Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH3:26])=[CH:20][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](I)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:18]#[N:19].C([Sn](CCCC)(CCCC)[C:32]1[CH:36]=[C:35]([CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])[O:34][CH:33]=1)CCC.BrC1C=C(C(OCC)OCC)OC=1.C([Sn](Cl)(CCCC)CCCC)CCC.[Li]CCCC>O1CCOCC1>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH3:26])=[CH:20][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:32]3[CH:36]=[C:35]([CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])[O:34][CH:33]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:18]#[N:19]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)c(OC)cc23)c(Cl)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1coc(C(OCC)OCC)c1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CCOC(OCC)c1cc(Br)co1
Agent: [Li]CCCC
Solvent: C1COCCO1
Product: CCOC(OCC)c1cc(-c2cc3ncc(C#N)c(Nc4cc(OC)c(Cl)cc4Cl)c3cc2OC)co1

Procedure:
A mixture of 4-(2,4-dichloro-5-methoxyanilino)-7-iodo-6-methoxy-3-quinolinecarbonitrile (3.5 g, 7.00 mmol), tributyl [5-(diethoxymethyl)-3-furanyl]stannane (generated from reaction of 4-bromo-2-(diethoxymethyl)-furan [ref. Chiarello, J, Joullie, M. M., Tetrahedron, 44(1), 41-48 (1988)] with tributyl tin chloride in the presence of n-BuLi) (5.76 g, 12.55 mmol), and dichlorobis(triphenylphosphine)pallidium (II) (100 mg) in 80 mL of dioxane is heated at reflux for 5 hours. Additional dichlorobis(triphenylphosphine)pallidium (II) (100 mg) is added and the reaction mixture is heated at reflux overnight. The reaction mixture is partitioned between ethyl acetate and water. The insoluble material is collected by filtration to provide 1.09 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[5-(diethoxymethyl)-3-furyl]-6-methoxy-3-quinolinecarbonitrile as a pale green solid; 1H NMR (DMSO-d6) δ 1.18 (t, J=7 Hz, 6H), 3.63 (q, J=7 Hz, 4H), 3.87 (s, 3H), 4.07 (s, 3H), 5.60 (s, 1H), 7.13 (s, 1H), 7.37 (s, 1H), 7.76 (s, 1H), 7.95 (s, 1H), 8.15 (s, 1H), 8.35 (s, 1H), 8.45 (s, 1H), 9.84 (s, 1H); MS 542.1, 544.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=[O:8].[BH4-].[Na+]>CO>[Br:15][C:11]1[CH:10]=[C:9]([CH:7]([OH:8])[CH2:6][N:5]([CH2:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])[CH3:16])[CH:14]=[CH:13][CH:12]=1
Reactant: CN(CC(=O)c1cccc(Br)c1)Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 1 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-bromophenyl)ethanone (77 g, 198.97 mmol, 1.00 equiv, theoretical yield) in methanol (300 mL). This was followed by the addition of NaBH4 (15 g, 394.74 mmol, 1.98 equiv) in several batches at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of acetone. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 50 g (65%) of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-bromophenyl)ethanol as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C@H:10]([CH3:25])[C@@H:11]([CH3:24])[O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH:42]2[CH2:44][CH2:43]2)(=[N:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:29][CH:28]=1>O1CCOCC1.C(#N)C.C(OCC)(=O)C>[CH2:2]([O:9][C@H:10]([CH3:25])[C@H:11]([O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH:42]3[CH2:44][CH2:43]3)(=[N:35][C:36](=[O:41])[C:37]([F:40])([F:38])[F:39])=[O:34])=[CH:31][CH:32]=2)[N:14]=1)[CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc(S(=O)(=NC(=O)C(F)(F)F)C2CC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(=NC(=O)C(F)(F)F)C3CC3)cc2)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
0.96 ml of 4N solution of hydrogen chloride in dioxane was added to 1.39 g (3.85 mmol) of 4-((1R,2R)-2-benzyloxy-1-methyl-propoxy)-2-chloro-5-trifluoromethyl-pyrimidine and 1.35 g (4.62 mmol) (RS)-S-(4-aminophenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulfoximide in 18.8 ml acetonitrile and stirred for 5 hours at 80° C. After cooling, the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 4:1). 1.32 g (2.14 mmol, yield: 56%) of the product was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](NN)[N:6]=[C:5]([F:12])[C:4]=1[F:13].O.CCCCCC.C(OCC)C.[ClH:26]>[Cu](Cl)Cl>[Cl:26][C:7]1[C:8]([F:9])=[C:3]([CH2:2][OH:1])[C:4]([F:13])=[C:5]([F:12])[N:6]=1
Reactant: Cl
Reactant: NNc1nc(F)c(F)c(CO)c1F
Agent: Cl[Cu]Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: OCc1c(F)c(F)nc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.35 g (0.0026 mole) of copper (II) chloride in 25 ml of concentrated hydrochloric acid was added slowly at room temperature 0.5 g (0.0026 mole) of (4-hydroxymethyl-2,3,5-trifluoropyridin-6-yl)hydrazine (from Example 6). This mixture was stirred at ambient temperature for two hours and was then refluxed for one hour. After being cooled, the reaction mixture was poured into water and was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, leaving a brown, oily residue. This residue was passed through a short column of silica gel using a hexane/diethyl ether (50/50) mixture as eluant. The appropriate fractions were combined, and the solvent evaporated under reduced pressure, yielding 0.31 g of 2-chloro-4-hydroxymethyl-3,5,6-trifluoropyridine as a yellowish-brown liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]3([CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[CH3:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(#N)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]([CH2:16][N:20]([CH3:19])[C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=3)([OH:15])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Reactant: CNc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
Scandium trifluoromethanesulfonate (609 mg) was added to a mixture of the compound (500 mg) obtained in Step 3 of Example 1, 4-methylaminobenzoic acid (343 mg) and anhydrous acetonitrile (10 mL) under cooling with ice-water, and the mixture was stirred at room temperature for sixty eight hours under nitrogen atmosphere. Water (50 mL) and acetonitrile (10 mL) were added to the resulting mixture and the pH of the mixture was adjusted to above 9 with sodium hydrogen carbonate, insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. Water in the residue was removed by azeotrope with ethanol, soluble components in the residue were dissolved in ethanol and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure and then, the residue was dissolved in water (50 mL) and the pH of the solution was adjusted to 7 by diluted hydrochloric acid. Precipitate was collected by filtration and washed with water and ethyl acetate successively under stirring. The precipitate was collected by filtration and dried to obtain the titled compound (524 mg) as powder.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23]([C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)c1cccc(-c2csc(Cl)n2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(Cl)nc1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 10.1 g (38.3 mmole) of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole in 120 mL of tetrahydrofuran at −78 degrees was added over 20 minutes, 20 mL of 2.5 M n-butyl lithium in hexanes. The mixture was stirred for 2 hours and then 19 mL (93.4 mmole) of ethyl chloroformate was added quickly. The mixture was stirred for 15 minutes, then the cooling bath was removed. After 25 minutes, the reaction was quenched by the addition of 150 mL of 1M hydrochloric acid. The mixture was stirred for 5 minutes, and then diluted with 1 L of ethyl acetate. The ethyl acetate layer was washed twice with 150 mL of water, once with 100 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-hexanes (gradient 10:90-50:50) to give 5.62 g of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a golden oil.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:39])([F:38])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)(=[O:24])=[O:23])[CH2:18][C@@H:17]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:12][CH:11]=1)([OH:9])[C:5]([F:8])([F:7])[F:6].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[ClH:1].[F:8][C:5]([F:6])([F:7])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:24])[CH2:18][C@H:17]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:12][CH:11]=1)([OH:9])[C:3]([F:39])([F:38])[F:2]
Reactant: Cc1cccc(C[C@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c1
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: Cc1cccc(C[C@@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c1

Procedure:
1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(3-methylbenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol hydrochloride. 1H NMR (400 MHz, CD3OD) δ 7.87-7.83 (m, 1H), 7.62-7.58 (m, 3H), 7.24-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.08-6.99 (m, 5H), 4.17-4.11 (m, 1H), 3.88-3.82 (m, 1H), 3.68-3.56 (m, 2H), 3.42-3.34 (m, 1H), 3.12-3.04 (m, 1H), 2.62-2.53 (m, 2H), 2.51-2.46 (m, 1H), 2.31 (s, 3H). m/z (ESI, +ve ion) 578.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.724 μM; GK-GKRP EC50 (LC MS/MS)=0.688 μM.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti](Cl)(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:1][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: Nc1ncccn1
Reactant: COc1ccc(C=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Product: COc1ccc(CNc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 2-aminopyrimidine (104.7 g, 1.1 mol, 1 eq) and 4-methoxybenzaldehyde (150 g, 1.1 mol, 1 eq) in DCM (3 L), was added titanium(IV) chloride triisopropoxide (572 g, 2.2 mol, 2 eq). The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (933 g, 4.4 mol, 4 eq) was added portionwise and stirred overnight at RT. After completion of reaction, the reaction mixture was cooled to 0° C., quenched with ice water and the solid was filtered through celite pad. The layers were separated and the aqueous layer extracted in DCM (1 L). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude material which was purified by column chromatography (Silica [60-120 mesh]; eluted with 20-35% EtOAc in hexane) to yield 125 g (0.58 mol, 52% yield) of the title compound as a white solid. MS (ESI pos. ion) m/z: (M+2)+=216.2. 1H-NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=3.68 Hz, 2H), 7.63 (t, J=6.16 Hz, 1H), 7.23 (d, J=8.48 Hz, 2H), 6.86 (d, J=8.56 Hz, 2H), 6.56-6.54 (m, 1H), 4.42 (d, J=6.32 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[S:12][CH2:11][C:10](=[O:13])[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[C:15]([O:19][Al](OC(C)(C)C)OC(C)(C)C)(C)(C)[CH3:16].[Li+].C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.CN(C1C=CN=CC=1)C.CCCCCC.C(OCC)(=O)C>[C:1]([O:6][CH2:7][CH:8]1[S:12][CH2:11][CH:10]([O:13][C:15](=[O:19])[CH3:16])[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Reactant: CCCC(=O)OCC1OC(=O)CS1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [H-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC(=O)OCC1OC(OC(C)=O)CS1
Temperature: -7.5 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 25 (0.50 g, 2.5 mmol) in anhydrous THF (15 ml) at −5 to −10° C., a solution of 1.0 M lithium tri-t-butoxy aluminum hydride in THF (2.7 ml) was added by syringe pump over 2 hours, while the temperature was maintained at −5 to −10° C. Upon completion of addition, the solution was allowed to stand at 3° C. for 18 hours, and was then warmed to room temperature. DMAP (1.7 mmole, 0.20 g) and acetic anhydride (25.0 mmole, 2.4 ml) were added and the resulting orange solution was stirred at ambient temperature for 3 hours, at which point concentrated NaHCO3 (25 ml) was added. After stirring for 1 hour, the phases were separated, and the aqueous phase was extracted with two additional portions of AcOEt. The organic fractions were combined, dried (MgSO4), filtered and evaporated to afford crude product (0.77 g). After flash chromatography (20 g of silica gel with 20% ethyl acetate in hexane), compound 26 (0.50 g, 2.0 mmol, 80%) was isolated as an oil: TLC (25% ethyl acetate:hexane)—one spot with Rf=0.51; 1H-nmr (CDCl3)—compatible with structure.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21]C(=S)N[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[OH-:24].[Na+]>>[C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([SH:21])[C:18]([OH:23])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:1]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C)c1cc(C=C(S)C(=O)O)cc(C(C)(C)C)c1O

Procedure:
A solution of 174.5 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-thiazolidinone in 1250 ml of a 10% sodium hydroxide solution was heated on a steam bath for four hours. Decolorizing carbon was added and the mixture filtered through a high flow diatomaceous earth pad. The filtrate was chilled by adding ice and treated with 6N hydrochloric acid. The precipitated product was recovered by filtration, washed with water, and dried providing 150 g of the desired subtitled intermediate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:26][CH2:23][CH2:24][CH3:25])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: CCCN
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3 ]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and propylamine in DME. ES-MS m/e (%): 298 (M+H+, 100).
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[O:27][CH2:26][C:25](=[O:28])[NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[C:16]([O:15][C:14](=[O:20])[N:13]([C@@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])[CH2:21][CH:22]1[O:27][CH2:26][C:25](=[O:28])[N:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23]1)([CH3:17])([CH3:19])[CH3:18]
Reactant: Ic1ccccc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNC(=O)CO1)C(=O)OC(C)(C)C
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2ccccc2)C(=O)CO1)C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 104.4 %

Procedure:
tert-Butyl ((R)-1-(naphthalen-1-yl)ethyl)((5-oxomorpholin-2-yl)methyl)carbamate (300 mg, 0.78 mmol) (Intermediate-9), iodobenzene (104 μL, 0.93 mmol), potassium phosphate (330 mg, 1.56 mmol), copper iodide (14.8 mg, 0.078 mmol) and N,N′-dimethylaminoethane (17 μL, 0.15 mmol) were added in 1,4-dioxane. The reaction mixture was heated to 110° C. and further stirred overnight at the same temperature. After reaction completion the reaction mixture was concentrated and the residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain the title compound (375 mg) as an oil. m/z 461.08
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[C-:13]#[N:14].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]([OH:5])[C:13]#[N:14]
Reactant: COc1cc(C=O)c(F)cc1F
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(O)C#N)c(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 98A (506 mg, 2.94 mmol) in ethyl acetate (10 mL) was added a solution of KCN (574 mg, 8.82 mmol) and NaHSO3 (917 mg, 8.82 mmol) dissolved in H2O (10 mL). The reaction was stirred at rt for 48 h. It was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated to give 98B as an oil. It was used for next step without purification.
Reaction SMILES: [C:1](=[O:14])(OC(Cl)C(Cl)(Cl)Cl)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:3]([O:2][C:1]([C:16]1[NH:15][CH:19]=[CH:18][N:17]=1)=[O:14])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)OC(Cl)C(Cl)(Cl)Cl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ncc[nH]1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5 g (17.5 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate dissolved in 10 ml of THF are added at 0° C. to a solution of imidazole (1.2 g; 17.6 mmol) in THF (20 ml) in the presence of 5M aqueous potassium carbonate solution (5 ml). The mixture is stirred for 1 hour at 20° C., and the organic phase is decanted and washed with 10 ml of saturated aqueous NaCl solution.
Reaction SMILES: [Cl-].C[Al+]C.C(O[C:8]([C:10]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:17])[CH3:16])[C:11]=1[CH:18]([NH:27][C:28]1[CH:33]=[C:32]([Cl:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)=[O:9])C>>[Cl:34][C:32]1[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=[C:28]([N:27]2[C:8](=[O:9])[C:10]3[CH:14]=[CH:13][N:12]([CH:15]([CH3:16])[CH3:17])[C:11]=3[CH:18]2[C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[CH:33]=1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(C#N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Product: CC(C)n1ccc2c1C(c1ccc(C#N)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Step H1, but dimethylaluminium chloride (1M in hexanes) was used instead of trimethylaluminium chloride, and 2-[(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step AS2) was used instead of 2-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester to afford the title compound as a brown oil. tR: 2.57 min (HPLC 5); ESI-MS: tR=0.86 min, [M+H]+ 407/409 (LC-MS 1).
Reaction SMILES: [N:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:10]1([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>>[C@H:10]1([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][S:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)(=[O:8])=[O:7])[CH:26]=3)[N:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=S(=O)(Cl)N1CCCC1
Product: O=S(=O)(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCCC1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from pyrrolidine-1-sulfonyl chloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=409.6 (M+H+).
Reaction SMILES: I[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[CH2:14]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[CH2:15][CH2:16][C:17]#[CH:18].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>O.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.[Cu]I>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH3:13])[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(I)ccnc1OC
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C#CCCCN2C(=O)c3ccccc3C2=O)ccnc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of methyl 4-iodo-2-methoxynicotinate (400 mg, 1.36 mmol), 2-(pent-4-ynyl)isoindoline-1,3-dione (318 mg, 1.5 mmol), Pd(PPh3)2Cl2 (47 mg, 0.068 mmol), CuI (7.7 mg, 0.04 mmol) and triethylamine (400 uL) is stirred at room temperature for 20 hours. The mixture is diluted with water, made alkaline with K2CO3 and extracted with CHCl3. The organic layer is washed with brine, water and concentrated under vacuum. The title compound is purified by silica gel column chromatography using hexane/ethyl acetate as eluent. MS m/z 379.1 (M+1).