–2.10 (m, 2 H), 1.86–1.64 (m, 6 H); 13 C NMR (CDCl3): δ 163.20 (d, JCF=246.6 Hz), 161.55, 160.11, 156.76, 152.27, 142.72, 141.15, 139.74, 131.47 (d, JCF=8.3 Hz), 129.72 (d, JCF=3.4 Hz), 128.82, 128.66, 122.28, 119.52, 115.60 (d, JCF=21.3 Hz), 110.83, 106.91, 105.15, 90.34, 53.86, 33.32, 24.05; MS m/z 465 (M+1).
Reaction SMILES: [H-].[K+].NCCCN.[CH2:8]([OH:16])[CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH3:15]>CCCCCC>[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: CCCCC#CCCO
Agent: NCCCN
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Product: C#CCCCCCCO
Temperature: 25 °C

Procedure:
Potassium hydride, (35%) in mineral oil (27 g, 240 mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C. and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50 mL) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSO4). Evaporation gave the captioned product as a colorless oil which was used without further purification: 1H NMR (90 MHz CDCl3)δ3.65 (t, J=5 Hz, 2H, O-CH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat)nmax 3350, 2930, 2125 cm-1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]1([F:25])[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1>CCO>[F:16][C:17]1([F:25])[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH2:18]1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)acetamide (1.15 g, 5.84 mmol) and [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (1.30 g, 7.59 mmol) were stirred in 30 mL of EtOH containing TEA (2.40 mL, 17.5 mmol) at 80° C. for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was crystallized from EtOAc. The left over mother liquor was purified by silica gel flash chromatography using 2:1/hexanes:acetone as eluent. Yield: 1.50 g (78%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.33-1.47 (m, 2 H), 1.66-1.77 (m, 2 H), 1.77-1.86 (m, 1 H), 1.89-1.93 (m, 1 H), 1.93-1.97 (m, 1 H), 2.10-2.17 (m, 2 H), 2.18 (s, 3 H), 3.23 (dd, J=6.74, 5.76 Hz, 2 H), 6.83 (d, J=9.37 Hz, 1 H), 7.15 (s, 1 H), 7.80 (dd, J=9.18, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 2 H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:17]=[CH:16][CH2:15][CH:14]2[CH:10]1[C:11](=O)[NH:12][C:13]2=O)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>FC(F)(F)C(O)=O.O1CCCC1>[NH2:8][CH:9]1[CH:17]=[CH:16][CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2
Reactant: CC(C)(C)OC(=O)NC1C=CCC2C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: NC1C=CCC2CNCC12

Procedure:
13.3 g (50 mmol) of 4-tert.-butyloxycarbonylamino-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-isoindole (from Example Z23, method II) are stirred overnight at room temperature in 166 ml of trifluoroacetic acid. The trifluoroacetic acid is then distilled off at 10 mbar, and the residue is freed from remaining acid in a high vacuum at 50° C. The residue is subsequently taken up in absolute tetrahydrofuran and concentrated in vacuo. The residue is taken up in 100 ml of absolute tetrahydrofuran and the mixture is added dropwise under nitrogen to a solution of 11.3 g (0.3 mol) of lithium aluminium hydride in 300 ml of absolute tetrahydrofuran. The mixture is then refluxed for 16 hours. 11.3 g of water in 34 ml of tetrahydrofuran, 11.3 ml of 10% strength sodium hydroxide solution and 34 ml of water are added dropwise in succession to the cold mixture. The precipitate is filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[CH:11]=1.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26]Cl)[CH:21]=1.[OH-].[Na+].[K+].[Br-]>C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:10][C:8]2[NH:7][C:6]3[CH:11]=[C:2]([F:1])[C:3]([N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)=[CH:4][C:5]=3[N:9]=2)[CH:21]=1
Reactant: COc1ccnc(CCl)c1
Reactant: Fc1cc2[nH]c(S)nc2cc1-n1ccnc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: COc1ccnc(CSc2nc3cc(-n4ccnc4)c(F)cc3[nH]2)c1
Yield: 59.4 %

Procedure:
The title compound (1.9 g, 60%) was prepared by the general procedure using, 6-fluoro-5-(imidazol-1-yl)-2-mercapto-1H-benzimidazole (2.1 g, 9.0 mmol), (obtained in preparation 1) 4-methoxy-2-chloromethylpyridine hydrochloride (1.74 g, 9.0 mmol), sodium hydroxide (0.72 g, 18.0 mmol) and ethanol (25 mL). mp 86-87° C.; IR (KBr) 3443, 1600 cm-1 ; 1H NMR (CDCl3) δ 3.90 (s, 3H, OCH3), 4.38 (s, 2H, SCH2), 6.92 (d, J=5.7 Hz, 1H), 6.96 (s, 1H), 7.30 (m, 2H), 7.42 (d, J=10.2 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 8.50 (d, J=6.0 Hz, 1H), 14.00 (brs, 1H, NH); Mass (m/z) 355 (M+.).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: COC(=O)CCCCCBr
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCN(c1ccccn1)c1ccccn1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
NaH (112 mg, 2.92 mmol) was added to di-pyridin-2-yl-amine (500 mg, 2.92 mmol) in DMF (10 mL) at rt. After 10 min, KI (485 mg, 2.92 mmol) and methyl 6-bromohexanoate, I (0.464 mL, 2.92 mmol) were added, and the reaction mixture was stirred at 90° C. for 21 h. Brine (200 mL) and EtOAc (200 mL) were then added, the phases were separated, and the aqueous phase was extracted with EtOAc (100 mL). The organic phases were combined, dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:0.5 to 100:1) as eluant to furnish II as a colourless oil (206 mg, 24%).
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:22]=[C:21]([NH:23][C:24]3[C:29]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:28][C:27]([S:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[CH:26][N:25]=3)[S:20][N:19]=2)[CH2:14][CH2:13]1)[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:44]>C(Cl)Cl.CO.O1CCOCC1>[ClH:44].[ClH:44].[NH2:4][CH2:3][C:2]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[N:22]=[C:21]([NH:23][C:24]3[C:29]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:28][C:27]([S:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[CH:26][N:25]=3)[S:20][N:19]=2)[CH2:16][CH2:17]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: NCC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
tert-Butyl 2-oxo-2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethylcarbamate (0.098 g, 0.16 mmol) was dissolved in CH2Cl2:MeOH (1:1, 20 mL) and added 5 mL of 4M HCl in dioxane and stirred for 2 hours. The reaction was concentrated and dried in high vacuum oven to provide 2-amino-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone dihydrochloride (0.081 g, 78% yield). 1H NMR (d6-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 8.13 (m, 3H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.43 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H), 3.90 (m, 2H), 3.70 (m, 2H), 3.48 (m, 1H), 3.26-3.02 (m, 2H), 2.94 (t, 1H), 2.06 (d, 2H), 1.76-1.53 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH:35]1[CH:36]=[CH:37]C2N(O)N=[N:41][C:39]=2[CH:40]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[CH3:21][C@H:17]([N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:22])[C:18](=[O:20])[N:41]1[CH2:37][CH2:36][CH2:35][CH2:40][CH2:39]1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.8 %

Procedure:
To a solution of (2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (3.1 g) in DCM (30 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.6 g), HOBT (3.2 g) and triethylamine (2.5 ml) and the mixture was stirred at room temperature for 5 min. Piperidine (2.9 ml) was added and the resultant mixture stirred at room temperature for 72 h. The mixture was washed with potassium carbonate (2M), dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using Biotage™ chromatography (silica, eluting with cyclohexane:ethyl acetate 3:1 and then ethyl acetate) to give the title compound (2.6 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[O:6])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Product: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 83.3 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide from Example 15 (0.834 g, 3.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.6124 g, 3.00 mmol) to afford the product (1.206 g) in 3 crops; m.p. 180-183° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][P:10]([CH2:15][C:16]([OH:18])=O)([O:12][CH2:13][CH3:14])=[O:11])[CH3:8].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.C(N(CC)CC)C>C1C=CC=CC=1.C1COCC1.CN(C)C=O>[CH2:13]([O:12][P:10]([CH2:15][C:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])(=[O:11])[O:9][CH2:7][CH3:8])[CH3:14]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(CC(=O)N1CCc2ccccc21)OCC
Temperature: 23 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
Oxalyl chloride (5.96 mL, 68.3 mmol, 1.05 equiv) was added to a solution of diethylphosphonoacetic acid (12.8 g, 65.0 mmol, 1 equiv) and N,N-dimethylformamide (0.03 mL, 0.39 mmol, 0.006 equiv) in benzene (150 mL) at 23° C. The reaction mixture was stirred at 23° C. for 1 hour and then concentrated under reduced pressure. The resulting oil was dissolved in THF (30 mL) and added via cannula to a solution of indoline (7.38 g, 61.9 mmol, 0.95 equiv) and triethylamine (10.9 mL, 78.0 mmol, 1.2 equiv) in THF (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, and it then was partitioned between 0.5 M HCl (150 mL) and EtOAc (2×150 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford a tan solid. Recrystallization from Et2O provided [2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-phosphonic acid diethyl ester (12.2 g, 63%) as a light brown solid: mp: 97-99° C.; Rf=0.06 (50% EtOAc in hexanes); IR (cm−1) 3460, 1657, 1597, 1482; 1H NMR (CDCl3) δ 1.35 (t, 6H, J=7.2), 3.14 (d, 2H, J=22.4), 3.22 (d, 2H, J=8.4), 4.15-4.30 (m, 6H), 7.04 (t, 1H, J=7.0), 7.17-7.28 (m, 2H), 8.21 (d, 1H, J=9.0); Anal. (C14H20NO4P) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[CH2:31]([NH2:34])[C:32]#[CH:33]>C(O)CCC.CO>[Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[N:6]3[C:32]([CH3:33])=[CH:31][N:34]=[C:7]3[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=S)C2)cc1
Reactant: C#CCN
Solvent: CCCCO
Solvent: CO
Product: Cc1cnc2n1-c1cc(Cl)c(Cl)cc1N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)C2

Procedure:
A mixture of 7,8-dichloro-2,3-dihydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (452 mg, 1.0 mmol), propargylamine (110 mg, 2.0 mmol) and red mercuric oxide (216 mg, 1.0 mmol) in n-butanol (5 ml) was heated at reflux for 10 hours. The mixture was cooled, diluted with methanol (50 ml) and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure, and purified by flash chromatography (eluting with ethyl acetate:methanol=3:1). The product was further purified by trituration with ether to give the title compound as a buff solid, (170 mg, 38%), m.p. 243°-246° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:24])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>COCCO>[CH2:17]([O:16][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:6](=[O:24])[O:7]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1c(O)c2c(OCc3ccccc3)cccc2oc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2c(OCc3ccccc3)cccc2oc1=O
Yield: 71.7 %

Procedure:
A mixture of 5-benzyloxy-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (54 mg, 0.17 mmol) and sodium glycinate (241 mg, 2.48 mmol) in 2-methoxyethanol was refluxed for 18 h and then concentrated. Residue was dissolved in water (60 mL) and acidified using 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo. Crude product was triturated with hexanes. Solid was collected and dried to provide the title compound (45 mg). MS ESI(+) m/e: 370.13 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)CC.C(=O)CCC>CO>[NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCC(=O)O
Solvent: CO
Solvent: CCCC=O
Product: NC(Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3 g of L-phenylalanine, 90 ml of 80% propionic acid and 0.3 ml (0.2 mole per mole of L-phenylalanine) of n-butyraldehyde were admixed. The mixture was stirred at 100° C. for 3 hours. After the reaction, the mixture was condensed to dryness, and 10 ml of methanol were added to the residue. The methanolic mixture was ice-cooled, and the crystalline precipitates were collected by filtration. 2.70 g of DL-phenylalanine were thereby obtained.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH:6]=1)C=C.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH3:26])=[C:18]([CH:23]=1)[CH2:17][NH:16][C:7]1[CH:6]=[C:5]([NH2:4])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH:13]=2)[N:8]=1
Reactant: C=CCNc1cc(NCc2cc(F)ccc2OC)nc2ccc(Cl)cc12
Reactant: NCc1cccnc1
Product: COc1ccc(F)cc1CNc1cc(N)c2cc(NCc3cccnc3)ccc2n1

Procedure:
The title compound, MS: m/e=404.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine and 3-picolylamine
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=[N+]=[N-]>CO.[Pd]>[N:13]1[CH:12]=[N:11][N:8]2[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=12
Reactant: [N-]=[N+]=NCc1ccn2ncnc2c1
Agent: [Pd]
Solvent: CO
Product: NCc1ccn2ncnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a solution of 7-(azidomethyl)-[1,2,4]triazolo[1,5-a]pyridine (4-4) (340 mg, 1.9 mmol) in methanol (20 mL) was added Pd/C (30 mg). The reaction mixture was stirred at room temperature under H2 (1 atm) for 2 h. The mixture was filtered to remove Pd/C. The filtrate was concentrated to afford the title compound (300 mg) MS (m/z): 149 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[OH-].[Na+].Cl>CCO>[NH2:1][C:2]1[C:11]([Cl:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(Cl)c(N)c2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(F)c(Cl)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A mixture of ethyl 5-amino-6-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (236 mg, 0.665 mmol) and 1M aq. NaOH (1.06 mL, 1.06 mmol) in EtOH (3 mL) was stirred at 50° C. for 1 h. To the reaction mixture, ice-water and 2M HCl was added to pH<3 and the resulting precipitate was collected by filtration in vacuo, washed with water and dried to yield 5-amino-6-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (204 mg, 94%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH3:13])=[C:4]([CH2:14][O:15][CH3:16])[CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23]>C1COCC1>[CH3:16][O:15][CH2:14][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[C:22]([OH:24])=[O:23]
Reactant: COCc1cc(Br)ccc1N1CCCC1C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1cc(C(=O)O)ccc1N1CCCC1C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-Bromo-2-(methoxymethyl)phenyl]-2-methylpyrrolidine (16.5 g, 58 mmol) in anhydrous THF (160 mL) was added n-butyl lithium in drops at −78° C. After 3 hours at −78° C., the reaction mixture was poured onto crushed dry-ice (100 g). Once the excess carbon dioxide was escaped, the reaction mixture was evaporated, and then acidified with 1.5 N HCl. The precipitate was filtered off and washed with pet ether to afford title compound as a solid. LC/MS, M+(ESI): 249.9. 1H NMR (DMSO-d6, 400 MHz) δ 12.4 (1H, brs), 7.84 (1H, s), 7.70 (1H, d), 6.85 (1H, d), 4.32-4.42 (2H, m), 3.59-3.87 (1H, m), 3.56 (1H, m), 3.29 (3H, s), 3.13 (1H, m), 2.14 (1H, m), 1.89 (1H, m), 1.74 (1H, m), 1.55 (1H, m), 0.99 (3H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH:8]([NH:16]C(OCC1C=CC=CC=1)=O)[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH:8]([NH2:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(OCC)C(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(OCC)C(N)CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a suspension of 3-Benzyloxycarbonylamino-4,4-diethoxy-butyric acid tert-butyl ester (0.50 g, 1.31 mmol) in Ethyl acetate (50 mL) at room temperature was added 10 mol % Pd/C (˜0.05 g). The reaction flask was purged between H2 (1atm) and vacuum three times before stirring under H2 (1atm) at room temperature. After stirring at room temperature for 3 hrs, the reaction mixture was filtered through celite and then evaporated to dryness to give the title compound (0.32 g, 98%) as a clear oil. 1HNMR (CDCl3) δ 4.29 (d, J=5.4 Hz, 1H), 3.79–3.67 (m, 2H), 3.61–3.49 (m, 2H), 3.29–3.21 (m, 1H), 2.60–2.53 (dd, J=16.2, 4.2 Hz, 1H), 2.30–2.21 (dd, J=16.2, 9.0 Hz, 1H), 1.46 (s, 9H), 1.25–1.19 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]([C:8](=[O:24])[N:9]([CH2:21][CH:22]=C)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])=C>C(Cl)Cl.[Ru]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:8](=[O:24])[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[CH2:21][CH:22]=1
Reactant: C=CCN(Cc1ccc(OC)cc1OC)C(=O)C(=C)CCC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)CCC1=CCN(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
324 mg of the compound (1c) (0.933 mmol) prepared by the above Step 2 was added to the catalyst solution containing 74 mg of ruthenium (0.09 mmol) dissolved in 93 ml of CH2Cl2. Then the mixture was stirred for 24 hrs at room temperature, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:1) as an eluant to give 268 m g of 3-[1-(2,4-dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrrole-3-yl]-propionic acid methyl ester (1d) (yield: 90%).