Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:11])=[C:5]([OH:10])[C:6]([CH3:9])=[CH:7][CH:8]=1.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=1.[OH-].[NH4+].OO>O.C(O)C>[NH2:2][C:3]1[C:8](=[N:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][OH:23])=[CH:18][CH:19]=2)[CH:7]=[C:6]([CH3:9])[C:5](=[O:10])[C:4]=1[Cl:11]
Reactant: CCN(CCO)c1ccc(N)cc1
Reactant: Cc1ccc(N)c(Cl)c1O
Agent: Cl
Agent: OO
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCN(CCO)c1ccc(N=C2C=C(C)C(=O)C(Cl)=C2N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
1.94 g of 3-amino-2-chloro-6-methylphenol hydrochloride are added to 2.53 g of 2-[(4-aminophenyl)(ethyl)amino]ethanol hydrochloride in solution in 20 ml of water and 10 ml of ethanol. The pH is adjusted to 9.5 with 20% ammonium hydroxide in water. 36 ml of 9% aqueous hydrogen peroxide solution are subsequently added and the reaction medium is stirred at ambient temperature for 4 h 30. The solid form is filtered off and washed with water; 2.44 g of 3-amino-2-chloro-4-({4-[ethyl(2-hydroxyethyl)amino]phenyl}imino)-6-methylcyclohexa-2,5-dien-1-one (1k) are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9](=[CH:26][CH2:27][CH3:28])[C:10](N3CCN(C)CC3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[S].C(N(CC)CC)C.Cl.C[S:39](C)=O>C(O)CC.ClCCl>[CH3:28][C:27]1[S:39][C:10]2[NH:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:9]=2[CH:26]=1
Reactant: CS(C)=O
Reactant: CCC=C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Agent: Cl
Agent: [S]
Solvent: CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 100 °C
Yield: 12 %

Procedure:
A suspension of 2,4-bis(4-methyl-1-piperazinyl)-3-propylidene-3H-[1,5]benzodiazepine (11.90 g, 31.3 mmol), sulphur (20.07 g, 626 mmol) and triethyl amine (4.34 ml, 31.3 mmol) in dimethyl sulfoxide (100 ml) and 1-propanol (100 ml) was heated at 100° C. for five days. The resulting black suspension was cooled and filtered off and the filtrate was evaporated at reduced pressure to obtain a viscous black oil. Dichloromethane (600 ml) and HCl (0.2 M, 600 ml) were added and the phases were separated. The organic phase was extracted again with HCl (0.5 M, 100 ml). The combined water phases were made alkalic at a pH of 9 to 10. Dark brown precipitate was filtered off. Dichloromethane (250 ml) was added to the filtrate. The phases were separated and the water phase was extracted with dichloromethane (2×60 ml). The organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure. The black oil was combined with precipitate and purified by chromatography on silica gel, eluted with ethyl acetate/triethylamine 50/1 to obtain 1.195 g (12%) of the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[NH:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(CNC(=O)OC(C)(C)C)n1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC(CNC(=O)OC(C)(C)C)N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 6-((tert-butoxycarbonylamino)methyl)picolinate (8.74 g, 31.2 mmol) was dissolved in AcOH and degassed with argon in a reactor (Roth), then catalytical amount PtO2 was added and degassed with argon again. The reaction was stirred at room temperature under H2 (40 bar) for 3 days. 8a was not fully converted. The reaction mixture was filtered through celite, concentrated in vacuo and purified with flash chromatography in EE. The retrieval of 8a was repeated until 100% converted with the same procedure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1I.[Br-].[CH:17]1([Zn+])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.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].[Cu]I>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Reactant: [Zn+]C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(F)(F)F)cc1C1CCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
To a solution of 300 mg (0.909 mmol) 2-iodo-4-trifluoromethyl-benzoic acid methyl ester, 14.4 mg (0.0455 mmol) Pd(dppf)Cl2 and 10.6 mg (0.0545 mmol) copper (I) iodide in THF (5 ml) was added at room temperature 2.73 ml (1.364 mmol) cyclohexylzinc bromide (0.5M). The mixture was stirred for 3 hours. Then it was heated to 50° C. and stirred for 4 hours and at room temperature over night. The mixture was concentrated in vacuo and dissolved in ethyl acetate. Then it was washed twice with a 1N HCl solution, twice with a saturated sodium bicarbonate solution and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 20%) to provide 176 mg (68%) of the title compound as a light yellow oil. MS (m/e): 286 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: NCc1ccccn1
Solvent: CC#N
Product: COc1cc2c(NCc3ccccn3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 110 °C
Reaction time: 4 h

Procedure:
The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see Intermediate 40, 6 g, 18 mmol) was reacted with 2-aminomethylpyridine (2.5 eq, 4.23 g, 45 mmol) in CH3CN (100 ml) was stirred at 110° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2SO4 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-[(2-pyridinylmethyl)amino]-3-quinoline carboxamide (5.84 g) which was used in the next step without purification.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:31]([OH:33])=[O:32])=[C:17]([CH2:20][O:21][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.FC(F)(F)C([O-])=O.[ClH:43].C>CO.O1CCCC1>[ClH:43].[ClH:43].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:31]([OH:33])=[O:32])=[C:17]([CH2:20][O:21][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CN1CCN(C(=O)OCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(NC=O)n4)[C@H]3SC2)CC1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(C(=O)OCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(N)n4)[C@H]3SC2)CC1

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.trifluoroacetate (1.25 g) and conc.hydrochloric acid (0.6 ml) in methanol (12 ml) and tetrahydrofuran (12 ml) was stirred for 1 hour and 15 minutes at ambient temperature. The reaction mixture was treated with activated charcoal and filtered. The filtrate was evaporated and to the residue was added isopropyl alcohol followed by evaporation. The residue was pulverized in diethyl ether, collected by filtration, washed with ethyl acetate and then dried under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.dihydrochloride (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[N:17]=1.Cl>CO>[ClH:1].[NH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1
Yield: 231.1 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-30 by using methyl 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate (1.00 g, 2.19 mmol), methanol (20 mL) and HCl (10 mL) to afford 1.00 g of desired product.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=C(O)C=2)C(F)=C[N:29]=1.N1C=CC=CC=1CN>>[F:18][C:17]1[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)=[N:13][C:14]([NH:19][CH2:20][C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][N:29]=2)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: NCc1ccccn1
Product: Oc1cccc(Nc2nc(NCc3ccccn3)ncc2F)c1
Yield: 62 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and 2-pyridylmethylamine (68 mg, 0.63 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (CDCl3): δ 4.73 (d, J=6.3 Hz, 2H), 5.85 (t, J=6.0 Hz, 1H, NH), 6.48 (d, J=6.9 Hz, 1H), 6.61 (dd, J=2.7 and 8.1 Hz, 1H), 6.67 (s, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.21 (dd, J=5.1 and 7.5 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.69 (td, J=1.8 and 7.8 Hz, 1H), 7.85 (d, J=3.6 Hz, 1H), 8.38 (br, 1H), 8.56 (dd, J=4.2 and 3.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −170.49; LCMS: ret. time: 10.10 min.; purity: 100%; MS (m/e): 312.08 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:21][S:20][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:8]3[C:9](=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:5])[C:7]=3[OH:30])[S:20][N:21]=2)=[CH:28][CH:27]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)c2snc(-c3ccc(Cl)cc3)c2c1O
Product: COc1ccc(-c2nc(C(=O)NCC(=O)O)c(O)c3c(-c4ccc(Cl)cc4)nsc23)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(4-Chloro-phenyl)-4-hydroxy-7-(4-methoxy-phenyl)-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 470.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.[C:36](Cl)(=O)[CH:37](C)[CH3:38]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:9]([CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH:37]([CH3:38])[CH3:36])[CH2:16]2)=[N:10][NH:11][C:12]1=[O:13]
Reactant: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50 mL round bottom flask was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-4′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.342 mmol). Added to the flask was 4N HCl in dioxane (2 mL). The flask was capped and the contents were stirred at room temperature for 1 h. The solution was concentrated in vacuo. Added to the flask in succession were dichloromethane (3 mL) and N,N-diisopropylethylamine (0.200 mL). The flask was cooled to 0° C. in an ice bath. In a separate vial, isobutryl chloride (0.348 mmol) was taken up with dichloromethane (2 mL) and was added to the cold solution dropwise via pipette. The reaction was stirred for 2 h while the ice bath was allowed to warm to room temperature. The reaction was then diluted with dichloromethane (20 mL) and washed with saturated aq NH4Cl. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (65 mg, 43%). MS(ES)+ m/e 439.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[C:4]([CH:14]=O)[CH:3]=1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[C:4](/[CH:14]=[N:16]/[OH:17])[CH:3]=1
Reactant: CC1(C)OB(O)c2cc(C=O)cc(F)c21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2cc(/C=N/O)cc(F)c21
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (1.86 g, 8.94 mmol) and NH2OH.HCl (0.69 g, 9.84 mmol) in THF (16 mL) and H2O (4 mL) at rt was added NaOAc (0.92 g, 11.18 mmol). The reaction mixture was stirred for 3 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (5:1 to 2:1) to give (E)-4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime (1.8 g, 95.8% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.34 (s, 1H), 8.19 (s, 1H), 7.74 (s, 1H), 7.46 (dd, J=1.2 Hz, J=11.2 Hz, 1H), 1.524 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19](I)[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19]([C:27]#[C:26][CH2:25][OH:28])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-7-ethyl-2-iodo4-oxo4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide (Example No. 12) (0.267 g) in diethylamine (14 mL) is added copper iodide (0.032 g) and Pd(PPh3)2Cl2 (0.009 g) followed by addition of propargyl alcohol (39 mL). The reaction is stirred at rt for 18 h. The diethylamine is removed in vacuo, and the resulting residue is partitioned between H2O (25 mL) and CH2Cl2 (25 mL). The organic layer is removed, and the aqueous layer is extracted with CH2Cl2 (3×25 mL). The combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:CH3OH, 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.158 g (70%) of the title compound as a yellow, crystalline solid.
Reaction SMILES: CN(C)CCCN=C=NCC.[C:12]([OH:20])(=O)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:21]([NH:28][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: C#CCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 112.1 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.3 g, 17.4 mmol) was added to a mixture of 6-heptynoic acid (1.1 g, 8.7 mmol), benzylamine (950 μl, 8.7 mmol), 1-hydroxybenzotriazole (1.2 g, 8.7 mmol) and triethylamine (2.4 ml, 17.4 mmol) in tetrahydrofuran (25 ml) and the mixture was stirred at room temperature for 16 hours. The reaction was diluted with sodium hydrogen carbonate (sat, 60 ml) and extracted with ethyl acetate (2×100 ml). The extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to provide 6-heptynoic acid N-benzylamide as a brown solid (2.1 g, 99%). (ES+) 216 ([MH]+).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[S:9][CH:10]=1)C.[OH-].[Na+].O1CCCC1.Cl>[Cl-].[Na+].O.C(OCC)(=O)C>[O:30]=[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[N:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1nc(CC(=O)OCC)cs1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1nc(CC(=O)O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
Ethyl-2-[((Z)-1-oxo-9-octadecenyl)amino]-4-thiazoleacetate (4.00 g, 8.89 mmol), sodium hydroxide (0.79 g, 19.8 mmol) and tetrahydrofuran (50 mL) were combined and cooled in an ice bath under N2 atmosphere. Enough distilled water was added to the mixture to dissolve the hydroxide and provide a homogeneous solution. The reaction was kept at 0° C. for 2 h, then allowed to warm to room temperature and stirred overnight. 10% aqueous HCl solution was added to the mixture, and stirring continued for 1 h. Ethyl acetate and saturated aqueous brine solution were added to the mixture, and the organic phase was separated and dried over MgSO4. After filtration and concentration the crude dark amber oil was treated with ether, stirred for 0.5 h and the product was collected on a Buehner funnel and air dried to give 1.5 g of the title compound as a white solid, mp 106°-108.5° C.
Reaction SMILES: [C:1]([NH:14][CH:15]([CH:19]([OH:21])[CH3:20])[C:16]([OH:18])=O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[O:23][C:24](=[O:30])[CH:25]([NH2:29])[CH:26]([OH:28])[CH3:27].C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>>[C:1]([NH:14][CH:15]([CH:19]([OH:21])[CH3:20])[C:16]([NH:29][CH:25]([CH:26]([OH:28])[CH3:27])[C:24]([OH:30])=[O:23])=[O:18])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NC(C(=O)O)C(C)O
Reactant: COC(=O)C(N)C(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC(=O)NC(C(=O)NC(C(=O)O)C(C)O)C(C)O
Yield: 50.9 %

Procedure:
2-Dodecanoylamino-3-hydroxybutanoic acid (15.07 g) and 2-amino-3-hydroxybutanoic acid methyl ester (6.66 g) were condensed with dicyclohexylcarbodiimide (10.31 g). Thereafter, methyl ester was hydrolyzed with sodium hydroxide to give 2-(2-dodecanoylamino-3-hydroxybutanoylamino)-3-hydroxybutanoic acid (10.24 g). The structure thereof was identified by 1H-NMR (400 MHz, CD3OD, r.t.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[Cl:37])[N:30]([CH3:38])[N:29]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH2:27][C:28]2[C:36]3[C:31](=[N:32][CH:33]=[N:34][C:35]=3[Cl:37])[N:30]([CH3:38])[N:29]=2)[CH:9]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1O
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (105.9 mg, 0.379 mmol) and potassium carbonate (59.6 mg, 0.431 mmol) in dimethylformamide was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.7 mg, 0.347 mmol, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly for the next step or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 50/50) to give pure 3-chloro-N-[3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-4-methyl-phenyl]-4-fluoro-benzamide as a white solid. (Yield 35.5 mg).
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)[C:17]([N+:33]([O-:35])=[O:34])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:44]1(P(C2CCCCC2)C2CCCCC2)CCCC[CH2:45]1.C([Sn](CCCC)(CCCC)C=C)CCC>O1CCOCC1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CO>[N+:33]([C:17]1[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)=[CH:19][C:2]([CH:44]=[CH2:45])=[C:3]([CH:16]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])=[O:5])([O-:35])=[O:34]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(=O)NCCCN1CCCC1=O
Temperature: 100 °C
Yield: 100 %

Procedure:
2-Chloro-5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 1f (400.0 mg, 0.80 mmol, 100 mol %), 1M aqueous potassium phosphate, tribasic (1.6 ml, 1.60 mmol, 200 mol %), tricyclohexylphosphine (22.4 mg, 0.08 mmol, 10 mol %), tributyl-vinyl-stannane (304.4 mg, 0.96 mmol, 120 mol %) and palladium(II) acetate (9.0 mg, 0.04 mmol, 5 mol %) were dissolved in 12.0 mL of dioxane in a 40 mL scintillation vial and the vessel was sealed and heated to 100° C. for 16 h. The reaction was then diluted with water and ethyl acetate and filtered through a pad of Celite. The filtrate was extracted twice with ethyl acetate and the combined organics were dried over sodium sulfate and concentrated. After two column chromatography runs, first with dichloromethane/methanol and then with ethyl acetate/methanol, 5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-2-vinyl-benzamide 6a (41.0 mg, 0.08 mmol, 10.4%) was obtained in pure form. LCMS (ESI) 492 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:13][S:16]([CH3:15])(=[O:18])=[O:17])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cc(C(=O)NC2CC2)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C(=O)NC2CC2)ccc1F

Procedure:
N-cyclopropyl-4-fluoro-3-methanesulfonylaminobenzamide was prepared by treatment of N-cyclopropyl-4-fluoro-3-aminobenzamide (prepared by a procedure similar to Example 1) with methanesulfonyl chloride in the presence of pyridine by standard procedure.