Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[CH2:12][C:11](=[O:30])[NH:10]2)=[O:6])[CH:2]=[CH2:3].[ClH:31]>O1CCOCC1>[ClH:31].[ClH:31].[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH2:12][C:11](=[O:30])[NH:10]2)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc2c(c1)NC(=O)CN2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)c1ccc2c(c1)NC(=O)CN2C1CCNCC1

Procedure:
A solution of 1-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid allyl ester (1.40 g, 3.37 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 316.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Br:16][C:17]([CH2:19]Br)=[CH2:18].[H-].[Na+]>O1CCCC1>[Br:16][C:17](=[CH2:18])[CH2:19][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of diethyl acetamidomalonate (217 g, 1.0 mol) and 2,3-dibromopropene (240 g, 1.2 mol) in dry tetrahydrofuran (2.50 L), under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in several portions. The reaction mixture was stirred at room temperature for 30 min, then heated to reflux. After heating for 18 h, the resultant slurry was cooled to room temperature and suction filtered through a short pad of silica gel. The solid residue was washed with tetrahydrofuran (2×50 mL), and the filtrates were combined and concentrated. The residue was dissolved in ethyl acetate (2.0 L), washed with water and brine, and then was dried over MgSO4. Filtration and concentration gave a yellow oil which solidified upon drying. The resultant solid was recrystallized from a mixture of hot ethyl acetate/hexane to give 301 g (89%) of the desired product: m.p. 85°-87° C. 1H NMR (300 MHz, CDCl3) δ1.28 (t, J=7.4 Hz, 6H), 2.04 (s, 3H), 3.57 (s, 2H), 4.27 (m, 4H), 5.55 (bs, 1H), 5.61 (bs, 1H), 6.82 (broad, 1H); IR (KBr) 1745, 1635 cm-1. Anal. Calcd. for C12H18BrNO5 : C, 42.87; H, 5.40; Br, 23.77; N, 4.12. Found: C, 43.25; H, 5.56; Br, 22.97; N, 4.12.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[N:12]1[CH:17]=[CH:16][N:15]=[C:14]2[C:18]([O:20][C:21](=[O:22])[C:13]=12)=[O:19].Cl>C1COCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:18]([C:14]2[C:13]([C:21]([OH:22])=[O:20])=[N:12][CH:17]=[CH:16][N:15]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C1OC(=O)c2nccnc21
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1nccnc1C(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a suspension of magnesium (4.2 g) in THF (20 ml) was added iodine (catalytic amount) while stirring at room temperature under argon atmosphere. To the mixture was then added dropwise a solution of 1-bromo-4-fluorobenzene (22.8 g) in THF (60 ml), and the mixture was stirred for 30 minutes. The mixture was added dropwise, while stirring at room temperature, to a solution of 2,3-pyrazinedicarboxylic anhydride (20.0 g) in THF (100 ml), followed by stirring for one hour. The reaction mixture was poured into dilute HCl (adjusting the pH to 4 to 5), followed by extraction with ethyl acetate. The extract solution was washed with water and dried, then the solvent was distilled off to give 3-(4-fluorobenzoyl)-2-pyrazinecarboxylic acid as a colorless oily product (25.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](=[CH:9]/[CH:10]([CH3:12])[CH3:11])/[CH3:8].NC1C=CSC=1/C(=C\C(C)C)/C>>[NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH2:8]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
95% Sulfuric acid (0.4 g, 3.9 mol) was added to a 0.5% 4-methyl-2-pentanone solution (30.0 g, 1.5 mmol) of 3-aminothiophene obtained by diluting a 4-methyl-2-pentanone solution of 3-aminothiophene, which was obtained in the same manner as in Example 14 using methyl-3-aminothiophene-2-carboxylate as a starting material at room temperature, and the resulting solution was stirred under nitrogen atmosphere at 60 degree centigrade for 6 hours. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution, and separated. As a result of the analysis by the HPLC internal standard method of the obtained organic layer, 0.2 g was produced as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([I:15])=[C:5]([C:10]([I:14])=[CH:11][C:12]=1[I:13])[C:6]([O:8]C)=[O:7].[OH-].[Li+].Cl>O1CCOCC1.CO.O>[CH3:1][O:2][C:3]1[C:4]([I:15])=[C:5]([C:10]([I:14])=[CH:11][C:12]=1[I:13])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(I)cc(I)c(OC)c1I
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1c(I)cc(I)c(C(=O)O)c1I
Temperature: 60 °C
Reaction time: 72 h

Procedure:
In a 250 mL round-bottom flask equipped with a condenser, methyl 3-methoxy-2,4,6-triiodobenzoate (11.07 g) was dissolved in a 3:1 mixture of dioxane/ MeOH (88 mL). Lithium hydroxide (1.71 g) dissolved in 22 mL H2O was added and the reaction mixture was stirred for 72 h at 60° C. Dioxane and methanol were evaporated and the residue was diluted with 100 mL H2O. The aqueous solution was filtered and the filtrate was extracted with Et2O (2×100 mL). The ether layers were combined and dried over MgSO4. Evaporation of solvent gave 7.64 g of un-reacted starting material (69%). The aqueous layer was acidified to pH 2 with 2N HCl and was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4. Evaporation of solvent gave the desired acid. Yield 3.14 g (29%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[CH:20]=[N:1]2
Reactant: Nc1cccc(Cl)c1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1CCC(n2cnc3cccc(Cl)c3c2=O)C(=O)N1
Reaction time: 0.08 h
Yield: 48 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-chloro-benzamide (0.8 g, 2.8 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (280 mg) was heated to 150° C. via a microwave oven for 30 minutes. To the mixture, was added methanol (15 mL), and the mixture was stirred for 5 minutes. The suspension was filtered and washed with methanol to give 3-(5-chloro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (400 mg, 48% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.35 min (99.2%); mp: 308-310° C.; 1H NMR (DMSO-d6) δ 2.13-2.19 (m, 1H, CHH), 2.57-2.72 (m, 2H, 2CHH), 2.83-2.89 (m, 1H, CHH), 5.43 (br, 1H, NCH), 7.60 (dd, J=1, 8 Hz, 1H, Ar), 7.66 (dd, J=1, 8 Hz, 1H, Ar), 7.79 (t, J=8 Hz, 1H, Ar), 8.39 (s, 1H, CH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.18, 30.84, 56.16, 118.35, 126.81, 129.74, 132.45, 134.54, 148.18, 149.98, 157.62, 169.68, 172.39; LCMS: MH=292, 294; Anal Calcd for C13H10N3O3Cl+0.15H2O: C, 53.04; H, 3.53; N, 14.27. Found: C, 52.68; H, 3.14; N, 14.17.
Reaction SMILES: [CH3:1][C:2](CC)=O.C(=O)([O-])[O-].[K+].[K+].C(I)C.[OH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[OH:26])[O:22][C:21]([CH3:28])([CH3:27])[CH2:20][C:19]2=[O:29]>>[OH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:1][CH3:2])[O:22][C:21]([CH3:27])([CH3:28])[CH2:20][C:19]2=[O:29]
Reactant: CCC(C)=O
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCOc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reaction time: 3 h
Yield: 85 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved. To the solution 4.1 g (30 millimoles) of potassium carbonate and 4.7 g (2.4 ml, 30 millimoles) of ethyl iodide are added and the reaction mixture is heated to boiling for 3 hours. The reaction mixture is worked up according to Example 17. Thus 4.0 g of the title compound are obtained, yield 85%. Mp.: 129°-130° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:14]([CH:11]3[CH2:13][CH2:12]3)=[O:15])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc2[nH]ccc2c1)C1CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-1, using 1H-indol-5-amine and cyclopropanecarbonyl chloride; MS: 201.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]C)=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OCc1noc(C(C)C)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
To a solution of methyl 6-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (23 mg, 0.043 mmol) in 2:1 tetrahydrofuran:methanol (0.75 mL) was added 1 N sodium hydroxide (0.064 mL, 0.064 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The mixture was concentrated and water was added followed by 1 N hydrochloric acid (0.064 mL, 0.064 mmol). The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine and concentrated to afford of 6-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (14 mg, 62%). 1H-NMR (400 MHz, CDCl3) δ 8.43 (d, J=9 Hz, 1H), 8.29 (d, J=8 Hz, 1H), 8.21 (d, J=9 Hz, 1H), 8.07 (m, 2H), 7.70 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.01-6.62 (m, 3H), 5.06 (s, 2H), 4.97 (s, 2H), 3.30 (septet, J=7 Hz, 1H), 2.23 (s, 6H), 1.39 (d, J=7 Hz, 6H). HRMS (ESI) C32H30N2O5 calculated: 437.2263 (M+H)+, found: 437.2263 (M+H)+.
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7]C)=[O:6])([O-:3])=[O:2].[CH3:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1SC>C(O)(C)C>[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([OH:7])=[O:6]
Reactant: CSC1=NCCN1C
Reactant: COC(=O)C[N+](=O)[O-]
Solvent: CC(C)O
Product: CN1CCNC1=C(C(=O)O)[N+](=O)[O-]

Procedure:
35.7 g methyl nitroacetate was added slowly to a refluxing mixture of 39.0 g of 1A and 300 ml of isopropyl alcohol. The mixture then was refluxed for 1 hour with provision to remove the methyl mercaptan by-product. The mixture was cooled and filtered to give the methyl ester of (1-methyl-2-imidazolidinylidene)nitroacetic acid (1B) as a solid, m.p.: 214°-217° (with decomposition).
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:22][NH2:23]>C(O)C.O1CCOCC1>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:22][NH2:23])[C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: COc1ccc2c(c1)C(=O)Cc1c(C#N)cccc1S2
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=NN)Cc1c(C#N)cccc1S2
Reaction time: 7.5 h
Yield: 79.4 %

Procedure:
900mg of 9-cyano-2-methoxy-10,11-dihydro-11-oxo-dibenzo-[b,f]thiepin was dissolved in the mixed solvent of 8ml of ethanol and 8ml of dioxane. To this was added 1.0g of 100% hydrazine hydrate and the resulting mixture was refluxed with stirring for 7.5 hours. After the completion of reaction, the solvent was distilled off to obtain the residue, which was washed with a small amount of ethanol, and there was obtained 750mg of 9-cyano-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin hydrazone as colorless needles having a melting point of 186°-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:49][C@H:50]([C:55]1[NH:59][C:58]2[CH:60]=[CH:61][C:62]([Cl:64])=[CH:63][C:57]=2[N:56]=1)[CH2:51][C:52]([NH2:54])=[O:53].ClCl>CN(C)C=O.ClCCl.CO>[NH2:54][C:52]([CH2:51][C@H:50]([NH:49][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:55]1[NH:59][C:58]2[CH:60]=[CH:61][C:62]([Cl:64])=[CH:63][C:57]=2[N:56]=1)=[O:53]
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC(=O)C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](CC(N)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 10d from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-3-amino-3-(5-chloro-1H-benzimidazol-2-yl)propionic acid amide in dimethylformamide. Yield: 97 mg (43% of theory); Rf value: 0.37 (silica gel; dichloromethane/methanol=9:1); C23H24ClN5O3 (453.93); mass spectrum: (M+H)+=454/456 (chlorine isotope).
Reaction SMILES: C([Si]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[O:26][C:27]3[CH:33]=[C:32]([O:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)[CH:31]=[CH:30][C:28]=3[CH:29]=2)[CH2:21][CH2:20]1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:36]1([CH2:35][O:34][C:32]2[CH:31]=[CH:30][C:28]3[CH:29]=[C:25]([C@H:22]4[CH2:23][CH2:24][C@H:19]([OH:18])[CH2:20][CH2:21]4)[O:26][C:27]=3[CH:33]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)[Si](OC1CCC(c2cc3ccc(OCC4CC4)cc3o2)CC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
A solution of a solution of tert-butyl({4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)diphenylsilane (3.36 g) and tetrabutylammonium fluoride in THF (1.0 M, 12.8 mL) in THF (30 mL) was stirred at room temperature overnight and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (0.66 g).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][CH:32]=O)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH2:32][CH2:31][C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=CCc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NCCc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with (3,5-Difluoro-phenyl)-acetaldehyde to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.4, 24.3, 26.7, 36.0, 36.4, 50.0, 56.0, 59.1, 63.1, 67.2, 101.8, 102.1, 102.3, 104.8, 111.5, 111.8, 131.2, 137.3, 143.5, 162.0, 162.1, 164.5, 164.6, 171.7; MS m/z 448.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH:17]=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O.[NH2:20][NH2:21]>C(O)C>[NH2:20][N:21]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Yield: 95 %

Procedure:
To a solution of 2.7 parts of 5-chloro-2-formamidobenzophenone in 40 volume parts of ethanol is added 2.5 volume parts of hydrazine hydrate, followed by refluxing for 20 minutes. After cooling, the resulting crystals are recovered by filtration and washed with ethanol and ether and then dried. This procedure gives 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline as crystals melting at 189° to 192° C. Yield: 95%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([NH2:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]#[N:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(N)=O)cc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C#N)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]I.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:29])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)C(CCCI)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C(CCCN1CCCCC1)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 842.4 %

Procedure:
A solution of 0.111 g (0.20 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-iodo-pentanoic acid methyl ester in 1 ml of DMA was treated at 0° C. with 0.021 ml (0.21 mmol) of piperidine and stirred 30 min at 0° C. and 1 h at RT. 0.065 g (0.20 mmol) of cesium carbonate was added at 0° C. and stirring was continued for 2 h. After additional 3 h at RT, the reaction was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and precipitated with CH2Cl2/n-pentane to yield 0.86 g (84%) of the title compound as a white foam. MS: 510.3 (MH+, 2Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([N:29]1[CH2:33][CH2:32][CH:31]([C:34]2[S:35][C:36]([NH:42]C(OC(C)(C)C)=O)=[C:37]([C:39](O)=[O:40])[N:38]=2)[CH2:30]1)=O)(C)(C)C>>[NH2:42][C:36]1[S:35][C:34]([CH:31]2[CH2:32][CH2:33][NH:29][CH2:30]2)=[N:38][C:37]=1[C:39]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[CH2:9]1)=[O:40]
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(C2CCN(C(=O)OC(C)(C)C)C2)nc1C(=O)O
Product: Nc1sc(C2CCNC2)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Yield: 32 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate and 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (13.5 mg, 32%). 1H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.26 (s, 2H), 7.09 (d, J=5.2 Hz, 1H), 3.08 (d, J=10.9 Hz, 2H), 2.96 (d, J=11.4 Hz, 4H), 2.62 (d, J=17.6 Hz, 1H), 2.43-2.36 (m, 1H), 2.15 (s, 1H), 1.82 (dd, J=63.4, 20.3 Hz, 4H), 1.18 (d, J=11.6 Hz, 2H). ESIMS m/z=388.2 (M+1).