Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C@H:13]1[CH2:17][CH2:16][NH:15][C@H:14]1[CH3:18].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([N:15]2[CH2:16][CH2:17][C@H:13]([OH:12])[C@@H:14]2[CH3:18])[C:7]([CH3:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1O
Reactant: Cc1cc(C#N)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)c(Cl)cc1N1CC[C@H](O)[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution (25 mL) of 2-chloro-4-fluoro-5-methylbenzonitrile (848 mg) in dimethyl sulfoxide were added 0.9M-dimethyl sulfoxide solution (5.56 mL) of (2S,3S)-3-hydroxy-2-methylpyrrolidine and lithium carbonate (370 mg), and the mixture was stirred at 100° C. for 1 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) and crystallized from ethyl acetate-hexane to give the title compound as a colorless solid (yield: 374 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[N:4]([CH2:23][C:24](NC2C=CC=CC=2)=[O:25])[N:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[F:41])[NH2:37]>>[F:33][C:34]1[CH:35]=[C:36]([NH:37][C:24](=[O:25])[CH2:23][N:4]2[C:5]([NH:7][C:8]3[CH:17]=[CH:16][N:15]=[C:14]4[C:9]=3[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12](=[O:18])[NH:13]4)=[CH:6][C:2]([CH3:1])=[N:3]2)[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: Nc1ccc(F)c(F)c1
Reactant: Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n(CC(=O)Nc2ccccc2)n1
Product: Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n(CC(=O)Nc2ccc(F)c(F)c2)n1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 308 and 3,4-di-fluoroaniline to provide 309. LC-MS (M+H=461, obsd.=461).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:5](N(OC)C)=[O:6].[CH3:18][Mg]Br.O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:18])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:16])[CH3:17]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(OC(C)C)c(F)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OC(C)C)c(F)c1
Yield: 98.8 %

Procedure:
To a solution of 3-fluoro-4-(1-methylethoxy)-N-methoxy-N-methylbenzamide (117 mg, 0.485 mmol) in tetrahydrofuran (2.4 mL), methylmagnesium bromide (750 μL, 0.728 mmol) was added under ice-cold conditions, and the resultant mixture was stirred for 1 hour under ice-cold conditions. The reaction solution was added with water and 5% aqueous solution of hydrochloric acid under ice-cold conditions, and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-(3-Fluoro-4-(1-methylethoxy)phenyl)ethanone (94 mg, yield 99%) was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([S:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH:1]1([S:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)C2CCCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1cccc(CS(=O)(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of 1-[(cyclopentylsulfonyl)methyl]-3-nitrobenzene (4.9 g) in ethanol (37 mL) and water (11.1 mL) was treated with ammonium chloride (4.9 g) at 0° C. Then zinc powder (5.9 g) was cautiously added in portions and stirred for 3 hours at room temperature. Then the mixture was filtered over cellite, washed with ethanol, condensed to dryness, treated with ethyl acetate, washed with brine, dried with sodium sulfate and condensed to dryness. Crystallization of the crude product (4.5 g) from diethyl ether furnished the pure title compound (3.6 g).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[OH-].[Na+].Br[CH:25]([CH2:33][CH3:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:21][CH:25]([CH2:33][CH3:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reactant: CCC(Br)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 35.9 %

Procedure:
Tetrabutylammonium chloride (0.55 g, 1.98 mmol) was added to a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol, (3.50 g, 12.1 mmol) in toluene (35 mL) at ambient temperature under nitrogen. An aqueous solution of sodium hydroxide (50% (w/w), 11.7 mL) was added under vigorous stirring at room temperature, followed by t-butyl 2-bromobutyrate (5.41 g, 24.3 mmol). The resulting mixture was heated to 50° C. and additional t-butyl 2-bromobutyrate was added after 1.5 hours (2.70 g, 12.1 mmol), 3.5 hours (2.70 g, 12.1 mmol) and 4.5 hours (2.70 g, 12.1 mmol) and stirred for 12 hours in total. After cooling to room temperature, ice water (25 mL) was added and the resulting two phases were separated. The organic phase was washed with a mixture of NaOH (5%) and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0→95:5) as eluent. Concentration of the appropriate fractions afforded 1.87 g (36% yield) of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 0.85-1.10 (m, 6H), 1.35-1.54 (m, 11H), 1.53-1.87 (m, 4H), 1.96-2.26 (m, 4H), 2.70-3.02 (m, 8H), 3.31 (dt, 1H), 3.51-3.67 (m, 2H), 5.10-5.58 (m, 10H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:20]([O-:22])=[O:21])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1
Reactant: Cc1cc(-c2cc3ccccc3n2C)ccc1C#N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(-c2cc3cc([N+](=O)[O-])ccc3n2C)ccc1C#N

Procedure:
6.9 g (28 mmol) of 4-(1-methyl-1H-indol-2-yl)-methyl-benzonitrile are placed in 50 ml conc. sulphuric acid. At 2° C. 2.9 g (28 mmol) of potassium nitrate are added batchwise, whereupon the temperature rises to 10° C. After 30 minutes at 2° C. the mixture is poured onto ice and the product precipitated is suction filtered, washed with ice water, dried and recrystallised from acetone.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
2-Methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.23 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.2 g of 5-amino-3-phenylethynyl-1H-indazole in 3.5 ml of pyridine. The reaction mixture is then stirred for 1.5 hours at 0° C. and then 2 hours at a temperature in the region of 20° C., and is then diluted with 10 ml of water. After settling out, the aqueous phase is washed with 3 times 15 ml of ethyl acetate. The organic extracts are pooled, washed with 3 times 5 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 25 g of silica (particle size 20-40 μm), eluting with pure dichloromethane then successively with dichloromethane/methanol (99.5/0.5; 99/1 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue is recrystallized from 5 ml of isopropanol in the presence of 3S black. The crystals are filtered through sintered glass, washed with diisopropyl ether, partially dried, and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. for 2 hours. 66 mg of 2-methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of an off-white powder melting at 198° C. (analysis C22H17N3O4S2 % calculated C, 58.52; H, 3.79; N, 9.31; O, 14.17; S, 14.20. % found C, 58.37; H, 3.88; N, 9.11; S, 13.73).
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]=O)[CH:12]=[CH:11]2.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]=[N:2][CH3:1])[CH:12]=[CH:11]2
Reactant: CN
Reactant: COc1ccc2cc(C=O)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: CN=Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96 %

Procedure:
A mixture of an 8.03M solution of methylamine in ethanol (67 mL, 537 mmol) and 50 mL of methylene chloride was added dropwise under nitrogen to a mixture of 6-methoxy-naphthalene-2-carbaldehyde (20 g, 107.4 mmol), magnesium sulfate (20 g) and 200 mL of methylene chloride. The mixture stirred at room temperature under nitrogen for 17 h. The MgSO4 was removed by filtration and the solvent was removed under reduced pressure to give (6-methoxy-naphthalen-2-ylmethylene)-methyl-amine (20.59 g, 96%) as a yellow solid, mp 109-110° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][NH2:23]>CO.C(O)(=O)C>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][N:23]=[C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: Cn1c(NN)nc2ccccc21
Reactant: COc1cccnc1C(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccnc1C(C)=NNc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl-3-methoxypyridine (0.50 g, 3.31 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.54 g, 3.31 mmol) in 10 ml of methanol is stirred at room temperature for 3 days after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of 20 ml of methanol and 10 ml of water. Yield: 0.87 g (89% of theory).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C(=O)C)[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].O[Li].O.CO.C1COCC1.O.OC1C=CC=C(O)C=1C(OC)=O>CCCCCC.CCOC(C)=O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1c(OC(C)=O)cccc1OC(C)=O
Agent: COC(=O)c1c(O)cccc1O
Agent: [Li]O
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cccc1OC(C)=O
Yield: 27.2 %

Procedure:
A solution of Part C methyl 2,6-diacetoxybenzoate (3.4 g, 14 mmol) and LiOH.H2O (60 mg, 1.5 mmol) in 2:2:1 MeOH/THF/H2O (30 mL) was stirred for 2 hr at 20° until tlc analysis (4:1 hexane/EtOAc) revealed comparable amounts of starting bis-acetate and methyl 2,6-dihydroxybenzoate. The solution was quenched with pH 7 Na2HPO4 buffer, diluted with H2O prior to 4 EtOAc extractions. The combined organic phase was washed with H2O 2×, brine 1× prior to drying over Na2SO4. After removal of the volatiles, chromatography on silica gel using 3:2 hexane/CH2Cl2 eluted 1.1 g of a 1:2 mixture of methyl 2,6-dihydroxybenzoate/methyl 2-acetoxy-6-hydroxybenzoate followed by 0.7 g of pure methyl 2-acetoxy-6-hydroxybenzoate. Re-chromatography of the mixed fraction yielded another 0.8 g of methyl 2-acetoxy-6-hydroxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4](F)[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4]([O:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=2[CH3:27])[CH:3]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(Cl)cc1F
Reactant: Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(F)ccc1Oc1cc(Cl)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of 4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (500 mg, 1.87 mmol) in NMP (5 mL) was added 4-fluoro-2-methyl-phenol (709.5 mg, 5.62 mmol) and Cs2CO3 (1.83 g, 5.62 mmol) and the reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with 3N NaOH (3×), water, brine, dried (Na2SO4) and evaporated to dryness. Purification by silica gel column chromatography gave 4-chloro-2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide (13a) (300 mg, 43%) as a tan solid. ESI-MS m/z calc. 372.07, found 373.1 (M+1)+; Retention time: 1.5 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.48 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.30 (dd, J=7.9, 1.6 Hz, 2H), 7.21 (d, J=8.7 Hz, 1H), 7.09 (d, J=5.5 Hz, 2H), 6.75 (dd, J=5.1, 1.8 Hz, 2H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.16 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.O.[NH2:32][NH2:33]>C(O)CCC.CO>[Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:32][NH2:33])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=S)C2)cc1
Reactant: NN
Solvent: CO
Solvent: CCCCO
Solvent: O
Product: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3N=C(NN)C2)cc1
Temperature: 100 °C

Procedure:
A mixture of 7,8-dichloro-2,3-dihydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (452 mg, 1.0 mmol), hydrazine hydrate (100 mg, 2 mmol) and red mercuric oxide (217 mg, 1.0 mmol) in n-butanol was heated at 100° C. for 30 minutes. The mixture was diluted with methanol (300 ml), filtered through Arbocel filter aid and the filtrate was concentrated under reduced pressure. The crude product was used directly for Example 32.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:14]O)[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>C(Cl)Cl.C(OCC)(=O)C.[Cl-].[Na+].O.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:14][N:32]2[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]2=[O:33])[CH2:12][CH2:13]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCCC1(CO)CC1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [K]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC1(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 80 °C
Yield: 37.5 %

Procedure:
To solution of {1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropyl}-methanol (0.41 g, 1.78 mmol) in CH2Cl2 (18 mL) was added Et3N (0.50 mL, 3.59 mmol) followed by methanesulfonyl chloride (0.21 mL, 2.71 mmol). The resultant mixture was stirred at room temperature for 17 hours. The mixture was diluted CH2Cl2 (50 mL), washed with brine (3×20 mL), dried (Na2SO4), and concentrated. The resultant oil was dissolved in DMF (16 mL), treated with potassium phthalimide (0.606 g, 3.27 mmol), and the mixture was heated at 80° C. for 6 hours then cooled to room temperature. The mixture was diluted with ethyl acetate (40 mL), brine (20 mL), and water (10 mL) and the phases were separated. The organic phase was washed with brine (3×10 mL), dried (MgSO4), and concentrated. The crude material was purified by column chromatography on silica gel (20:1 hexanes-ethyl acetate) and provided 0.24 g (38%) of 2-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-cyclopropylmethyl}-isoindole-1,3-dione as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[C:19]1(S)[CH:24]=[CH:23]C=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][C:18]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Sc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. ES-MS m/e (%): 295 (M+H+, 100).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:38])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)=[O:4].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:39](=[O:42])[CH:40]=[CH2:41])[CH3:38])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)[C@H](C)N
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Yield: 24 %

Procedure:
205 mg of (2S)-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 10 ml of a mixture of THF and water (3:1), and reacted with 0.047 ml of acryloylchloride at room temperature for 1 hour after adding 97 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (55 mg, 24%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[OH:15].[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O>CN(C=O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[O:15][CH2:30][CH:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:29][CH2:28]1
Reactant: COc1ccc2nccc(O)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nccc(OCC3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C

Procedure:
NaH dispersion (55% in mineral oil, 88 mg, 2 mmol) was added to a suspension of 6-methoxy-4-hydroxyquinoline (350 mg, 2 mmol) in DMF (4 ml) and stirred at room temperature until a solution formed. trans-Methanesulphonic acid 4-tert-butoxycarbonylaminocyclohexylmethyl ester (635 mg, 2 mmol) was added and the reaction mixture was stirred overnight at 80° C. Water was added to the mixture and extraction was carried out with ethyl acetate. Organic extracts washed with water, dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel (DCM/MeOH 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+].[ClH:19]>O>[ClH:19].[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1)[NH2:15]
Reactant: O=N[O-]
Reactant: CN(C)S(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(C)S(=O)(=O)Cc1ccc(NN)cc1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a suspension of 4.30 g (20.1 mmol, 1.0 equiv.) of 4-amino-N,N-dimethylbenzenemethanesulfonamide in 40 mL of concentrated aqueous hydrochloric acid and 20 mL of water cooled to 0° C. was added a solution of 1.38 g (20.1 mmol, 1.0 equiv.) of sodium nitrite in 20 mL of water dropwise. The reaction mixture became homogeneous during the addition. The reaction was stirred for fifteen minutes at 0° C. after the addition was complete. Meanwhile a solution of 22.6 g (100 mmol, 5.0 equiv.) of stannous chloride dihydrate in 40 mL of concentrated aqueous hydrochloric acid was prepared and cooled to -40° C. The solution of the diazonium salt was filtered into the stannous chloride solution. The reaction was allowed to warm to room temperature over the course of one hour. The reaction was then recooled to 0° C. and the precipitated product was collected by filtration. The solid was dried at 65° C. at 0.05 mm Hg for 45 minutes to yield 5.02 g (94%) of 4 -hydrazinyl-N,N-dimethylbenzenemethanesulfonamide hydrochloride.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]([CH3:16])([CH3:15])[C:5]1=[O:17].Cl>CCO>[OH:14][CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH3:3])[C:5](=[O:17])[C:6]1([CH3:16])[CH3:15]
Reactant: CN1C(=O)C(C)(C)C(=O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)C(C)(C)C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
NaBH4 (excess amount) is added to a solution of 1,3,3-Trimethyl-1H-quinoline-2,4-dione (330 mg, 1.62 mmol) in EtOH (8 mL) at 0° C. The resulting mixture is slowly warmed up to room temperature. After 1 h, HCl (10%, 3 mL) is added dropwise. The solvent is removed under vacuum, the residue is dissolved into ether and washed with water, brine, and dried over anhydrous Na2SO4. After concentration, the title compound is yielded (275 mg, 82% yield).