Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.C([O:21][C:22](=O)[C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C>C(O)C>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:22](=[O:21])[C:23]([OH:31])=[C:24]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: O=C1C(O)=C(c2ccccc2)C(c2ccccc2F)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 2-Fluoro-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-phenyl-propionic acid ethylester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.[CH2:13]([Li])[CH2:14]CC.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[N:20]=1.C(Cl)(=O)C(Cl)=O.C([Mg]Br)#C>C1COCC1>[Cl:25][C:21]1[N:20]=[C:19]([CH:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10](=[O:12])[C:13]#[CH:14])[CH:24]=[CH:23][CH:22]=1
Reactant: [Li]CCCC
Reactant: Clc1cccc(Cl)n1
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: C#C[Mg]Br
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: C#CC(=O)C(c1cccc(Cl)n1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-dichlorophenylacetic acid (4.1 g) in THF (100 mL) was added n-butyl lithium (1.4 M, in hexanes, 30 mL) slowly at 0° C. The resulting mixture was stirred at 0° C. for ½ hr and then cooled to −78° C. To this solution was added 2,6-dichloropyridine (2.96 g) at −78° C. then warmed to room temperature and stirred for approximately 1-3 hours. The mixture was re-cooled to −78° C. and oxalyl chloride (1.9 mL) was added. The resulting mixture was warmed to room temperature and stirred for 1 hr. The solution was re-cooled to −78° C. and ethynylmagnesium bromide (0.5 N, 44 mL) was added. The mixture was slowly warmed to room temperature. The reaction was quenched with 0.1 N HCl, and extracted with ether. The organic layer was separated, washed with brine solution, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel (hexanes/methylene chloride=3/1) to give desired compound as a yellowish solid (0.59 g).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=1[CH2:24][NH2:25]>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:25]([CH2:24][C:17]2[C:18]([F:23])=[CH:19][CH:20]=[C:21]([F:22])[C:16]=2[F:15])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1c(F)ccc(F)c1F
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1c(F)ccc(F)c1F

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-(2,3,6-trifluorophenyl)methanamine to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[O:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][NH2:45]>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:45][CH2:44][C@@H:40]4[CH2:41][CH2:42][CH2:43][O:39]4)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: NC[C@@H]1CCCO1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). (S)-(tetrahydrofuran-2-yl)methanamine (45.6 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography using dichloromethane and methanol as eluent. The fractions containing the title compound were pulled together and the solvent was evaporated yielding (S)-tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (50.0 mg, 21.94%). MS (ES+) m/z 506.4 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccncc3)cc(Cl)n2n1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccncc3)nc3cc(C)nn23)CC1
Yield: 9.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (13D, 100 mg, 0.305 mmol) and N-(piperidin-4-yl)acetamide (87 mg, 0.610 mmol) in NMP (1 mL) was stirred at room temperature overnight. The mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (10-40% MeCN)/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12 mg, 9%). 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.45 (d, J=5.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=6.1 Hz, 2H), 6.08 (s, 1H), 4.28 (br. s., 2H), 3.88 (br. s., 2H), 3.15 (d, J=3.0 Hz, 2H), 2.40-2.47 (m, 2H), 2.30-2.37 (m, 3H), 1.85-1.96 (m, 2H), 1.81 (s, 3H), 1.46-1.62 (m, 3H). ESI-MS: m/z 434.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[F:9][C:10](I)([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]>>[F:9][C:10]([F:27])([C:2]1[CH:7]=[CH:6][C:5]([C:10]([F:27])([F:9])[C:11]([F:25])([F:26])[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:4][CH:3]=1)[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Ic1ccc(I)cc1
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 70 °C
Yield: 78.6 %

Procedure:
A 100 ml Schlenk flask equipped with a stir bar was flame-dried and then charged with 1,4-diiodobenzene (3.30 g, 10 mmol), Cu powder (5.08 g, 80 mmol), and 2,2′-bipy (156 mg, 1 mmol). The flask was evacuated and back-filled with argon three times. Anhydrous dimethylsulfoxide (30 mL) was added via a syringe. Perfluorohexyl iodide (6.5 mL, 30 mmol) was added dropwise while stirring. Upon completion of addition, the reaction mixture was heated to 70° C. for 72 hours then removed from heat. The reaction mixture was poured into 100 mL H2O/100 mL diethyl ether and stirred vigorously for 30 min. Solid residues were removed by filtration, and the organic layer was washed twice with dilute NH4OH solution, twice with water, dried over MgSO4. The solvent was removed by evaporation under reduced pressure, and the resulting off-white solids were subjected to sublimation to give S5 as white solids (5.61 g, 78%). 1H NMR (300 MHz, CDCl3): δ 7.77 (s, 4H). 19F NMR (282 MHz, CDCl3): δ −126.58 (4F), −123.26 (4F), −122.15 (4F), −121.87 (4F), −111.71 (4F), −81.16 (6F).
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[C:28]3[C:35]([CH3:36])=[C:34]([C:37]([OH:39])=[O:38])[S:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O[N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47]>CN(C=O)C>[O:47]=[C:42]1[CH2:43][CH2:44][C:45](=[O:46])[N:41]1[O:38][C:37]([C:34]1[S:33][C:29]2[N:30]=[CH:31][N:32]=[C:27]([NH:26][C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[O:18][C@H:14]3[CH2:15][CH2:16][CH2:17][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[CH2:13]3)[C:28]=2[C:35]=1[CH3:36])=[O:39]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)ON2C(=O)CCC2=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (290 mg) was added into a solution of 4-[2-((S)-1-tert-butoxycarbonyl-piperidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (640 mg) and N-hydroxysuccinimide (218 mg) in anhydrous DMF (10 ml). The reaction was stirred at room temperature overnight. A further aliqout of EDC (58 mg) and N-hydroxysuccinimide (44 mg) were added and the reaction stirred for further 2 h. The DMF was removed in vacuo and the residue co-evaporated from toluene. The solid was portioned between EtOAc and water. The organic layer was separated and washed with brine. The combined organics were passed through a phase separator and concentrated in vacuo.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([S:16]([O-:19])(=[O:18])=[O:17])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].[K+:20].Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[OH:23][N:22]1[C:14](=[O:13])[C:7]2[CH:6]=[CH:5][C:4]([S:16]([O-:19])(=[O:18])=[O:17])=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12].[K+:20]
Reactant: O=C1OC(=O)c2ccc(S(=O)(=O)[O-])c3cccc1c23
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1c2cccc3c(S(=O)(=O)[O-])ccc(c23)C(=O)N1O
Yield: 102.2 %

Procedure:
4-Sulfo-1,8-naphthalic anhydride potassium salt (2.0 g, 6.2 mmol) and hydroxylamine hydrochloride (0.9 g, 12.4 mmol) were reacted in pyridine (50 mL) following the procedure of Example 1. The solids formed were filtered, washed with ethanol, and dried to give 2.1 g of the title compound, mp >380° C.;
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:8]=2[CH:24]=1)(O)=[O:2].[CH2:25]([S:30]([NH2:33])(=[O:32])=[O:31])[CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:14]([CH2:13][N:9]2[C:8]3[CH:24]=[C:4]([C:1](=[O:2])[NH:33][S:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[CH:5]=[CH:6][C:7]=3[N:11]=[C:10]2[CH3:12])[N:15]=1
Reactant: CCCCCS(N)(=O)=O
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1cc2ccccc2cn1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3cc4ccccc4cn3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.2 %

Procedure:
N,N′-carbonyldiimidazole (0.324 g) was added to a solution of 6-carboxy-1-(isoquinolin-3-ylmethyl)-2-methylbenzimidazole (0.413 g) as obtained in Production Example 5 in N,N-dimethylformamide (10 ml) all at once and the mixture was stirred at room temperature for 1.5 hour. Then, 1-pentanesulfonamide (0.302 g) and diazabicyclo-undecene (0.304 g) were added thereto, and the resulting mixture was stirred at 100° C. for 6.5 hour. The reaction solution was concentrated, brine was added to the concentrate, and the mixture was extracted with chloroform. The organic layer was concentrated and the residue was purified by silica gel column chromatography (eluate: methanol/chloroform=1/19) followed by recrystallization from hexane/ethyl acetate (2/3) to yield the desired compound, 1-(isoquinolin-3-ylmethyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole (13) (0.142 g).
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:18][N:19]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]1[CH2:25][C:26]([O:28][CH3:29])=[O:27].[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31]>C(O)C.CCOCC>[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31].[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:23]2[N:19]([CH3:18])[C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][C:22]=2[CH3:24])=[CH:5][CH:6]=1
Reactant: CN=C(Cl)c1ccc(OC)cc1
Reactant: COC(=O)Cc1cc(C)cn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: CCO
Product: CN=C(c1ccc(OC)cc1)c1c(C)cc(CC(=O)OC)n1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
N-Methyl 4-methoxybenzimidoyl chloride (6.67 g, 36.4 mmole) was placed in a dry 50 ml round bottom flask and treated with alcohol free chloroform (13 ml) and chlorosulfonic acid (0.42 g, 3.6 mmole). The reaction was blanketed with nitrogen and stirred while methyl 1,4-dimethyl-1H-pyrrole-2-acetate (6.03 g., 36.1 mmole) was added dropwise over a period of about five minutes. The reaction was stirred overnight, then heated at 40° C. for two hours. The reaction was quenched with saturated aqueous sodium bicarbonate. The phases were separated, and the organic phase was washed with saturated aqueous sodium bicarbonate and water, then dried over sodium sulfate. The chloroform was removed under reduced pressure to yield a red viscous liquid. The crude product was dissolved in absolute ethanol and treated with 70% perchloric acid (5.7 g, 40 mmole). The solution was cooled and treated with ether to induce crystallization. The yellow solid was isolated by filtration and washed with cold ethanol to yield 10.5 g (64%) of the title compound, m.p. 123°-129° C. (dec).
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[NH3:43]>CC(N(C)C)=O>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][S:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:41])/[C:20]/2=[CH:19]\[C:16]1[NH:15][C:14]([CH3:42])=[C:13]([C:11]([NH2:43])=[O:12])[C:17]=1[CH3:18])(=[O:31])=[O:30]
Reactant: N
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added ammonia (2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(N)c1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A suspension of 3-amino phenylacetic acid (5.0 g, 33 mmol) in methanol (50 ml) at 0° C. under argon was slowly treated with thionyl chloride (19.4 g, 165 mmol). After completion of addition, the reaction mixture was allowed to warm up to room temperature and stirred for 16 hours. The solvent was evaporated and the residue was triturated with ethyl ether to give 3-amino phenylacetic acid methylester hydrochloride (5.3 g, 96.8% ) as a colorless solid. 1H NMR (CDCl3) δ10.6 (s, 2H), 7.42 (m, 4H), 3.68 (s, 3H), 3.66 (s, 2H); 13C NMR (CDCl3) 172.5, 137.3, 133.1, 131.2, 130.8, 125.9, 123.7, 53.5, 41.5.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][CH2:4][C:5]2[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(CCN)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Reaction time: 2 h
Yield: 93.6 %

Procedure:
1 g of methyl 4-(2-aminoethyl)-2-fluorophenoxyacetate hydrochloride is added to a mixture of 30 ml of ethyl acetate, 1.58 g of potassium carbonate and 15 ml of water, and a solution of 0.78 g of 4-chlorophenylsulfonyl chloride in 15 ml of ethyl acetate is added dropwise thereto at room temperature. After the mixture is stirred for 2 hours, the ethyl acetate layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate, isopropylether and n-hexane. 1.39 g of methyl 4-[2-(4-chlorophenyl)sulfonylaminoethyl]-2-fluorophenoxyacetate are obtained as colorless prisms.
Reaction SMILES: [N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[CH:29]=[CH:28][NH:27][C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB(C2C=C3C=CN([Si:47]([CH:54]([CH3:56])[CH3:55])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])C3=NC=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[CH:29]=[CH:28][N:27]([Si:47]([CH:54]([CH3:56])[CH3:55])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])[C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: c1ccc2c(c1)CCCN2c1ncnc2ccc(-c3cnc4[nH]ccc4c3)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc21
Yield: 56.6 %

Procedure:
0.25 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline, 0.31 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 0.16 g of sodium hydrogencarbonate and 90 mg of PdCl2(PPh3)2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 18 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 16 min), giving 0.20 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline as yellow oil (yield 50%, content 83%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+].Cl.[NH2:18][C@@H:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22].CN1CCOCC1>O1CCOCC1.C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:18][C@@H:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N[C@H](CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 3 h

Procedure:
Naphthalene-2-sulfonyl chloride (18.18 g, 80.2 mmol) and NaOH (60 mL, 2 N) were added portion-wise over 1 h to a mixture of (R)-3-amino-3-phenyl-propionic acid HCl salt (14.70 g, 72.9 mmol) and N-methylmorpholine (4.0 mL, 36.5 mmol) in dioxane (250 mL). The pH was maintained at pH 11 with the 2N NaOH solution during the addition. After stirring for an additional 3 h, the mixture was diluted with CH2Cl2 (1 L), acidified, washed with water, dried over MgSO4, filtered, and concentrated in vacuo. Crystallization from CH2Cl2/hexane furnished the title compound. MS (-ESI, m/z) 354 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.C(N(CC)C(C)C)(C)C.Br[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:27].C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[Cl:35][C:30]1[CH:29]=[C:28]([CH:26]([N:1]2[CH2:6][CH2:5][O:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)[CH3:27])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Reactant: CC(Br)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 89.4 %

Procedure:
tert-Butyl (2R)-morpholin-2-ylmethylcarbamate (2.00 g) in N,N-dimethylformamide (16 ml) was treated with N,N-diisopropylethylamine (1.6 ml) followed by 4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g). After stirring for five days at room temperature, further portions of 4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g) and N,N-diisopropylethylamine (1.6 ml) were added and stirring continued for 24 h at room temperature. The solution was treated with dichloromethane (70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml) and the mixture shaken vigorously. The organic phase was separated and applied equally onto sulphonic acid ion exchange cartridges (5×10 g Isolute SCX, pre-treated with methanol). The cartridges were each eluted with methanol (one column volume) followed by 10% 0.880 ammonia in methanol (one column volume); evaporation in vacuo of the combined basic fractions gave the title compound as a clear colourless gum (3.22 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(O)c[n+]1[O-]
Reaction time: 1 h

Procedure:
5-Hydroxy-2-methylpyridine (25 g) was suspended in chloroform (500 ml) and treated with m-chloroperbenzoic acid (57 g of material described by the manufacturer as 57-86% pure). After stirring for 1 hour the solution was dried with MgSO4 and poured onto a silica column. Elution with EtOAc to remove byproducts and then with 20-50% EtOH in EtOAc gave a solid (27.7 g).