Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-])=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[CH:5]=[C:4](Cl)[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[CH:5]=[C:4]([N:18]2[CH2:19][CH:20]=[CH:21][CH2:22][CH2:23]2)[N:3]=1
Reactant: COCCOC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: C1=CCNCC1
Solvent: ClC(Cl)Cl
Product: COCCOC(=O)Nc1cc(N2CC=CCC2)nc(N)n1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
2.5 G. of 2-methoxyethyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide are mixed under argon with 3 ml. of 1,2,5,6-tetrahydropyridine and 25 ml. of chloroform. The mixture is stirred at 45° C. for 12 hours, then cooled and washed with 15 ml. of water. The product is extracted with chloroform, the organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue obtained is crystallized from methylene chloride/ether, there being obtained pure 2-methoxyethyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate having a melting point of 136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:31])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:12]=3)[O:8][C:7](=[O:29])[C:6]=2[CH:30]=1.[CH3:32][NH2:33].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:30]=[C:6]([C:7]([NH:33][CH3:32])=[O:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:12]=2)=[O:8])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21.8 %

Procedure:
To a suspension of the 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. precipitate product of Step E) (3.53 g, 7.5 mmol) in tetrahydrofuran (15 mL), methylamine (2.0 M solution in THF, 11 mL, 22 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 45 minutes. Thin layer chromatography then showed the reaction to be complete. Ethyl ether (100 mL) was added, and the reaction mixture was stirred for 2 hours while a precipitate formed. The precipitate was collected by filtration and then recrystallized from acetonitrile to yield a white solid (0.82 g). A second crop of white solid (0.35 g) precipitated from the acetonitrile mother liquor and was collected by filtration. The initial ether/tetrahydrofuran mother liquor was concentrated to dryness, and the residual solid was recrystallized from acetonitrile to yield a third crop of white solid (0.95 g). The three crops were combined, totaling 2.12 g (after drying) of the title compound, isolated as a white solid, melting at 207-208° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>C(#N)C>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Brc1ccc(-n2ccnc2)cc1
Reactant: c1cn[nH]c1
Solvent: CC#N
Product: c1cnn(-c2ccc(-n3ccnc3)cc2)c1

Procedure:
Operating protocol B (82° C., 48 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 535 mg of 1-(4′-bromophenyl)-1H-imidazole (2.4 mmoles), 136 mg of pyrazole (2 mmoles) and 1.2 ml of acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>CS(C)=O>[CH3:24][O:23][C:19]([C:20]1[S:21][C:4]2[CH:3]=[C:2]([Cl:1])[C:9]([O:10][CH3:11])=[CH:8][C:5]=2[CH:6]=1)=[O:22]
Reactant: COc1cc(C=O)c(F)cc1Cl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(OC)c(Cl)cc2s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-2-fluoro-5-methoxybenzaldehyde (0.821 g, 4.35 mmol) in 8.7 mL of DMSO were successively added K2CO3 (1.81 g, 3 eq.) and methyl thioglycolate (0.474 mL, 1.2 eq.), and the mixture was vigorously stirred at 50° C. for 2 h. After cooling, the reaction mixture was poured onto crashed ice/HCl, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated. Flash chromatography (SiO2, hexane/AcOEt=85/15), followed by crystallization from heptane/AcOEt, yielded 0.300 g of the title compound as off-white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[NH2:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[NH:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCCNc1cc(C(=O)OC)ccc1N
Yield: 97 %

Procedure:
A solution of methyl 3-(butylamino)-4-nitrobenzoate (1.1 g) and 10% Pd/C (110 mg) in methanol (20 mL) was shaken under an atmosphere of hydrogen at 50 psi for 2 h. The mixture was filtered through diatomaceous earth, and concentrated under reduced pressure to provide 940 mg of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.13, 6.94, 6.52, 3.72, 3.02, 1.60, 1.42, 0.93.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Cl.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CN(C)CCCl
Reactant: Nc1cc([N+](=O)[O-])cc2c1OCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCNc1cc([N+](=O)[O-])cc2c1OCC2
Yield: 14.9 %

Procedure:
A solution of 7-amino-5-nitro-2,3-dihydrobenzofuran (D4) (2 g) in ethanol (60 ml) was treated with 2-dimethylaminoethyl chloride hydrochloride (3.36 g) and excess sodium carbonate (6 g), and heated at reflux for 4 days under argon. The solvent was evaporated under reduced pressure, and the residue partitioned between water and chloroform. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to leave an oil which was chromatographed on silica, eluting with methanol and chloroform to give the title compound as a viscous red oil (416 mg, 15%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>C(Cl)Cl>[F:21][C:3]1[C:4]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[N:14]3)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=1)=[O:31]
Reactant: O=C=Nc1cccc(F)c1
Reactant: Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of (3-amino-2,6-difluorophenyl)(quinoxalin-6-yl)methanone (40 mg, 0.15 mmol, 1.0 eq.) in DCM (5 mL) were added TEA (42.4 mg, 0.42 mmol, 3.0 eq.) and 1-fluoro-3-isocyanatobenzene (23.3 mg, 0.17 mmol, 1.2 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was purified via flash column chromatography (PE/EA=1/1, v/v) to afford 1-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea (10.5 mg, 16.7%). LRMS (M−H+) m/z caculated 423.1. found 423.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.31 (s, 1H), 9.11-9.13 (d, 2H), 8.76 (s, 1H), 8.46 (s, 1H), 8.33-8.34 (m, 3H), 7.49-7.52 (d, 1H), 7.32-7.35 (m, 2H), 7.10-7.12 (d, 1H), 6.82 (t, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])#[N:2]>CO.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])#[N:2]
Reactant: COC(=O)C=CC=Cc1ccccc1C#N
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1ccccc1C#N
Reaction time: 6 h

Procedure:
Methyl 5-(2-cyanophenyl)-2,4-pentadienoate (15.2 g, 71.4 mmol) was dissolved in methanol (600 ml). After adding palladium black (0.6 g), the solution was subjected to catalytic reduction for 6 hours at room temperature and atmospheric pressure. After the reaction, the catalyst was filtered off and the filtrate was concentrated under vacuum to give an oily product in an amount of 16.47 g (yield: quantitative).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.Cl.[NH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([CH:36]=[CH:35][CH:34]=1)[NH:30][C:21]1[C:20]2[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][CH:14]3[CH2:15][CH2:16][N:11]([S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH2:12][CH2:13]3)[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)CCCCl)CC1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
3-chloropropanesulfonylchloride (174 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (190 mg; starting material for Example 16) and diisopropylethylamine (140 mg) in methylene chloride (5 ml) at ambient temperature and the reaction mixture was stirred for 16 hours. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piperidin-4-yloxy}-7-methoxyquinazoline as a brown gum (0.15 g); Mass Spectrum: (M+H)+ 543.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([N:6]1[N:5]=[C:4]([Cl:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 0.92 g, 22.8 mmol) was added in one portion to a stirred suspension of 4-chloro-2H-phthalazin-1-one (3.74 g, 20.7 mmol) in anhydrous DMF (80 mL). The reaction was stirred for 15 min and then cooled to 10° C. Benzyl bromide (4.25 g, 24.8 mmol) was added drop wise and the reaction mixture was then stirred for 21 h at rt. After that time the reaction was diluted with ethyl acetate (200 mL), washed with water (5×80 mL) then brine (80 mL), dried over MgSO4 and concentrated under reduced pressure. The resulting pale yellow solid was suspended in hexanes (80 mL) and stirred for 3 h. After that time, the precipitate was collected by filtration, washed with hexanes and dried to give 2-benzyl-4-chloro-2H-phthalazin-1-one (5.05 g, 90%) as white solid: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.97-7.83 (m, 2H), 7.50 (d, J=6.8 Hz, 2H), 7.36-7.7.29 (m, 3H), 5.37 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C:11]1([CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a stirred solution of [1-(tert-butoxycarbonylamino-methyl)-cyclopropyl]-carbamic acid benzyl ester (0.912 g, 2.85 mmol) in 120 mL of methanol was added 10% Pd on carbon (200 mg) in one portion at room temperature. Then the mixture was degassed by bubbling hydrogen for 5 minutes then stirred under a hydrogen atmosphere at room temperature for 16 hours. The mixture was filtered to remove the catalyst and the filtrate was evaporated at 40° C. under reduced pressure to give tert-butyl (1-aminocyclopropyl)methylcarbamate (0.4 g, 75.4%) as a colorless oil which was used into next step without further purification. MS: (M+H)+=187.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 2-methoxycarbonyl-5-(4-fluorophenyl)thiophene (1.15 g) in methanol (10 ml) and tetrahydrofuran (10 ml) was added an aqueous solution of sodium hydroxide (1N, 7.3 ml) followed by stirring at 60° C. for 3 hours. To the mixture was added hydrochloric acid (1N, 8 ml). The resulting precipitate was collected by filtration and dried to give 5-(4-fluorophenyl)thiophene-2-carboxylic acid (1.06 g, 98.1%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:10]=[C:9]([CH3:19])[C:8]=1[CH3:20])(=O)=O.P(O)(O)(O)=O.[S:28]1[C:36]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]=2[CH:30]=[C:29]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:19][C:9]1[C:8]([CH3:20])=[C:7]([C:29]2[S:28][C:36]3[CH:35]=[CH:34][N:33]=[CH:32][C:31]=3[CH:30]=2)[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:10]=1
Reactant: OB(O)c1cc2cnccc2s1
Reactant: Cc1cccc(-n2nc(C)c(C)c2OS(=O)(=O)C(F)(F)F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P(O)(O)O
Solvent: C1COCCO1
Product: Cc1cccc(-n2nc(C)c(C)c2-c2cc3cnccc3s2)n1
Temperature: 100 °C

Procedure:
In a 100 mL three neck round bottom flask fitted with a reflux condenser was added 3,4-dimethyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl trifluoromethanesulfonate (0.90 g. 2.7 mmol, 1.2 equivalents), thieno[3,2-c]pyridin-2-ylboronic acid trihydrogen phosphate (0.72 g, 2.6 mmol, 1 equivalent), potassium phosphate tribasic and 20 mL dioxane. The flask was evacuated under a vacuum and the suspension bubbled with nitrogen gas. To this was added PdCl2 (dppf) (Strem, Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, 0.54 g, 0.65 mmol, 0.3 equivalents). Again the flask was evacuated under a vacuum and the suspension bubbled with nitrogen gas. The reaction was heated to 100° C. for 16 hours and then cooled to room temperature.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:22]1(O)[CH2:27]CC[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:8]1)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reactant: OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C(=O)OC1CCCCC1)=C(c1ccccc1)c1ccccc1
Reaction time: 6 h
Yield: 67 %

Procedure:
139 g (0.5 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 200 ml of cyclohexanol and 10 g of Na2CO3 were reacted together at 150° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 6 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried, giving 111 g (67%) of cyclohexyl 2-cyano-3,3-diphenylacrylate as a colorless solid. [λmax 300 nm; E11, (MeOH) 381]
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([N:11]([C:19]3[CH:20]=[N:21][C:22]([N:26]([CH3:28])[CH3:27])=[CH:23][C:24]=3[CH3:25])C(=O)OC(C)(C)C)[N:7]([CH2:29][CH:30]=C)[C:6]=2[C:5]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:4][CH:3]=1.B.[O:38]1CCC[CH2:39]1.O.O.O.O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:19]3[CH:20]=[N:21][C:22]([N:26]([CH3:28])[CH3:27])=[CH:23][C:24]=3[CH3:25])[N:7]([CH2:29][CH2:30][CH2:39][OH:38])[C:6]=2[C:5]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:4][CH:3]=1
Reactant: C=CCn1c(N(C(=O)OC(C)(C)C)c2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: C1CCOC1
Agent: B
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCO)c12
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a solution of tert-butyl [4-chloro-7-(1-ethylpropyl)-1-prop-2-en-1-yl-1H-benzimidazol-2-yl][6-(dimethylamino)-4-methylpyridin-3-yl]carbamate (450 mg, 0.88 mmol) in tetrahydrofuran (8.8 mL) was added borane-tetrahydrofuran complex (1.18 M in tetrahydrofuran, 7.46 mL, 8.8 mmol) at room temperature. After stirring for 2 hr, the mixture was poured into a suspension of sodium peroxyborate tetrahydrate (2.03 g, 13.2 mmol) in water (10 mL). The mixture was stirred for 14 hr at room temperature. The mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol (5 mL) followed by addition of 6 N hydrochloric acid (5 mL). After stirring for 14 hr at room temperature, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (110 mg, 0.26 mmol, 29%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][C:14](=[O:17])[CH2:15]Br)C>CN(C=O)C>[CH3:11][O:13][C:14](=[O:17])[CH2:15][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Sc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1cccc(Cl)c1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
In analogy to example 81.1, 4.34 g (0.030 mol) of 3-chloro-benzenethiol in 50 mL of DMF at 0° C. were treated with 1.32 g (0.033 mol, 1.1 eq) of NaH (55% in oil) over 45 min. 4.82 g (0.032 g, 1.05 eq) of bromo-acetic acid ethyl ester were added, and stirring was continued for 2 hours. Workup and purification gave 5.9 g (91%) of (3-chloro-phenylsulfanyl)-acetic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:31].[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:22][C:21]=2[Cl:31])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.68 g, 13.1 mmol) in dry DMF (95 ml) is added sodium hydride (577 mg of a 60% dispersion in mineral oil, 14.41 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-ethanesulfonyl-benzene (6.6 g, 22.2 mmol) and sodium iodide (3.3 g, 22.2 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (600 ml) and extracted with 1:1 ethyl acetate/diethyl ether (4×300 ml). The organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:2) to yield the titled product. (MH+ 421)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[N:14]([CH3:18])[C:13](=[O:15])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A THF (10 ml) solution of the (5S)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (3.71 g, 16.2 mmols) was added dropwise to a THF (70 ml) suspension of NaH (60% oil disp. 778 mg, 19.4 mmols), with the system being cooled with ice, whereafter the mixture was stirred for 30 minutes at room temperature. To the mixture, MeI (5.0 ml, 81 mmols) was added during cooling with ice, and the mixture was stirred for 15 hours at room temperature. During cooling with ice, a saturated aqueous solution (50 ml) of NH4Cl was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3), and the organic layer was dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 150 g, MeOH—CHCl3 3:97 v/v) to obtain (5S)-5-[(tert-butyldimethylsilyloxy)methyl]-1-methylpyrrolidin-2-one (3.86 g, 97.9%): [α]D29+3.46 (c 1.13, CHCl3). IR νmax (film) cm−1: 1682. 1H-NMR (CDCl3)δ: 3.73 (1H, dd, J=10.2, 3.3 Hz), 3.60 (1H, dd, J=10.2, 4.1 Hz), 3.55 (1H, quint, J=4.1 Hz), 2.85 (3H, s), 2.50-2.37 (1H, m), 2.35−2.23 (1H, m), 2.15-2.01 (1H, m), 1.89-1.77 (1H, m), 0.89 (9H, s), 0.06 (3H, s), 0.05 (3H, s). MS m/z: 228 (M+−15), 186, 98 (100%). HRMS: Calculated for C11H22NO2Si: 228.1420 (M+−15). Found: 228.1441 (M+−15).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][C:6]=2[I:15].Cl>[Fe]>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH2:12])=[CH:7][C:6]=2[I:15]
Reactant: O=[N+]([O-])c1cc(I)c2ncc(Br)cc2c1
Agent: [Fe]
Agent: Cl
Product: Nc1cc(I)c2ncc(Br)cc2c1

Procedure:
In a similar procedure to Stage 1, Step 1 of Example 6, 3-bromo-8-iodo-6-nitro-quinoline was treated with concentrated hydrochloric acid and iron powder to give 3-bromo-8-iodo-quinolin-6-ylamine as a beige powder ((M+1)+ 351).