Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)=[CH:7][CH:6]=2.[CH:17]12[O:23][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:16]=[N:15][N:14]([CH:21]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:22]3[OH:23])[CH:13]=1)=[CH:7][CH:6]=2
Reactant: Clc1cc2cc(-c3cn[nH]c3)ccc2cn1
Reactant: C1CCC2OC2C1
Product: OC1CCCCC1n1cc(-c2ccc3cnc(Cl)cc3c2)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 45 using 3-chloro-6-(1H-pyrazol-4-yl)isoquinoline and 7-oxabicyclo[4.1.0]heptane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:13][CH2:14][CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH3:13][CH2:14][CH2:15][CH:16]([NH:20][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc2occc2c1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc2occc2c1
Yield: 41 %

Procedure:
Prepared in a similar manner to example 4 using benzofuran-5-carboxylic acid and heptan-4-amine. Yield 41%. MS (M+H, 260.2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]([F:26])([F:25])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([CH2:21][C:22](O)=[O:23])[N:13]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C>[F:26][C:11]([F:10])([F:25])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([CH2:21][C:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[O:23])[N:13]=1
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1ccsc1NC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 120 °C
Yield: 1.7 %

Procedure:
2-aminothiophene-3-carboxamide (23 mg, 0.16 mmol) and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-1-yl)acetic acid (40 mg, 0.16 mmol) were dissolved in DCM/DMF (2 mL/50 μL) and polymer supported carbonyldiimidazole (264 mg, 1.2 mmol/g, 0.32 mmol) added. The reaction mixture was heated at 120° C. for 10 min in a Biotage SmithCreator microwave. The reaction mixture was filtered washing with MeOH (10 mL), EtOAc (10 mL), and MeCN (10 mL). The filtrate was concentrated in vacuo to give a yellow gum. Purification by preparative reverse phase HPLC gave desired product (1 mg, 2%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=O)[O:26][C:24](=[O:25])[C:23]2=[CH:29][CH:30]=1>CC#N>[Cl:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:29][CH:30]=1)[C:24](=[O:25])[N:1]([CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:4][CH2:3]1)[C:27]2=[O:26]
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: CC#N
Product: O=C1c2ccc(Cl)cc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 43.5 %

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (3.86 g, 15.9 mmol) was dissolved in warm methyl cyanide (50 cm3) and a solution of 4-chlorophthalic anhydride (2.9 g, 15.9 mmol) in methyl cyanide (20 cm3) was added dropwise with stirring, to precipitate a solid. The suspension was stirred at room temperature overnight then cooled briefly in ice and the solid collected. This crude material was heated in acetic anhydride (70 cm3) for 21/2 hours then the solvent was evaporated. The residue was dissolved in methanol, to destroy excess acetic anhydride, then the methanol was evaporated. The residue was dissolved in very dilute aqueous acetic acid and the solution was basified by addition of conc. ammonia to precipitate a gum. The supernatant layer was decanted and the gum triturated with boiling ethanol and cooled in ice to give crystals of the title compound (2.82 g, 43.6%), m.p. 188°-190° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])[C:6]1=[O:20].[C:21](=O)([O:29]C1C=CC([N+]([O-])=O)=CC=1)[O:22][CH:23]([O:25][C:26](=[O:28])[CH3:27])[CH3:24].C(N(CC)CC)C>CN(C=O)C>[C:26]([O:25][CH:23]([O:22][C:21]([NH:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])[C:6]1=[O:20])=[O:29])[CH3:24])(=[O:28])[CH3:27]
Reactant: NCCC[C@@H]1NC(=O)N(c2cccc(C(=O)O)c2)C1=O
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)NCCC[C@@H]1NC(=O)N(c2cccc(C(=O)O)c2)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2.50 g (7.97 mmol) of 3-(5-(S)-3-aminopropyl-2,4-dioxoimidazolidin-3-yl)benzoic acid and 2.15 g (7.97 mmol) of 1-acetoxyethyl p-nitrophenyl carbonate are dissolved in 50 ml of DMF, treated with 3.33 ml (24 mmol) of triethylamine and stirred at room temperature for 3 d. The mixture is concentrated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol/glacial acetic acid).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([Mg]Br)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCCC[Mg]Br
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC(=O)c1ccc(F)cc1

Procedure:
100 mL of tetrahydrofuran was placed into a four-neck round-bottom flask, then 7.92 g (0.05 mol) of 4-fluorobenzoyl chloride and 0.53 g (1.5 mmol) of tris(acetylacetone)iron (III) were added and stirred under a nitrogen atmosphere. To this solution pentylmagnesium bromide was added at a room temperature and stirred at a room temperature for 10 min. After completion of the reaction, this solution was acidified with dilute hydrochloric acid and the organic phase was extracted with diethyl ether. Further, the organic phase was neutralized with satd. sodium hydrogencarbonate solution and washed with satd. sodium chloride solution. The organic phase was dehydrated with anhydrous magnesium sulfate, then diethyl ether was evaporated by a rotary evaporator and dried by a vacuum pump to obtain crude FPHxO.
Reaction SMILES: N[C@H:2](C(O)=O)CC(O)=O.C(OC(Cl)=O)C1C=CC=CC=1.C(OC(N[C@H](C(O)=O)CC(O)=O)=O)C1C=CC=CC=1.[NH2:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CO>[CH3:2][O:50][C:49](=[O:51])[C@H:41]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH2:40]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Accordingly, this invention provide a process for producing an addition compound of a dipeptide ester and an amino acid ester, in which aspartic acid and benzyloxycarbonyl chloride is reacted in an aqueous solution in the presence of a base to prepare a solution containing N-benzyloxycarbonyl aspartic acid; phenylalanine and methanol are separatedly reacted in the presence of an acid to produce phenylalanine methyl ester; excess methanol is substituted with water to convert it to an aqueous solution of phenylalanine methyl ester; it is admixed with the above-prepared aqueous solution containing N-benzyloxycarbonyl aspartic acid; an proteolytic enzyme is added into the resulting mixture under conditions, under which no substantial deactivation of the enzyme occurrs; N-benzyloxycarbonyl aspartic acid and phenylalanine methyl ester are reacted under conditions, under which the proteolytic enzyme exerts the enzymatic activity, to deposit an addition compound of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester and phenylalanine methyl ester; and then the addition compound is recovered.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[C:15]([CH:25]=[O:26])=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(C=O)c(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine in THF (0.1M) at 0° C. was added n-BuLi (1.1 eq.). The solution was stirred for 30 min and then was cannulated in a solution of commercially available 5-bromo-2-methoxypyridine in THF (0.1M) at −78° C. The resulting solution was stirred at −78° C. for 30 min then DMF (1.5 eq.) was added. Final reaction mixture was allowed to warm to 0° C. before it was quenched with saturated aqueous NH4Cl and then extracted with EtOAc. The organic extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound as a white solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[N:17][C:18]=1Cl>CS(C)=O>[C:20]([C:15]1[CH:14]=[C:13]([Cl:12])[C:18]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[N:17][CH:16]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ncc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 32.2 %

Procedure:
Dimethyl malonate (4.69 g, 35.5 mmol) was dissolved in DMSO (24.0 ml). This solution was added 70% NaH (1.33 g, 33.2 mmol) at 0° C. The resulting mixture was warmed up to room temperature, then stirred at the same temperature for 40 min. To this solution was added 1-(5,6-dichloropyridin-3-yl)ethanone (Tetrahedron 1992, 48, 9233-9236, 4.50 g, 23.7 mmol) at room temperature, then the resulting mixture was stirred at 100° C. for 4 hours. The mixture was partitioned between Et2O and water. The organic layer was washed with water and brine, dried over Na2SO4, then concentrated to give a brown syrup. The crude material was purified by SiO2 column chromatography (100 g, EtOAc/hexane (1/2)) to give the title compound (2.18 g, 32%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.64 (3H, s), 3.83 (6H, s), 5.31 (1H, s), 8.26 (1H, s), 9.02 (1H, s).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([CH3:10])=[CH2:9])[N:7]=1
Reactant: CC(C)(O)c1cccc(Br)n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1cccc(Br)n1
Reaction time: 3 h

Procedure:
To a solution of 2-(6-bromopyridin-2-yl)propan-2-ol (Example 2, Step 1) (2.44 g, 11.29 mmol) and methansulfonic anhydride (5.90 g, 33.9 mmol) in dichloromethane (35 mL) was added triethylamine (6.26 mL, 45.2 mmol). After three hours, the reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) and brine (2×25 mL), dried over sodium sulfate, filtered, and concentrated. The resulting yellow liquid was purified by silica gel chromatography (2-20% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.[OH-].[Li+].O>>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(Oc3cccc(C(F)(F)F)c3)ccc2c1
Temperature: 80 °C
Yield: 53.2 %

Procedure:
(R)-4-Methyl-4-(6-(3-(trifluoromethyl)phenoxy)naphthalen-2-yl)oxazolidin-2-one (20.0 mg, 0.000052 mol) was dissolved in ethanol (2 mL, 0.03 mol), followed by 4 M of lithium hydroxide in water (1 mL, 0.004 mol). The reaction mixture was then heated at 80° C. for 5 hours. All solvent was removed. The solid was extracted with DCM, and was purified via HPLC to give the desired product (10 mg, 52%). 1H NMR (MeOD) δ: 7.91-8.00 (m, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.64 (dd, J=8.8, 1.8 Hz, 1H), 7.51-7.58 (m, 1H), 7.35-7.44 (m, 2H), 7.22-7.30 (m, 3H), 3.64-3.78 (m, 2H), 1.52 (s, 3H). MS (M+1): 362.0
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].[C:8]1([C:14](=O)[CH2:15][CH2:16][CH2:17]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(C)C>[CH3:7][N:6]1[C:4](=[S:5])[N:2]([CH3:1])[N:3]2[CH2:17][CH2:16][CH2:15][C:14]12[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC(=S)N(C)N
Reactant: O=C(CCCCl)c1ccccc1
Solvent: CC(C)O
Product: CN1C(=S)N(C)C2(c3ccccc3)CCCN12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 4.0 g of 2,4-dimethyl-thiosemicarbazide and 6.7 g of 1-phenyl-4-chlorobutan-1-one in 165 ml of isopropanol is refluxed for 48 hours. The mixture is then allowed to cool to room temperature and stirred for an additional 48 hours. The solvent is evaporated, the residue is dissolved in methylene chloride, and the methylene chloride solution is washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent leaves a brownish oil which crystallizes and is treated with hexane. The resulting greyish powder is purified by flash chromatography using 4% ethyl acetate/methylene chloride as eluent, followed by crystallization from hexane to give 5,6,7,7a-tetrahydro-1,3-dimethyl-7a-phenyl-1H-pyrrolo[1,2-b][1,2,4]triazole-2(3H)-thione as tiny colorless needles melting at about 83°-85° C.
Reaction SMILES: Br.Br.[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1.CCN(CC)CC.Cl[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35]>C(Cl)Cl>[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][N:22]([CH2:33][C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC1CCN(c2nc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(CC(=O)N4CCOCC4)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
A solution of 4-methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl dihydrobromide (as prepared in Example 67, step (c), 0.10 g, 0.21 mmol) in CH2Cl2 (5 mL) was treated with Et3N (0.10 mL, 0.75 mmol) and 2-chloro-1-morpholin-4-yl-ethanone (as prepared in the previous step, 39 mg, 0.24 mmol). The reaction stirred at room temperature for 18.5 h. The reaction was diluted with CH2Cl2 and washed with water. The aqueous layer was further extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.11 g, 117%, some salt remains) as a yellow solid, which was used directly in the next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 1H, J=9.2 Hz), 6.02 (d, 1H, J=9.2 Hz), 3.76-3.67 (m, 8H), 3.26 (br s, 2H), 3.14-3.07 (m, 2H), 3.03-2.93 (m, 2H), 2.63 (br s, 4H), 1.74-1.65 (m, 2H), 1.65-1.58 (m, 1H), 1.45-1.39 (m, 3H), 1.37-1.24 (m, 3H), 0.97 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C21H32N6O4, 433.2 (M+H), found 433.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:6]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].F[C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[N+:47]([O-:49])=[O:48])[C:42]#[N:43]>C(#N)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[CH2:6][C:5]3([CH2:20][CH2:21][CH2:22][C:3]([CH2:2][NH:1][C:44]4[CH:45]=[C:46]([N+:47]([O-:49])=[O:48])[CH:39]=[CH:40][C:41]=4[C:42]#[N:43])([CH2:23][O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:4]3)[O:9][C:8]2=[O:10])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COc1ccc(CN2CC3(CCCC(CN)(COCc4ccccc4)C3)OC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CN2CC3(CCCC(CNc4cc([N+](=O)[O-])ccc4C#N)(COCc4ccccc4)C3)OC2=O)cc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a light yellow solution of 7-(aminomethyl)-7-((benzyloxy)methyl)-3-(4-methoxybenzyl)-1-oxa-3-azaspiro[4.5]decan-2-one (4.27 g, 10.1 mmol) in acetonitrile (67.1 mL) was added potassium carbonate (2.78 g, 20.1 mmol) and 3-fluoro-4-nitrobenzonitrile (2.51 g, 15.1 mmol) and the reaction was stirred at RT. After stirring 15 h, the reaction was filtered through a frit. The collected inorganics were washed with DCM/EtOAc. The filtrate was concentrated onto florisil and purified on a 80 g silica gel column (20-55% EtOAc/hexanes, 30 min gradient; 55% EtOAc/hexanes, 5 min.; 60 mL/min elution; 254 nm detection) to provide 3-{[(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-ylmethyl]amino)-4-nitrobenzonitrile (5.02 g, 83% yield) as a reddish-orange oil. MS (m/z) 571.0 (M+H+).
Reaction SMILES: [N:1]1N=N[N:4]2[CH:9]=[C:8]([CH:10]3[O:15][CH2:14][C:13](=[O:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]3)[CH:7]=[CH:6][C:5]=12.O.O.Cl[Sn]Cl.Cl>CO>[NH2:1][C:5]1[N:4]=[CH:9][C:8]([CH:10]2[O:15][CH2:14][C:13](=[O:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)N1CC(c2ccc3nnnn3c2)OCC1=O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)N1CC(c2ccc(N)nc2)OCC1=O
Yield: 88.7 %

Procedure:
A solution of 2-(tetrazolo[1,5-a]pyrid-6-yl)-4-(1,1-dimethylethyl)-5-oxo-morpholine (550 mg), SnCl2.2H2O (968 mg) and 0.2 ml of 12N hydrochloric acid in 60 ml of methanol was heated at reflux for 14.5 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and then poured into ice water containing 5N sodium hydroxide. The basic aqueous mixture was repeatedly extracted with methylene chloride. The combined organic fractions were washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Concentration gave 603 mg of crude product which was chromatographed on silica gel (95:5:1 methylene chloride:ethanol:ammonium hydroxide) to give 442 mg of product. Mass spectrum (FAB) 250 (M+1). 13C NMR (CDCl3) 27.9 49.5 57.7 69.2 74.3 108.5 123.6 135.8 146.3 158.7 167.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH:17]([CH3:21])[C:18](O)=[O:19])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:32]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)=[O:19])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2)C(C)C(=O)O)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 135° to 137°).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.FC(F)(F)C(O)=O.[H][H]>[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nnc2ccc(-c3cccc([N+](=O)[O-])c3)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12

Procedure:
A mixture of 5.1 g. of 3-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 23), 60 ml. of trifluoroacetic acid and 0.9 g. of 10% palladium catalyst on carbon is shaken in a Parr hydrogenator under about 35 pounds of hydrogen pressure until hydrogen uptake is complete. The catalyst is filtered off and the reaction mixture is concentrated. The residue is dissolved in water and adjusted to pH 5 by addition of 5N NaOH. The insoluble material is filtered off and washed with water to obtain 6-(m-aminophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine, m.p. 193° C.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O>C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: COc1ccc(C=O)cc1OC
Solvent: CCO
Product: COc1ccc(C=C(C#N)C#N)cc1OC

Procedure:
A suspension of malononitrile (7.52 g) and 3,4-dimethoxybenzaldehyde (18.95 g) in ethanol (100 ml) was warmed to reflux temperature with stirring. The orange solution was removed from the heat and piperidine (0.5 ml) added down the condenser. Once the vigorous reaction had subsided, the reaction mixture was reheated to reflux temperature and this maintained for 35 minutes. Copious quantities of a bright yellow solid had appeared by this time. The mixture was cooled in an ice bath for 10 minutes and the yellow solid filtered off, washed with ethanol and ether and dried in vacuo at 70° C. yielding 3,4-dimethoxy benzylidenemalononitrile, m.p.137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:78]3[CH2:79][CH2:80][N:75]([CH3:74])[CH2:76][CH2:77]3)=[O:30])=[CH:24][CH:23]=2)=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-methylpiperazine (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 h. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with DCM/ethanol/ammonia (100:8:1 then 40:8:1), which after evaporation of the solvents under vacuum gave N-{6-methyl-4′-[(4-methylpiperazin-1-yl)carbonyl]-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (14 mg, 29%). NMR; δH [2H6]-DMSO 10.26,(1H, s), 8.19,(1H, d), 7.69–7.67,(2H, m), 7.47–7.41,(4H, m), 7.29,(1H, d), 6.96,(1H, d), 6.86,(1H, s), 3.59,(2H, b), 3.43,(4H, m), 2.33,(6H, b), 2.21,(3H, s), 2.21,(3H, s), 1.95,(4H, m). MS: MH+484.