Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: NCCCNc1nsc2ncccc12
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4ncccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N1-(isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine (1.20 g, 5.77 mmol), 4′-methoxybiphenyl-4-carbaldehyde (1.22 g, 5.77 mmol), sodium triacetoxyborohydride (2.50 g, 11.8 mmol) and acetic acid (one drop) was taken up in methylene chloride (25 mL) and stirred overnight at room temperature under argon. The crude reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 95:5 methylene chloride:methanol yielded N1-(isothiazolo[5,4-b]pyridin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine. 1H NMR (300 MHz, CD3OD): 8.66-8.68 (d, 1H), 8.40-8.45 (d, 1H), 7.33-7.45 (m, 7H), 6.96 (s, 1H), 6.93 (s, 3.83 (s, 2H), 3.80 (s, 3H), 3.58-3.63 (t, 2H), 2.78-2.83 (t, 2H), 1.96-2.00 ppm (t, 2H). MW=405 confirmed by LC-MS, tr=9.08 min (Method Y) MH+=406.
Reaction SMILES: C(NC(=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3C[CH2:20][N:19]([C:22]([O:24][C:25](C)([CH3:27])C)=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)C.ClC1N=C(N2CCOC[C@@H]2C)C2CN(C(OCC)=O)CC=2N=1.[F:59]C1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1N>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:27])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][C:7]=1[F:59]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Agent: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(N)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 88 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and reduced in vacuo. The residue was purified by flash SCX2 chromatography affording the title compound (130 mg, 0.32 mmol, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([CH3:16])[N:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>COCCOCCOC.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)n1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: COCCOCCOC
Solvent: ClC(Cl)Cl
Product: Cc1cc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C)n1
Temperature: 165 °C
Yield: 126.4 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 2,6-dimethyl-pyridin-4-yl ester (0.50 g, 1.96 mmol) in diglyme (50 mL) was added 4-nitrophenyl piperazine (0.37 g, 0.76 mmol) and heated in the microwave at 165° C. for 40 minutes. The mixture was diluted with chloroform (100 mL) and washed with water (5×50 mL). The organic layer was separated, washed with brine solution (5×40 mL), dried over sodium sulfate and filtered. The solvent was evaporated, and the crude material was purified by column chromatography over silica gel (60-120 mesh) using 12% methanol in chloroform as eluent to afford 4-[4-(2,6-dimethyl-pyridin-4-yl)-1-(4-nitrophenyl)-piperazine (0.30 g, 49%) as a yellow solid.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH:17]([OH:26])[C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8]>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH:17]([OH:26])[C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)c1csc2cncn12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(O)c1csc2cncn12
Temperature: 80 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
Potassium thioacetate (149 mg) is added to a solution of 355 mg of crude (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]-3-methanesulfonyloxypyrrolidine (stereoisomer B) in a mixture of 3 ml of dry DMF and 1.5 ml of dry toluene, and the mixture is stirred in an argon atmosphere at a bath temperature of 80° C. for 12 hr. The mixture is diluted with 100 ml of ethyl acetate and washed twice with 40 ml of a 5% aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure. The residue is dried under reduced pressure by means of a vacuum pump for 2 hr. The resultant brown oil is successively purified by column chromatography on silica gel (ethyl acetate) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 139.1 mg of the title compound as a slightly red amorphous material.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3S(C)(=O)=O)[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C(N)CCCCC.C(#N)C.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3[NH:13][CH2:11][CH2:8][CH2:7][CH2:6][CH2:5][CH3:1])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)N2CCC(n3c(S(C)(=O)=O)nc4ccccc43)CC2)cc1
Solvent: CCCCCCN
Solvent: O
Solvent: CC#N
Product: CCCCCCNc1nc2ccccc2n1C1CCN(C(=O)c2ccc(CCCC)cc2)CC1
Yield: 101.8 %

Procedure:
In a sealed glass tube, (4-butyl-phenyl)-[4-(2-methanesulfonyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (9 mg) and hexyl amine (3 drops) were heated at 120-150° C. for 18 h. The crude product was taken into 1 ml 1:1 acetonitrile/water and purified via preparative liquid chromatography to give (4-butyl-phenyl)-[4-(2-hexylamino-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (4.8 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.CC1C=CC=CC=1C(N)=S.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1ccc(-c2nc(CCl)cs2)cc1
Agent: Cc1ccccc1C(N)=S
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 4-chloromethyl-2-p-tolyl-thiazole (prepared from 4 methyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[3-fluoro-4-(2-p-tolyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-[3-fluoro-4-(2-p-tolyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][CH:26]([OH:29])[CH2:27][OH:28])([OH:24])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][CH:26]([OH:29])[CH2:27][OH:28])([OH:24])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@](O)(CC(O)CO)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCC(O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)propane-1,2-diol, 58d, (0.11 g, 0.18 mmol) in MeOH (5 mL) was added sodium methanolate (2 mL of 25% w/v solution, 9.26 mmol) and the reaction mixture was stirred at room temperature. After 20 min, the reaction mixture was diluted with aqueous saturated NH4Cl solution and extracted twice with 20% IPA/CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification via silica gel chromatography using 5-20% MeOH: CH2Cl2 gradient to afford 56 mg of a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[N:16][CH:17]=1.[CH2:20]([Mg]Br)[CH2:21][CH2:22][CH2:23][CH3:24].BrCCCCC>C1COCC1>[OH:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:17][N:16]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC[Mg]Br
Reactant: O=Cc1ccc(Oc2ccc3ccccc3n2)cn1
Solvent: C1CCOC1
Solvent: CCCCCBr
Product: CCCCCC(O)c1ccc(Oc2ccc3ccccc3n2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
To a cold (-30° C.) solution of 5-(2-quinolinyloxy)-2-pyridine carboxaldehyde (8 g, 0.032 mol) in dry THF (125 ml) was added a solution of pentylmagnesium bromide (prepared from 4.83 g (0.032 mol) of 1-bromopentane and 0.78 g (0.032 mol) of Mg turnings in THF (60 ml). After the addition of the Grignard reagent was complete (-45° C.), the solution was stirred at this temperature for 90 minutes, and allowed to slowly warm up to room temperature in about 2 hours. The reaction was quenched by adding a saturated solution of ammonium chloride. The clear organic layer was decanted, and most of the volatiles were removed. The residue was taken up in ethyl acetate, and then washed with water, brine, and dried over MgSO4. After removal of the ethyl acetate the crude residue (7.7 g) was purified by HPLC (silica gel; 25% ethyl acetate in hexane) to give 3.6 g (35%) of pure product.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1.[CH3:12][N:13]([CH3:17])[C:14](=[S:16])[S-:15].C[NH2+]C>C(=S)=S>[CH3:12][N:13]([CH3:17])[C:14](=[S:15])[S:16][CH:7]([CH2:8][N+:9]([O-:11])=[O:10])[C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)s1
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc(Cl)s1

Procedure:
As in Example 17, reaction of 2-chloro-5-(2-nitrovinyl)thiophene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 5-chloro-α-(nitromethyl)-2-thenyl dimethyldithiocarbamate melting at 76° C.-77° C., after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: [OH:1][C:2]1([CH3:35])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13](/[CH:17]=[CH:18]/[S:19]([N:22]3[CH2:33][CH2:32][C:25]4([NH:29][C:28](=S)[NH:27][C:26]4=[O:31])[CH2:24][CH2:23]3)(=[O:21])=[O:20])=[C:12]([CH3:34])[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[Cl:43].C(N[C@H](C(O)=O)CS)(=O)C>CN1C(=O)CCC1.C1C=C(C([O-])=O)SC=1.[Cu+]>[Cl:36][C:37]1[CH:38]=[C:39]([C:28]2[NH:27][C:26](=[O:31])[C:25]3([CH2:32][CH2:33][N:22]([S:19](/[CH:18]=[CH:17]/[C:13]4[C:14]([CH3:16])=[CH:15][C:10]([C:8]([N:5]5[CH2:4][CH2:3][C:2]([OH:1])([CH3:35])[CH2:7][CH2:6]5)=[O:9])=[CH:11][C:12]=4[CH3:34])(=[O:20])=[O:21])[CH2:23][CH2:24]3)[N:29]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C(=O)N2CCC(C)(O)CC2)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)NC(=S)NC2=O
Agent: [Cu+]
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])c1cccs1
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)N2CCC(C)(O)CC2)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1ccc(Cl)c(Cl)c1)NC2=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A solution of 8-{(E)-2-[4-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-2,6-dimethyl-phenyl]-ethenesulfonyl}-2-thioxo-1,3,8-triaza-spiro[4.5]decan-4-one (25 mg, 0.048 mmol), 3,4-dichlorophenylboronic acid (27.5 mg, 0.144 mmol), palladium tetrakistriphenylphosphine (11.1 mg, 0.0096 mmol) and CuTC (36.8 mg, 0.192 mmol) in NMP (0.1 mL) was heated with stirring at 80° C. for 30 minutes in a nitrogen atmosphere. After cooling to room temperature, N-acetylcysteine (33 mg, 0.2 mmol) was added to the reaction mixture. The reaction mixture was purified by silica gel column chromatography (NH silica gel, methylene chloride:methanol=100:0→90:10) to give 2-(3,4-dichloro-phenyl)-8-{(E)-2-[4-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-2,6-dimethyl-phenyl]-ethenesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a white solid (13.4 mg, 44%).
Reaction SMILES: OO.[CH3:3][O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:17](=[CH:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](=[O:26])[CH:15]=[CH:14]1)=[O:6].[OH-].[Na+].[Cl-:29].[NH4+].Cl>CO.CC(C)=O>[Cl:29][C:15]1[C:16](=[O:26])[C:17](=[CH:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]([O:4][CH3:3])=[O:6])[CH:14]=1
Reactant: CCCCCC=CC=C1C(=O)C=CC1CCCCCCC(=O)OC
Reactant: [Cl-]
Agent: Cl
Agent: OO
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCC=CC=C1C(=O)C(Cl)=CC1CCCCCCC(=O)OC
Yield: 55 %

Procedure:
0.5 ml of 30% aqueous hydrogen peroxide was added to a solution of 95 mg (286 mmol) of 4-(6-methoxycarbonylhexyl)-5-(2-octenylidene)-2-cyclopentenone in 4 ml of methanol under ice cooling and stirring, and then 0.1 ml of 1N sodium hydroxide was added. The mixture was stirred at 0° C. for 20 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with hexane. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered and concentrated to give an oily product. The product was dissolved in 3 ml of acetone, and 0.5 ml of concentrated hydrochloric acid was added, the mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over an anhydrous sodium sulfate. The product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 10 g; eluent, cyclohexane:ethylacetate=10:1) to give 58 mg (yield 55%) of 2-chloro-4-(6-methoxycarbonylhexyl)-5-(2-octenylidene)-2-cyclopentenone.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](F)[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH2:37]>CS(C)=O.O>[CH2:29]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:28])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:37][CH3:36])[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Fc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1
Reactant: CN
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1

Procedure:
To a solution of dibenzyl-{2,4-difluoro-3-[4-(2-fluoro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-amine (400 mg, 0.849 mmol) in DMSO (4.24 mL), a 40% methyl amine solution in water (3.5 mL) was added. The mixture was irradiated in the microwave oven at 120° C. for one hour and then poured into water and extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous NaHCO3 and once with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduce pressure and the crude product was used in the following step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[K+].F[C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: Sc1ccccc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Sc1ccccc1Br
Temperature: 25 °C
Yield: 98.6 %

Procedure:
2-Bromobenzenethiol (7.2 ml, 85.9 mmol) was added to a solution of KOH (9.6 g, 172 mmol) in water (50 ml) degassed for 15 minutes. 2-Fluoro-5-nitrobenzoic acid (15.9 g, 85.9 mmol) was added to the reaction mixture, which was refluxed under a nitrogen atmosphere overnight. The reaction was cooled to room temperature and was acidified (pH 1) with conc. HCl. The precipitate formed was filtered and dried overnight in a vacuum oven (50° C.) to give the crude title compound as a pale yellow solid (30 g, 99%). The product was used without further purification. m/z (LC-MS, ESP), RT=4.51min, (M−−1)=352-354, (1:1, bromine isotope ratio present).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([CH3:21])(=[O:20])=[O:19])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([CH2:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@H:30]([C:31]([N:15]2[CH2:16][CH2:17][N:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:13][CH2:14]2)=[O:32])[CH2:29][C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of (cyclopropylmethyl)(methylsulfonyl)-(2-piperazinyl-phenyl)amine (HCl salt, 2.3 g, 6.0 mmol), (2S)-3-[(tert-butyl)oxycarbonyl]-2-[(4-chlorophenyl)-methyl]propanoic acid (1.8 g, 6.02 mmol, Step 4), HOBt (0.81 g, 6.0 mmol, Novabiochem), and TEA (1.67 mL, 12.0 mmol) in 20 mL of CH2Cl2 at 0° C. was added EDC (1.73 g, 9.03 mmol, Advanced Chemtech). The reaction was warmed to RT and stirred for 12 h. The reaction was quenched with satd NaHCO3, extracted with 80 mL of EtOAc and the organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The compound was further purified by silica gel column chromatography (50% EtOAc in hexane) to provide 2.3 g of tert-butyl (3S)-3-[(4-chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)-amino]phenyl}-piperazinyl)-4-oxobutanoate as a white foam. MS (ESI, pos. ion) m/z: 590.6 (M+1). Calc'd for C30H40ClN3O5S: 589.24. Anal. Calc'd for C30H40ClN3O5S: C, 61.05; H, 6.83; N, 7.12; Cl, 6.01. Found: C, 60.91; H, 6.69; N, 7.09; Cl, 6.16.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][CH:41]=[N:42][CH:43]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:38]3[CH:39]=[N:40][CH:41]=[N:42][CH:43]=3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cncnc5)ccc43)cc2OC)cn1
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 134.1 %

Procedure:
To a suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.37 g, 0.74 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.19 g, 0.93 mmol), potassium phosphate (0.55 g, 2.60 mmol), tricyclohexylphosphine (0.021 g, 0.074 mmol), and palladium(II)acetate (0.008 g, 0.037 mmol). The reaction mixture was heated to 125° C. in a microwave reactor. After 15 min, the reaction mixture was diluted with water. The mixture was extracted with chloroform (×3), and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.45 g of a light green solid. Chromatographic purification (Combi-Flash, 12 g SiO2 gold column, 1-5% methanol/dichloromethane elute) afforded 0.14 g (40%) of the product as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 9.17-9.14 (m, 3H), 8.50 (s, 1H), 8.20 (d, J=2.5, 1H), 8.12 (d, J=1.7, 1H), 7.77-7.70 (m, 2H), 7.65 (dd, J=8.4, 1.7 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.87-6.80 (m, 2H), 5.45 (s, 2H), 4.97 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H) ppm; (M+1)=454.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)=[O:8].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25].CCN(CC)CC>C(Cl)Cl>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[CH3:18])=[CH:15][N:14]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 9 (86 mg, 0.353 mmol) was taken up in CH2Cl2 (3 mL) and 3-(trifluoromethyl)benzoyl chloride (0.052 mL, 0.353 mmol) was added. The mixture was allowed to stir at rt for 2 h, becoming a thick yellow suspension. NEt3 (0.064 mL, 0.459 mmol) was added. After 0.5 h, a thick yellow suspension remained. Complete consumption of the amine starting material was indicated by LCMS. The crude reaction mixture was concentrated and the title compound was purified using automated medium pressure chromatography (Isco—40 g column; eluting with a linear gradient from 100% CH2Cl2 (A line) to 100% 90/10/1 CH2Cl2/MeOH/NH3 (B line) on silica gel) to afford N-(2-amino-5-pyrimidinyl)-2-methyl-5-(((3-(trifluoromethyl)phenyl)carbonyl)amino)benzamide 10 as an off-white solid. MS: m/z found 416 [MH+] (by ESI, positive ion); MS calculated for C20H16F3N5O2=415.13.