Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=2[C:19]#[N:20])[CH:6]1[O:21][C:22](=[O:24])[CH3:23])(=[O:3])[CH3:2].O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:13]=2[C:19]([NH2:20])=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([CH3:33])=[N:18]3)[CH:6]1[O:21][C:22](=[O:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)OC1CCCC(Oc2cccc(N)c2C#N)C1OC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCC(OC(C)=O)C3OC(C)=O)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)cyclohexane-1,2-diyl diacetate (Example 133b) and ethyl 3-oxobutanoate as a pale yellow solid (32%). MS 445 (MH+).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].CCN(C(C)C)C(C)C>ClCCl>[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:2](=[O:3])[O:4][CH3:5])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl chloroformate (13.2 mL, 170.2 mmol) was added dropwise to a cold (0° C.) dichloromethane (200 mL) solution of 4-fluoro-3-nitro aniline (24.15 g, 154.7 mmol) and DIPEA (35 mL, 201 mmol). The reaction mixture was stirred at rt overnight. The solution was then diluted with 200 mL of dichloromethane and washed with 2M HCl, brine and dried over anhydrous MgSO4. The solvent was concentrated and the product was directly used for next step without further purification. Yield: 35.5 g (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 3.81 (s, 3H), 7.02 (s, 1H), 7.23 (m, 1H), 7.72 (d, J=8.59 Hz, 1H), 8.17 (dd, J=6.35, 2.64 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[C:22]1[C:31]2[N:30]=[CH:29][CH:28]=[N:27][C:26]=2[C:25]([C:32](O)=[O:33])=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:32]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:22]([C:16]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])=[CH:23][CH:24]=2)=[O:33])=[CH:8][CH:7]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN(C)CCOc1ccc(N)cc1
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc(OCCN(C)C)cc2)c2nccnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-(2,6-dimethyl-phenyl)quinoxaline-5-carboxylic acid (Example 71). Title compound: ESI-MS: 441.1 [M+H]+; tR=3.52 min (System 3).
Reaction SMILES: ClC1C=CC([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:13][C:11]=3[N:12]=2)=CC=1.[C:22]([Cl:25])(=O)[CH3:23]>>[C:10]([O:21][C:17]([C:23]1[CH:16]=[CH:15][CH:14]=[CH:13][C:22]=1[Cl:25])([C:14]1[CH:15]=[CH:16][C:10]2[O:9][CH:8]=[N:12][C:11]=2[CH:13]=1)[C:18]([OH:20])=[O:19])(=[O:9])[CH3:11]
Reactant: O=C(O)C(O)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: CC(=O)Cl
Product: CC(=O)OC(C(=O)O)(c1ccc2ocnc2c1)c1ccccc1Cl

Procedure:
A mixture of 2-p-chlorophenyl-5-benzoxazolylglycolic acid (4 g.) and acetyl chloride (50 ml.) was heated under reflux for 24 hours. The residue on evaporation was crystallised to give pure α-acetoxy-2-chlorophenyl-5-benzoxazolylacetic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2ncccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Similar to the method described by C. Kaslow and W. Clark, (JOC 18, 55, 1953), to a stirred solution of methyl quinoline-6-carboxylate (10 g, 53 mmol) in THF (200 mL) at 0° C. was added LiAlH4 (1.3 g, 14.9 mmol) by small portion. The resulting mixture was stirred at 0° C. for 2 h then warmed to RT and stirred for 3 h. Acetone (10 mL) was added followed by MgSO4×10H2O. The resulting mixture was stirred for 1.5 h at RT and filtered over a silica pad. Solvents were removed to give the crude quinolin-6-yl-methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]2([S:15][C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13]2)[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]1([S:15][C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13]1)[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: Fc1ccc(C2(C3(SC(F)(F)F)CC3)CO2)c(F)c1
Reactant: c1nc[nH]n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C1(SC(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A solution of 15.9 g (54 mmol) of 2-(2,4-difluoro- phenyl)-2-[1-(trifluoromethylmercapto)-cycloprop-1-yl]oxirane in 20 ml of absolute dimethylformamide is added dropwise with stirring to a mixture of 12 g (174 mmol) of 1,2,4-triazole and 1.4 g (12.5 mmol) of potassium tert.butylate in 30 ml of absolute dimethylformamide under a nitrogen atmosphere The reaction mixture is stirred at 100° C. for 8 hours. The solvent is then stripped off under reduced pressure, the residue is taken up in ethyl acetate, and the solution is washed twice with water and concentrated under reduced pressure after drying over sodium sulphate The residue is chromatographed on a silica gel column using chloroform as eluent. In this manner, 12.5 g (65 % of theory) of 1-(2,4-difluorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-1-(1-trifluoromethylmercapto-cycloprop-1-yl)ethane of melting point 103° C. are obtained.
Reaction SMILES: [CH:1]1([C:4](=[O:14])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[C:15](OCC)(=O)[C:16]1C=CC=C[CH:17]=1.C1(C(C)=O)CC1.[NH2-].[Na+].C1(C(OCC)=O)CC1.C(C1C=CC=CC=1)(=O)C.[H-].[Na+]>>[CH:8]1([C:6](=[O:7])[CH2:5][C:4]([CH:1]2[CH2:3][CH2:2][CH2:17][CH2:16][CH2:15]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(CC(=O)C1CC1)c1ccccc1
Reactant: CCOC(=O)c1ccccc1
Agent: CC(=O)C1CC1
Agent: CCOC(=O)C1CC1
Agent: [H-]
Solvent: CC(=O)c1ccccc1
Product: O=C(CC(=O)C1CCCCC1)C1CCCCC1

Procedure:
Other β-diketones can be prepared from esters and ketones containing R3 and R5 as previously defined. Thus, 1-cyclopropyl-3-phenyl-1,3-propanedione has been reported by G. W. Cannon et al., Journal of Organic Chemistry 17, 685 (1952) to be prepared as a solid, melting point 36°C to 37°C, from ethyl benzoate and cyclopropyl methylketone in the presence of sodium amide. Alternatively, it has been found that the same compound, melting point 38°C to 40°C, could be prepared from ethyl cyclopropanecarboxylate, acetophenone and sodium hydride. J. T. Adams and C. R. Hauser in Journal of the American Chemical Society 66, 1220 (1944) have prepared a series of 1-alkyl-3-phenyl-1,3-propanediones from carboxylic acid ethyl esters and acetophenone in the presence of sodium amide. Illustrative examples are tabulated employing the following equation: ##EQU2## where R3 and R5 are set forth in the Table I below.
Reaction SMILES: [C:1]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9](S(C)(=O)=O)=[N:10][C:11]=2[NH:14][C@H:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16]O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[O-:29][CH2:30][CH3:31].[Na+]>C(O)C>[CH2:18]([C@@H:15]1[CH2:16][N:10]2[C:11]([C:12]3[NH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][C:7]=3[N:8]=[C:9]2[O:29][CH2:30][CH3:31])=[N:14]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)c1nc2nc(S(C)(=O)=O)nc(N[C@@H](CO)Cc3ccccc3)c2[nH]1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC1=Nc2nc(C(C)(C)C)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 70 °C
Yield: 54 %

Procedure:
In a manner similar to that in Example 66, a cyclized compound was obtained from Compound C8 prepared in Reference Example 43, to a solution of the cyclized compound (4.88 g, 14.3 mmol) in ethanol (30 mL) was added a 21% solution of sodium ethoxide (30 mL, 93.0 mmol, 6.5 equivalents) in ethanol, and then the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated, and the deposited crystals were collected by filtration and recrystallized from ethyl acetate to obtain the title compound (2.67 g, 54%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH3:26])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1(=[O:15])[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:22]([N:2]2[CH2:3][CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7]([CH:6]3[C:1]2=[O:15])=[CH:8][CH:9]=[CH:10][CH:11]=4)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1NCCN2C(=O)c3ccccc3C12
Reactant: O=C(Cl)C1CCCCC1
Product: O=C(C1CCCCC1)N1CCN2C(=O)c3ccccc3C2C1=O
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 19.2 %

Procedure:
A mixture of 3,4-dihydropyrazino[2,1-a]isoindole-1,6(2H, 10bH)-dione (6.0 g, 0.03 mol, described in Example 6) and cyclohexylcarbonyl chloride (6.5 g, 0.045 mol) is stirred at 120° C. for 6.5 hr and evaporated. The residue is chromatographed on silica gel using 20% acetone in benzene and the eluates are evaporated. The residue is crystallized from acetone to obtain 2-(cyclohexylcarbonyl)-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-1,6-dione (1.8 g), mp 167°-172° C., Anal. Calc'd. for C18H20N2O3 : C, 69.21% H, 6.45% N, 8.97% and Found: C, 69.25% H, 6.47% N, 8.93%.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[Se:10](=O)=O>C(O)C.O>[Br:1][C:2]1[C:3]2[C:4](=[N:8][Se:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Nc1cccc(Br)c1N
Solvent: CCO
Solvent: O
Product: Brc1cccc2n[se]nc12

Procedure:
The specific preparation is described as follows: refluxing 3-bromo-1,2-diaminobenzene in ethanol solution, then adding into selenium dioxide dissolved in hot water, after that, refluxing for 2 hours. The precipitation is recrystallized with ethyl acetate after being filtered to get 4-bromo-2,1,3-benzoselenadiazole finally.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C>[CH2:14]([CH:13]([CH2:16][CH3:17])[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]3[CH:25]=[CH:29][CH:28]=[CH:27]3)[CH:11]=2)[NH:6][C:7](=[O:19])[C:8]1=[O:18])[CH3:15]
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc21
Temperature: 0 °C
Yield: 27.4 %

Procedure:
2.5 g (8.2 mmol) of 7-amino-1-(2-ethylbutyl)-6-nitro-2,3(1H,4H)-quinoxalinedione and 1.1 g (8.2 mmol) of 2,5-dimethoxytetrahydrofuran were refluxed in 100 ml of acetic acid for 1 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction, washed with water and dried to yield 0.8 g (31%) of the product. Melting point 154°-155° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:39]3[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)c3)cc2)cn1

Procedure:
(2-{(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (3.0 g) and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.71 g) are dissolved in DME (93 mL), (Ph3P)3PdCl2 (580 mg) and 2M Na2CO3-solution (55 mL) are added and the resulting mixture is heated under reflux temperature under an inert gas atmosphere. The solution is filtered and evaporated. The residue is treated with water and dichloromethane. The organic phase is separated, dried and evaporated. The crude product is purified by silica gel flash chromatography. The title compound is obtained in 902 mg yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)CCl
Product: Cc1cccc(NC(=O)CCl)c1C(=O)O

Procedure:
2-amino-6-methylbenzoic acid is reacted with 2-chloroacetyl chloride to produce the 2-(-2-chloroacetamido)-6-methylbenzoic acid. Reaction with o-toluidine and phosphoryl trichloride yields the cyclized intermediate. Further reaction with diBOC-protected adenine give the BOC protected product, which is deprotected resulting in 2-((6-amino-9H-purin-9-yl) methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one (2c).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:35])/[CH:22]=[CH:23]/[C:24]3[CH:25]=[N:26][C:27](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2[N:48]([OH:49])N=NC=2C=1.NOC1CCCCO1>CN(C=O)C.C1COCC1>[OH:49][NH:48][C:32](=[O:34])/[CH:31]=[CH:30]/[C:27]1[CH:28]=[CH:29][C:24](/[CH:23]=[CH:22]/[C:21](=[O:35])[C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[CH:20][CH:19]=2)=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(N3CCNCC3)cc2)cn1)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester hydrochloride (184 mg, 0.363 mmol) was dissolved in DMF (5 ml), THF (5 ml) and TEA (0.190 ml, 1.47 mmol). Then EDC (140 mg, 0.736 mmol), HOBT (99 mg, 0.736 mmol) and NH2OTHP (51.6 mg, 0.441 mmol) were added to the resulting solution. The mixture was stirred at room temperature overnight and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 98:2:0.2) and the resulting compound was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off and washed with DCM. The hygroscopic powder was dissolved in water and freeze dried to give 53 mg of (E)-N-hydroxy-3-{5-[(E)-3-oxo-3-(4-piperazin-1-yl-phenyl)-propenyl]-pyridin-2-yl}-acrylamide as its bis-hydrochloride salt.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F-].[K+].O>CN(C)C=O>[C:4]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccccc1C=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 2-trimethylsilanylethynyl-benzaldehyde (6 g, 29.70 mmol) in N,N-dimethylformamide (10 mL) was added potassium fluoride (1 g, 17.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The resulting solution was poured into water, and then extracted with dichloromethane. The collected organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 0-25% ethyl acetate in hexane) gave 2-ethynyl-benzaldehyde (2.8 g, 73%) as a white solid. MS (ESI+) cald for C9H6O [(M+H)+] 130, obsd. 131.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11](=[NH:13])[O:12][CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 69 %

Procedure:
2,4-Dibenzyloxybenzoic acid was reacted with oxalyl chloride in toluene and DMF at 0-25° C. to give an acid chloride. The acid chloride was reacted with aqueous ammonia in methylene chloride to yield 87% (over 2 steps) of 2,4-dibenzyloxybenzamide. 2,4-Dibenzyloxybenzamide was reacted with triethyloxonium hexafluorophosphate in methylene chloride to yield 69% of ethyl 2,4-dibenzyloxybenzimidate. The ethyl 2,4-dibenzyloxybenzimidate was hydrogenated over a palladium/carbon catalyst with 1 atmosphere of hydrogen gas in ethanol, to yield 75% of ethyl 2,4-dihydroxybenzimidate. The overall yield for the reaction sequence was 34% for six steps.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH2:9]1)=O)(C)(C)C.[ClH:40].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:40].[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][C:27]([C@H:10]2[CH2:9][NH:8][CH2:13][CH2:12][N:11]2[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[O:39])=[CH:35][CH:34]=1)([CH3:38])[CH3:37]
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CC(C)c1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of the compound (973 mg) obtained in Step 2 in ethyl acetate (10 ml) was added, with stirring at room temperature, 4N hydrogen chloride/ethyl acetate solution (4.73 ml). After stirring at room temperature for 4 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in a mixed solvent of ethyl acetate and diisopropyl ether, collected by filtration and dried to give the title compound (742 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(F)c(Br)c4)ncnc3cn2)cc1
Temperature: 75 °C
Reaction time: 95 h
Yield: 78.9 %

Procedure:
A mixture of compound 162 (13.9 g, 41.3 mmol) and 4-methoxybenzylamine (54.3 mL, 413 mmol) in dry DMSO (100 mL) was stirred under a nitrogen atmosphere at 75° C. (bath temperature) for 95 h. The solution was then cooled and petroleum ether (500 mL) was added. After 15 min stirring at room temperature the layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated a further two times and then water (500 mL) was added to the resultant DMSO layer and the mixture was stirred at room temperature for 1 h to precipitate a yellow/orange solid that was collected by filtration and washed with water (5×100 mL), before being dried under vacuum and then washed with petroleum ether (2×100 mL). The yellowish orange solid was then stirred with warm acetone (1 L) for ca. 3 h before water (1 L) was added to precipitate the required product. The solid was collected by filtration, washed with acetone/water (1:1, 5×80 mL) and dried in vacuo over silica-gel, to give pure N4-(3-bromo-4-fluorophenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (165) (14.8 g, 79%) as a yellow/orange solid, mp 181-184° C.; 1H NMR δ [(CD3)2SO] 9.69 (s, 1H), 8.75 (s, 1H), 8.37 (s, 1H), 8.26 (dd, J=6.4, 2.6 Hz, 1H), 7.91-7.83 (m, 1H), 7.42 (t, J=8.8 Hz, 1H), 7.33 (br d, J=8.6 Hz, 2H), 7.27 (t, J=6.3 Hz, 1H), 7.16 (s, 1H), 6.91-6.85 (m, 2H), 4.49 (d, J=6.3 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C21H17BrFN5O: C, 55.52; H, 3.77; N, 15.42%. Found C, 55.75; H, 3.88; N, 15.44%.
Reaction SMILES: Br[C:2]1[S:20][C:5]2[C:6](=[O:19])[NH:7][C:8]([CH3:18])([CH3:17])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[C:8]([CH3:18])([CH3:17])[NH:7][C:6](=[O:19])[C:5]3[S:20][C:2]([C:24]4[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=4)=[CH:3][C:4]2=3)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2C1c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3ccncc3)cc2C1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 13.7 %

Procedure:
To a 20 mL vial was added a solution of 2-bromo-4-(4-chlorophenyl)-5,5-dimethyl-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.0440 g, 0.119 mmol) and pyridine-4-boronic acid (0.02726 g, 0.2218 mmol) in 1,4-dioxane (3.0 mL) and water (0.300 mL). Cesium carbonate (0.1160 g, 0.3561 mmol) was added followed by [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.0117 g, 0.0142 mmol). The reaction mixture was heated to 90° C. and allowed to stir for 18 h. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material as purified by prep HPLC to afford the product (0.0060 g, 13%) as a yellow solid. LC/MS (AA) ES+ 369, 371, 373. 1H NMR (dmso-d6, 400 MHz): d 8.59-8.57 (2H, m), 7.91 (1H, s), 7.68-7.66 (2H, m), 7.60 (1H, s), 7.40-7.38 (2H, m), 7.19-7.17 (2H, m), 4.21 (1H, s), 1.36 (3H, s), 0.94 (3H, s).