Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O:15]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOC(C)=O.ClC1C2C(=NC=CC=2)N=CC=1>C(OCCO)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Agent: Clc1ccnc2ncccc12
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 100 mL round-bottomed flask fitted with a condenser, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.250 g, 1.20 mmol) and 3-phenoxyaniline (0.245 g, 1.32 mmol) were taken up in 20 mL 2-ethoxyethanol and heated at reflux for 1 hour, until TLC analysis (20% EtOAc in hexanes) showed complete disappearance of the 4-chloronaphthyridine. After cooling to room temperature, the reaction mixture was partitioned between 40 mL each EtOAc and 5% Na2CO3. The aqueous layer was extracted twice more with EtOAc, and the combined organic layers washed three times with brine, dried over anhydrous MgSO4, filtered, and evaporated to give 6-fluoro-4-(3-phenoxyphenylamino)-1,7-naphthyridine-3-carbonitrile as a brown oil of sufficient purity to be used directly in the next step: 1H NMR (400 MHz, DMSO-D6) δ 6.94-7.18 (m, 6 H) 7.33-7.51 (m, 3 H) 8.15 (s, 1 H) 8.68 (s, 1 H) 9.05 (s, 1 H) 10.12 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:21]([F:32])[F:20])=[CH:28][N:27]=2)=[O:30])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)NC(=S)CO1
Yield: 82 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (75 mg, 0.26 mmol) and 5-difluoromethoxy-pyridine-2-carboxylic acid [CAS No. 1174323-34-2, described in example 48] (50 mg, 0.26 mmol). The compound was obtained as white foam (99 mg, 82%). MS (ISP): m/z=454.1 [(M+H)+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(O)C.CN(C)C(=O)C>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:21][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), ethyl bromopyruvate (0.21 g), ethanol (2 mL) and N,N-dimethylacetamide (2 mL) was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were recrystallized from ethyl acetate to give the title compound (0.14 g, yield 36%) as pale-yellow crystals. melting point 240-241° C.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:13]([Cl:26])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH:27][C:28](=[O:34])[CH2:29][C:30](OC)=[O:31])=O)C.[H-].[Na+].Cl.C(OCC)C>C1COCC1>[Cl:26][C:13]1[CH:12]=[C:11]([C:10]2[C:6]3[C:30]([OH:31])=[CH:29][C:28](=[O:34])[NH:27][C:7]=3[S:8][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1c(-c2cc(Cl)c(OCc3ccccc3)c(Cl)c2)csc1NC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1cc(O)c2c(-c3cc(Cl)c(OCc4ccccc4)c(Cl)c3)csc2[nH]1
Yield: 78.6 %

Procedure:
To a solution of 1.91 g (3.65 mmol) of 4-(4-benzyloxy-3,5-dichloro-phenyl)-2-(2-methoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid ethyl ester in 20 mL of THF was added 600 mg (15 mmol) of 60% NaH in mineral oil. The reaction was stirred at reflux under N2 for 18 h, then the excess NaH was quenched by the addition of 10 mL of water. The THF was removed in vacuo, then the remaining solution was taken up in 30 mL of 2M NaOH(aq.) and 30 mL of ethanol. This was stirred at 80° C. for 5 h, then concentrated to remove most of the ethanol. The remaining solution was diluted with 100 mL of water, and extracted with diethyl ether (2×30 mL). The ether layers were discarded, along with a small amount of precipitate that formed in the aqueous layer. The stirred aqueous layer was made acidic with 4M HCl to give a precipitate. Diethyl ether was added and the mixture was stirred to suspend the precipitate in the ether layer, then most of the water was decanted. The precipitate was filtered, and washed with water, then diethyl ether to give 1.20 g (79%) of the titled compound as a tan solid. MS (ESI) m/e 417.7, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 5.05 (s, 1H) 5.76 (s, 1H) 7.23 (s, 1H) 7.43 (m, 2H) 7.58 (m, 2H) 11.15 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:7]=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:7][CH:8]=1)[CH3:16]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=CC(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCNc1nc(Nc2ccccc2)ncc1CCC(=O)OCC
Yield: 47.7 %

Procedure:
A mixture of ethyl 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)acrylate (152 mg, 0.48 mmol) and 5% palladium on carbon in a solvent mixture of ethanol and tetrahydrofuran was hydrogenated under pressure. The catalyst was filtered off and the filtrate concentrated. The residue was purified by flash chromatography eluting with 2:1 ethyl acetate:hexane to give 72 mg (47%) of 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)propionic acid ethyl ester, mp 106-107° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:11]([CH2:24][C:25]([F:26])([F:27])[F:28])[CH2:10][CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:17]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N(CCOc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Reaction time: 22 h
Yield: 73.6 %

Procedure:
To a solution of 4-[{2-[(4-aminophenyl)oxy]ethyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.0423 g, 0.105 mmol) in dry pyridine (1 mL) at rt, under nitrogen, was added MsCl (0.010 mL, 0.12 mmol) in one portion. The mixture was stirred 22 h and concentrated in vacuo. The residue was partitioned between EtOAc and 10% v/v HCl and the layers were separated. The organic layer was washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.0372 g of the title compound as a colorless film: 1H NMR (300 MHz, CD3OD) δ 7.74 (d, J=8.8 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.8, 2.5 Hz, 1H), 7.19-7.12 (m, 2H), 6.90-6.83 (m, 2H), 4.43 (q, J=8.9 Hz, 2H), 4.22 (t, J=5.1 Hz, 2H), 4.04 (t, J=5.1 Hz, 2H), 2.85 (s, 3H); MS (APCI) m/z 480 (M−1).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:11][N:12]1[C@H:16]2[C:17]([C:20](OC)=O)=[CH:18][CH2:19][C@@H:13]1[CH2:14][CH2:15]2.FC(F)(F)C(O)=O.[ClH:31]>CCOCC.C(N(CC)CC)C.CCOCC>[Cl:2][C:3]1[CH:4]=[C:5]([C@H:18]2[CH2:19][C@H:13]3[N:12]([CH3:11])[C@H:16]([CH2:15][CH2:14]3)[C@H:17]2[CH2:20][Cl:31])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Clc1ccc(I)cc1Cl
Reactant: Cl
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Agent: [Mg]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1[C@H]2CC[C@@H]1[C@@H](CCl)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a three-neck, round-bottomed flask containing freshly distilled ether (125 mL) and magnesium turnings (268 mg, 11.0 mmol),was added 3,4-dichloroiodobenzene (2.26 g, 8.27 mmol). After 2 h, the reaction flask was equipped with a mechanical stirrer, and the Grignard reagent was cooled to -55° C. before adding anhydroecgonine methyl ester (500 mg, 2.75 mmol). The resulting solution was stirred for an additional 2.5 h before being cooled to -78° C. After 1 h, 2 mL of trifluoroacetic acid was added to the solution followed by 2 h of stirring. The quenched reaction mixture was then diluted with 1N HCl (100 mL) and extracted with ether (3×100 mL). The ethereal layers were discarded, and the aqueous layer was basified with conc. ammonium hydride and then extracted with chloroform (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield the crude product as a colorless oil. Flash chromatography (ether triethylamine, 9:1) yielded 71 mg (9.0%) of pure product: 1H NMR (250 MHz, CDCl3) δ1.52-1.76 (m, 2), 1.81-1.95 (m, 2), 1.96-2.22 (m, 2), 2.38 (s, 3), 3.07-3.15 (br s, 2), 3.21-3.32 (br s, 1), 3.45-3.65 (m, 1), 3.50 (s, 3), 7.10-7.38 (m, 3).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC3[O:33][CH2:34][O:35]C=3C=2)=CSC=1C(OC)=O.[CH:42](OCC)(OCC)[O:43]CC.COC1C=CC(N)=CC=1>C(O)(=O)C>[O:33]1[C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:10]4[N:9]=[CH:8][N:7]([C:1]5[CH:6]=[CH:5][C:4]([O:43][CH3:42])=[CH:3][CH:2]=5)[C:12](=[O:13])[C:11]=4[S:14][CH:15]=3)=[CH:18][C:19]=2[O:35][CH2:34]1
Reactant: COC(=O)c1scc(-c2ccc3c(c2)OCO3)c1N
Reactant: CCOC(OCC)OCC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: COc1ccc(N)cc1
Product: COc1ccc(-n2cnc3c(-c4ccc5c(c4)OCO5)csc3c2=O)cc1
Yield: 65.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(benzo[d][1,3]dioxol-5-yl)thiophene-2-carboxylate (60 mg, 0.21 mmol), triethyl orthoformate (0.46 ml), p-anisidine (49.6 mg, 0.4 mmol), and acetic acid (0.06 ml) were used to give 52.4 mg (0.14 mmol, 65.2% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(CC)CC.[CH3:22][CH2:23][OH:24]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([O:24][CH2:23][CH3:22])=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.0 g, 22.0 mmol) in THF (25 mL) was added Et3N (3.1 mL, 22.0 mmol) followed by EtOH (1.3 mL, 22.0 mmol). This mixture was stirred at ambient temperature for 1 h and quenched with saturated, aqueous NH4Cl (10 mL). The layers were separated and the aqueous layer was extracted with 3×10 mL EtOAc and the combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 60% hexanes in EtOAc) to give the title compound (4.8 g, 20.3 mmol, 92% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.42 (t, J=7.1 Hz, 3H), 4.43 (q, J=7.1 Hz, 2H), 7.23-7.34 (m, 1H), 7.74-7.82 (m, 1H), 8.23 (dd, J=6.3, 2.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=O)=[CH:14][CH:13]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[N:18]([OH:20])[C:15]2[CH:14]=[CH:13][C:12]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[CH3:1])=[CH:17][CH:16]=2)=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Cc1ncnc2nc[nH]c12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1ncnc2c1ncn2-c1ccc(N(O)C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 6-methylpurine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 45.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CO>C1(C)C=CC=CC=1>[CH2:16]([O:15][P:11]([CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:9]=[CH:8][CH:7]=1)([O:12][CH2:13][CH3:14])=[O:18])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CCOP(=O)(Cc1cccc(CCN)c1)OCC
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCc1cccc(CP(=O)(OCC)OCC)c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A solution of diethyl [[3-(2-aminoethyl)phenyl]methyl]phosphonate (Example D) (3.6 g, 13.2 mmol) in toluene (15 ml) and triethylamine (2.7 g, 26.4 mmol) is cooled in an ice/salt bath and a solution of ethyl bromoacetate (2.2 g, 13.2 mmol) in toluene (8 ml) is added dropwise over 20 minutes. A gum forms and methanol (5 ml) is added and stirred an additional two hours. After evaporation of the solvent, the residue is dissolved in ethyl acetate (75 ml) and washed with water (20 ml, and 10 ml) and then saturated sodium chloride solution (10 ml). The organic layer is dried over magnesium sulfate, filtered, and evaporated to give an oil (4.3 g). Chromatography over silica gel gives an analytical, colorless oil. 1H-NMR: 4H, m, 7.33-7.0 ppm; 6H, m, 4.33-3.86; 2H, s, 3.40; 2H, d, 3.13; 4H, m, 2.90-2.70; 1H, s, 1.8; 9H, m, 1.33-1.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].CO>C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:25]#[C:24][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[S:22][C:13]=12
Reactant: C#Cc1cccnc1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cccnc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (160 mg, 0.33 mmol), 3-ethynylpyridine (45 mg, 0.43 mmol), 5 mg of tetrakis(triphenylphosphine)palladium(0) and 20 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux overnight. The mixture is cooled to room temperature and 5 mL of methanol is added. The solvents are removed in vacuo and the residue is treated with 50 mL of chloroform. The insoluble material is removed by filtration, washing with chloroform. The filtrate is washed with water. The residue is suspended in acetone, combined with the chloroform phase and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% methanol in dichloromethane to 10% methanol and 1% ammonium hydroxide in dichloromethane. The fractions containing product are combined and concentrated to provide 99 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile as light brown crystals, mp 249–250° C.; MS 451.0(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.Cl.[OH-:23].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c12

Procedure:
A mixture of intermediate from Step B (100 mg, 0.32 mmol) in 2N aqueous NaOH (20 mL) was stirred at reflux temperature for 1.5 h. The solution was cooled in ice bath, neutralized with 2 N aqueous HCl and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent mixture of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1 and 5/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (90 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:42][CH:41]=3)=[CH:38][CH:39]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)#[N:2]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 300 mg (0.73 mmol) of methyl 4-[(4E)-3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-en-1-yl]benzoate in 30 ml of dry acetonitrile is mixed with 236.8 mg (0.87 mmol) of 4-(chloromethyl)-4′-(trifluoromethyl)biphenyl and 151 mg (1.09 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 331 mg (0.51 mmol, 70% of theory) of a solid are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C(CN1CCOCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
Working as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.54 cm3 of morpholine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa; 50° C.) and the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.), then dried (90 Pa; 45° C.) to give 470 mg of N-(6-chloro-1H-indazol-3-yl)-4-morpholineacetamide in the form of a white powder melting at about 82-90° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:10])C=O)=[CH:3][CH:2]=1.[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])CCC1C=CC=CC=1Cl)([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=CC=1C=CC=O>>[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH2:10][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Reactant: CC(C=O)c1ccncc1
Agent: O=CC=Cc1ccccc1Cl
Product: CC1CCN(C(=O)C(CCc2ccncc2)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-4-ylpropyl}carbamate is prepared from pyridin-4-yl propionaldehyde (Kitbunnadaj, R. et al. J. Med. Chem, 2004, 47, 2414-2417) in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 3-(2-chlorophenyl)propenal in Example 5.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]([C:41]2[C:45]([CH:46]=O)=[N:44][O:43][N:42]=2)=[O:40])[CH:34]=[CH:35][C:36]=1[F:37]>C1(C)C=CC=CC=1.C1COCC1>[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]([C:41]2[C:45](/[CH:46]=[CH:2]\[O:3][CH3:4])=[N:44][O:43][N:42]=2)=[O:40])[CH:34]=[CH:35][C:36]=1[F:37].[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]([C:41]2[C:45](/[CH:46]=[CH:2]/[O:3][CH3:4])=[N:44][O:43][N:42]=2)=[O:40])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=Cc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CO/C=C/c1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Product: CO/C=C\c1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)(triphenyl)phosphonium chloride (23.0 g, 66.0 mmol) in toluene (183 mL) was added sodium tert-butoxide (6.60 g, 0.066 mol) at rt under an atmosphere of nitrogen. After stirring for 30 min, a solution of N-(3-chloro-4-fluorophenyl)-4-formyl-1,2,5-oxadiazole-3-carboxamide (7.6 g, 28 mmol) in THF (18 mL) was cannulated into reaction flask. The resulting solution was stirred at rt for 1 h. The reaction was quenched with 1 N HCl and diluted with ethyl acetate and the aqueous layer was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (20% ethyl acetate/Hex) to give product (2.0 g 24%, E isomer, 2.6 g, 31%, Z isomer) as white solids. Z isomer: 1H NMR (400 MHz, CDCl3): δ□ 8.54 (s, 1 H) 7.87 (dd, J=6.4, 2.7 Hz, 1 H), 7.42 (m, 1 H), 7.16 (t, J=8.5 Hz, 1 H), 6.66 (d, J=6.6 Hz, 1 H), 6.03 (d, J=6.6 Hz, 1 H), 3.97 (s, 3 H). MF=C12H10ClFN3O3; LCMS for C12H10ClFN3O3(M+H)+: m/z=298.0.