Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:13]S[C:11](=[O:14])[N:10]=1.[Cl:15][C:16]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([Cl:27])=[CH:19][C:17]=1[NH2:18].C(P(CCCC)CCCC)CCC>ClCCl>[Cl:15][C:16]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][C:20]([Cl:27])=[CH:19][C:17]=1[NH:18][C:11]([NH:10][C:9](=[S:13])[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:14]
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Reactant: O=c1nc(-c2c(F)cccc2F)ss1
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: O=C(NC(=S)c1c(F)cccc1F)Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-1,2,4-dithiazole-3-one (0.9 g) in 20 ml of dichloromethane was added dropwise a solution of 2,5-dichloro-3-trifluoromethylaniline (0.9 g) and tributylphosphine (0.8 g) in 10 ml of dichloromethane under ice-cooling and the solution was stirred for 30 minutes at room temperature. The dichloromethane was then distilled off under reduced pressure and to the residue was added ligroin. The precipitated crystal was filtered and the crystal was washed with ligroin to obtain the desired product 1.3 g. (d.p. 176°-177° C.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](I)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:10]
Reactant: CCI
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(F)c1

Procedure:
3-Fluorophenol (20.0 g, 178.4 mmol), ethyl iodide (83.5 g, 535.2 mmol) and K2CO3 (49.3 g, 356.8 mmol) in 250 ml of acetone were stirred at 50° C. overnight. The mixture was filtered and evaporated to give 1-ethoxy-3-fluorobenzene.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH:23]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([O:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OC1CCCC1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCCC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclopentanol to give (1-Cyclopentyloxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 369(MH+).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 3 °C
Reaction time: 1 h

Procedure:
2.00 g (10.74 mmol) tert-butyl 1-piperazinecarboxylate, 1.30 g (12.89 mmol, 1.2 eq.) triethylamine were dissolved into 25 ml dichloromethan under argon gas. After cooling to 3° C., 1.33 g (11.81 mmol, 1.1 eq.) chloroacetyl chloride was diluted with 5 ml dichloromethane and added dropwise slowly into reaction solution. After stirring at 3° C. for 1 hour, 20 ml purified water was added, organic layer was separated and aqueous layer was extracted once with 40 ml dichloromethane again. Organic layer was collected, dried with magnesium sulfate and concentrated with decompression. Purifying residues by chromatography using silicagel, 2.00 g (71%) target compound as yellow syrup was yielded.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([F:18])[CH:3]=1.[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:32]([O:31][C@@H:27]1[C@@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[O:29][C@H:28]1[O:17][C:10]1[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:18])=[C:13]([CH:14]([CH3:16])[CH3:15])[NH:12][N:11]=1)(=[O:33])[CH3:34]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(Br)cc1F
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 4-[(4-bromo-2-fluorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]2[CH2:41][O:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:27])=[CH:21][CH:20]=1)=[O:18]>CO>[ClH:1].[ClH:1].[CH3:15][NH:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH:29]2[CH2:41][O:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:27])=[CH:23][CH:24]=1)=[O:18]
Reactant: CNC(=O)c1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)cc1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(NC(=O)N2CCNCC2COc2cccnc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(methylcarbamoyl)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (103 mg, 0.177 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 42.8 mg (55%) of the title compound as a white solid. LC-MS: RT=2.22 min, [M+H]+=370.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]1([CH3:17])[C:10]([CH:15]=O)=[CH:11][CH:12]=[CH:13][CH:14]=1.[C:18](#[N:20])C.C[Si](C#N)(C)C>C1(C)C=CC=CC=1>[C:9]1([CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)[C:18]#[N:20]
Reactant: CC#N
Reactant: Cc1ccccc1C=O
Reactant: Cc1cccc(N)c1
Agent: C[Si](C)(C)C#N
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(C#N)c2ccccc2C)c1
Yield: 68.1 %

Procedure:
To a flame-dried 25 mL round-bottom flask equipped with a magnetic stirring bar was added m-toluidine (365 mg, 3.4 mmol), o-tolualdehyde (391 mg, 3.3 mmol) and 5 mL of dry acetonitrile. The solution was stirred to make a homogeneous solution, then trimethylsilyl cyanide (480 μL, 3.6 mmol) was added and the solution stirred at room temperature for 23 h. The reaction was quenched by adding 5.5 mL satureated ammonium chloride solution and allowed to vent. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the crude product (50% dichloromethane/hexanes, Rf=0.025). The crude was dissolved in a minimal amount of boiling toluene, a 4-5 fold volume of hexanes added and the solution allowed to sit for several hours, filtered, and dried to give XXX (531 mg, 68.1% yield) as a crystalline solid. Approximately 400 mg of the recrystallized material was additionally purified by flash chromatography using 50% dichloromethane/hexanes, which, after concentration, gave XXX as a white crystalline solid (m.p. 103-104° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:23])[CH2:8]1)=[O:5])[CH3:2].[BrH:26].[Br:27]Br.C(OC(C)C)(C)C>C(Cl)Cl.C(O)(=O)C>[Br:26][C:13]1[NH:14][C:15]2[C:22]3[C:12]=1[CH2:11][C@@H:10]1[C@@H:20]([C:19]=3[CH:18]=[C:17]([Br:27])[CH:16]=2)[CH2:21][C@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])[CH2:8][N:9]1[CH3:23]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: Br
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
10 g of 1,1-diethyl-3-(6-methyl-8α-ergolinyl)urea (terguride) (30 mmol) is dissolved in 550 ml of methylene chloride and, under ice cooling, 8.8 ml of 33% strength solution of hydrogen bromide in glacial acetic acid is added thereto. With continued cooling, a solution of 3.1 ml of bromine (60 mmol) in 400 ml of methylene chloride is added dropwise thereto within 30 minutes. The crystalline slurry is combined with 200 ml of diisopropyl ether, and the crystals are filtered off after stirring for 20 minutes. Recrystallization from methylene chloride, methanol and diisopropyl ether yields 10.5 g of 3-(2,13-dibromo-6-methyl-8α-ergolinyl)-1,1-diethylurea (71% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=1.[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][NH2:31])=[CH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][NH:31][C:13](=[O:15])[C:10]3[CH:9]=[CH:8][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[CH:12][N:11]=3)=[CH:25][N:24]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(-c2ncc(CN)cc2C)ccn1
Reactant: O=C(O)c1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncc(CNC(=O)c3ccc(-c4cnccn4)cn3)cc2C)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(pyrazin-2-yl)picolinic acid 41-4 (20 mg, 0.1 mmol), (2′,3-dimethyl-2,4′-bipyridin-5-yl)methanamine 63-2 (21 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (38 mg, 0.1 mmol) in DMF (1.0 mL) was added DIEA (0.053 mL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-((2′,3-dimethyl-2,4′-bipyridin-5-yl)methyl)-5-(pyrazin-2-yl)picolinamide 63 as white solid. MS m/z 397.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.59 (t, 1H), 9.39 (d, 1H), 9.33 (d, 1H), 8.76 (m, 1H), 8.68 (m, 2H), 8.45 (d, 1H), 8.15 (d, 1H), 7.65 (d, 1H), 7.34 (b, 1H), 7.27 (d, 1H), 4.51 (d, 2H), 2.46 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:9]1[N:20](S(C2C=CC=CC=2)(=O)=O)[C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1)[CH3:8].C(OCC)(=O)C>CO.O>[CH2:7]([C:9]1[NH:20][C:12]2=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]2[CH:10]=1)[CH3:8]
Reactant: CCc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 80 °C
Yield: 99.1 %

Procedure:
Potassium carbonate (1.02 g, 7.394 mmol) was added to a solution of 2-ethyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.245 g, 0.739 mmol) in methanol (6.5 mL) and water (2.2 mL). The reaction mixture was heated at 80° C. overnight. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 2-ethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.14 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][OH:5].[C@H:11]1([N:20]=[C:21]=S)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C.O>[Cl:10][C:6]1[C:3]2[CH2:4][O:5][C:21]([NH:20][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)=[N:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(Cl)c1CO
Reactant: S=C=N[C@@H]1CCc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 23 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
To a stirred solution of commercially available 2-amino-6-chlorobenzyl alcohol (CAS-no. 39885-08-0) (315 mg, 2 mmol) in tetrahydrofuran (4 ml) at 23° C. was added commercially available (R)-(−)-1-indanyl isothiocyanate (CAS-no. 737000-97-4) (324 ul, 2 mmol) and the mixture was stirred at 23° C. for 18 h, then at reflux for another 3 h. Cooled to 23° C., the solvent was removed in vacuum, the residue was dissolved in acetonitrile (4 ml), added dicyclohexylcarbodiimide (DCC) (619 mg, 3.0 mmol) and refluxed for 2 h. Cooled to room temperature, diluted with ethyl acetate and water, added little 1 M NaH2PO4.2H2O solution to achieve pH 4, separated phases, washed organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left a yellow foam, which was purified by silica gel flash chromatography with n-heptane and ethyl acetate to give the title compound as a light yellow oil (215 mg, 36%), MS (ISP) m/e=299.1 [(M+H)+].
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.CC[O:14][C:15]([CH2:17][CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:16]>>[Cl:1][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:10]2[C:23]3[CH:18]([CH2:17][C:15]([OH:14])=[O:16])[CH2:19][CH2:20][CH2:21][C:22]=3[C:5]3[C:4]2=[C:3]([CH3:2])[CH:8]=[C:7]([CH3:9])[CH:6]=3)=[CH:4][CH:5]=1
Reactant: Cc1ccc(NN)c(C)c1
Reactant: Cl
Reactant: CCOC(=O)CC1CCCCC1=O
Product: Cc1cc(C)c2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 34, but using 1-(2,4-dimethylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate in Step I as starting materials, the title compound was prepared. m.p. 187°-188° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:16]=3)=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[SH2:30]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:17][CH:16]=3)=[O:13])[O:9][C:6]2=[N:7][CH:8]=1)(=[S:30])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)cnc3o2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)cnc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
t-Butyl 4-(5-cyanofuro[2,3-b]pyridine-2-carbonylamino)phenoxyacetate (430 mg, 1.10 mmol) was dissolved in a mixed solvent of pyridine (16 ml) and triethylamine (4 ml), and a hydrogen sulfide gas was blown in for 10 minutes. The mixture was stirred at room temperature for 18 hours. The solvent was distilled away from the reaction mixture under reduced pressure to give t-butyl 4-(5-thiocarbamoylfuro[2,3-b]pyridine-2-carbonylamino)phenoxyacetate as a yellow solid. This solid was dissolved in acetone (15 ml) and methyl iodide (1.0 ml) was added, which was followed by refluxing under heating for 1.5 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give t-butyl 4-[5-[(1-methylthio)iminomethyl]furo[2,3-b]pyridine-2-carbonylamino]phenoxyacetate as a yellow solid. Methanol (15 ml) and ammonium acetate (150 mg, 1.95 mmol) were added and the mixture was refluxed under heating for 2 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform/methanol=5/1) to give 35 mg of compound (238) as a yellow solid (11% in 3 steps).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([Cl:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[Cl:20][C:4]1[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Temperature: 30 °C
Yield: 73.6 %

Procedure:
A mixture of compound (2,6-dichloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.4 g, 1.23 mmol), morpholine (0.1 g, 1.16 mmol) and triethyl amine (0.5 ml, 3.66 mmol) in solvent ethanol (10 mL) was refluxed for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to temperature in the range of 20-40° C. and concentrated under vacuum. The crude compound was passed through the silica gel by using 8-10% ethylacetate in pet-ether to afford the compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.32 g, 69%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd-2](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>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COCCNc1ccc(C(=O)c2cc(Br)cnc2N)cn1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCNc1ccc(C(=O)c2cc(-c3ccc(OC)c(OC)c3)cnc2N)cn1
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To (2-amino-5-bromo-pyridin-3-yl)-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone, 3,4-dimethoxyphenylboronic acid (1.3 equiv.) and dichlorobis (triphenylphosphino)palladium (ii) (6 mol %) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water, and a 2 m solution of sodium carbonate in water to achieve an overall concentration of the starting material of 0.10 m. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture extracted three times with ethyl acetate. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone as a yellow solid (74% yield). 1H NMR (DMSO-d6): δ 8.49 (d, J=2.0 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.58 (broad s, 1H), 7.14 (s, 1H), 7.05 (m, 3H), 6.98 (d, J=8.5 Hz, 1H), 6.59 (d, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.50 (broad t, J=5.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.26 (s, 3H); HPLC/MS m/z: 409.2 [MH]+.
Reaction SMILES: ClCCl.[CH3:4][N:5]=[C:6]=[O:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[N:16]2[CH2:19][C:18](=[CH:20][S:21]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:22])[CH2:17]2)=[CH:11][CH:10]=1>O>[CH3:4][NH:5][C:6]([N:34]1[CH2:35][CH2:36][N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:21]([CH:20]=[C:18]3[CH2:17][N:16]([CH:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:19]3)(=[O:22])=[O:23])[CH:26]=2)[CH2:32][CH2:33]1)=[O:7]
Reactant: CN=C=O
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 4 h
Yield: 110.1 %

Procedure:
2 cm3 of dichloromethane and then 11.5 mg of methyl isocyanate are successively added, at a temperature close to 20° C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 4 hours at a temperature close to 20° C., 0.05 cm3 of water is added to the mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried over magnesium sulfate, filtered on paper and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 66 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid N-methylamide are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm):
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:26])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Br)=[C:8]([S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[NH2:25])(=[O:16])=[O:15])[CH:7]=1>CN(C)C=O>[CH3:3][O:4][C:5]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]2[NH:25][C:19]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][S:14](=[O:16])(=[O:15])[C:8]=2[CH:7]=1)=[O:26]
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cc2cccc(Cl)c2N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1N2
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.234 g, 5.07 mmol) was added in portions to a stirred solution of Example 37d (0.785 g, 1.69 mmol) in dry dimethylformamide (10 mL) at 0° C. The reaction mixture was stirred for 0.5 h. Excess sodium hydride was destroyed using methanol (5 mL). The reaction mixture was diluted with cold water (100 mL), the solid separated was filtered, crystallized using ethyl acetate/pet. ether 60-80° C. to obtain the title compound. Yield: 0.409 g, (64.10%); 1H NMR (DMSO-d6, 300 MHz): δ 2.65 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 7.25 (t, 1H, Ar), 7.65 (d, 1H, Ar), 7.75 (d, 1H, Ar), 7.85 (s, 1H, NH), 8.05 (s, 1H, Ar), 8.35 (s, 1H, Ar); MS: m/e (El) 351 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:3]=1[C:4]([NH:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[C:23](Cl)(Cl)=[O:24]>O1CCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:8]([O:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[C:18]([F:19])[C:17]([F:20])=[C:16]([F:21])[C:15]=2[F:22])[NH:1][C:23]1=[O:24])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(F)c(F)c(F)c(F)c1C(=O)NOCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1[nH]c2c(F)c(F)c(F)c(F)c2c(=O)n1OCc1ccccc1
Temperature: 80 °C
Yield: 51 %

Procedure:
A solution of 2-amino-N-benzyloxy-3,4,5,6-tetrafluoro-benzamide (Example V-3, 1.72 g, 5.47 mmol) in 1,4-dioxane (50 mL) was reacted with a 20% solution of phosgene (4.25 mL, 8.00 mmol) in toluene and heated to 80° C. in a sealed tube for 18 hours. The mixture was then cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3. The organic layer was dried with magnesium sulfate and concentrated. The residue was triturated with diethyl ether and filtered to provide 0.95 g of the title compound as a solid.