Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30].CO.[CH3:38][Si](C=[N+]=[N-])(C)C>O1CCCC1>[O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:20][CH:21]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([O:31][CH3:38])=[O:30]
Reactant: O=C(O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.5 h

Procedure:
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoic acid (Example 611, 30 mg, 0.065 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) and treated with (trimethylsilyl)diazomethane (0.065 mL, 2 M diethyl ether solution, 0.13 mmol, 2 equiv). After stirring for 30 minutes, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.15 (1H s), 8.46 (1H, d, J=2.5 Hz), 8.21 (1H, dd, J=7.8, 1.4 Hz), 7.83 (2H, d, J=8.8 Hz), 7.79 (1H, m), 7.77 (1H, d, J=2.3 Hz), 7.73-7.61 (3H, m), 7.56 (1H, t, J=7.7 Hz), 7.46 (2H, d, 8.7 Hz), 7.41 (1H, td, J=7.7, 1.1 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.77 (2H, s), 3.67 (3H, s) ppm; low resolution mass spectrometry (ES+) m/z 476.0 [(M+H)+; calculated for C28H22N5O3: 476.2].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[C:31]1[CH:39]=[CH:40][CH:41]=[C:29]([C:28]([F:27])([F:43])[F:42])[CH:30]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
(2S,3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (2.53 g, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (50 ml) and 4-methylmorpholine (2.53 ml) and cooled to 0° C. prior to the addition of (3-trifluoromethyl-benzoylamino)-acetic acid (1.49 g) and HATU (2.23 g). After the reaction was stirred overnight at room temperature, the CH2Cl2 was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S,3S)-{3-hydroxy-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (1.3 g). MS found: (M+H)+=492.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: CCOc1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-ethoxyphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 14.7, 22.6, 28.9, 32.0, 42.6, 60.5, 63.2, 115.0, 126.6, 127.1, 128.2, 130.6, 138.4, 143.5 and 158.9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:18]N1C(=O)CCC1=O.O>O1CCCC1>[Cl:18][C:13]1[NH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: COC(=O)c1c[nH]cc1-c1cccc(C#N)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c[nH]c(Cl)c1-c1cccc(C#N)c1
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 16.5 g (72.9 mmol) of methyl 4-(3-cyano-phenyl)-1H-pyrrole-3-carboxylate in 150 ml of tetrahydrofuran are added portionwise 9.93 g (74.4 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 6 hours at reflux. After cooling, 250 ml of water are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 17.1 g of methyl 5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured powder after recrystallizing from acetonitrile, filtering off and drying.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26]C1C=CC([N+]([O-])=O)=CC=1)=O.Cl.[NH2:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41]>CN(C)C=O>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([OH:51])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[O:26]
Reactant: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)C(=O)N[C@@H](CO)C(=O)O

Procedure:
1.5 ml of triethylamine are added to a solution of 4.2 g of 4-nitrophenyl 2-(2,6-dichlorophenyl-amino)-phenyl-acetate and 3.6 g of the hydrochloride of the methyl ester of L-leucyl-L-serine in 30 ml of dimethylformamide and the mixture is allowed to react for one hour at room temperature. It is then acidified to pH 5 with 1 N hydrochloric acid and partitioned between chloroform and water. After washing with water, the organic phase is dried and evaporated. The residue is ground with diethyl ether. After recrystallising from a mixture of ethyl acetate and petroleum ether, the methyl ester of N-{[2-(2,6-dichlorophenyl-amino)-phenyl]-acetyl}-L-leucyl-L-serine is obtained as colourless crystals; melting point 216°-218°: [α]D =-30° (c=0.635 in chloroform).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10]O.[C:12]1(=[O:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14][NH:13]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][N:13]1[N:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1=[O:22]
Reactant: OCCC#Cc1ccccn1
Reactant: O=c1[nH]ncc2ccccc12
Product: O=c1c2ccccc2cnn1CCC#Cc1ccccn1
Yield: 11449.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 3(B), from 4-(pyridin-2-yl)but-3-yn-1-ol (102 mg, 0.69 mmol, Example 3(A)) and phthalazin-1(2H)-one (152 mg, 1.04 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 97:3) followed by bulb-to-bulb distillation (100° C., 0.1 mbar) to yield 22 mg (79 mmol, 11%) of 2-(4-(pyridin-2-yl)but-3-ynyl)phthalazin-1(2H)-one as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[O:10])[CH2:12][CH2:13]4)=[O:16])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:40][CH:41]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)c(F)c3)ccn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)cc1
Yield: 57 %

Procedure:
1-((4-Fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (see Example B1, 171 mg, 0.77 mmol), N-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine (see PCT Publication No. WO 2008/046003, 200 mg, 0.59 mmol), TBTU (284 mg, 0.88 mol) and DIEA (0.12 ml, 0.73 mmol) were combined in DMF (1.5 mL) and the resultant mixture was stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The organic was washed with water (10 mL), brine (10 mL), and 5% aqueous lithium chloride solution (10 mL), and was then dried over MgSO4 and concentrated in vacuo. Dichloromethane was added to the residue and the resultant slurry was filtered. The collected precipitate was washed with CH2Cl2 and dried in vacuo to provide N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (137 mg) as a white solid. The filtrate was concentrated and a second crop (46 mg, total yield 57%) was collected. MS (ESI) m/z: 545.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:42]=[CH:43][CH:44]=1>CN(C=O)C.O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:38][C:39]2[CH:40]=[C:41]([CH:45]3[CH2:49][CH2:48][CH2:47][N:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:42]=[CH:43][CH:44]=2)=[O:11])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(C(C)(C)C)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)C)ccc1C(=O)Nc1cccc(C2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 17 h
Yield: 34.8 %

Procedure:
To a solution of 4-tert-butyl-2-methoxy-benzoic acid (0.05 g) in DMF (1.5 mL) at room temperature, was added in order, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.046 g), 1-hydroxy-benzotriazole (0.033 g) and 15 min. later, (±)-2-(3-aminophenyl)-1-(tert-butyloxycarbonyl)-pyrrolidine (0.05 g). The reaction mixture was allowed to stir for 17 h and then poured into water. The aqueous mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo to afford an amber oil. Suction silica gel chromatography eluting with ethyl acetate in hexane (from 30% to 100%, in 10% increments) gave desired product as an amber solid (0.03 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:35]([C@H:42]([CH2:46][C:47]([N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)=[O:48])[C:43]([OH:45])=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[CH2:35]([C@H:42]([CH2:46][C:47]([N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)=[O:48])[C:43]([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@H:27]1[O:31][C:30](=[O:32])[C@H:29]([CH3:33])[CH2:28]1)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:45])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)OC(C)(C)C)OC1=O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)[C@@H](CC(=O)N2CCOCC2)Cc2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 1.7 g (3.64 mmole) of (3R, 5S)-5-{(1S)-1-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl ]amino-2-cyclohexylethyl}-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 25) and 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 60 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the resulting mixture was concentrated by evaporation under reduced pressure. This operation was repeated three times, in total. After the final residue had been dried under reduced pressure for 8 hours, the dried materials were suspended in 30 ml of anhydrous tetrahydrofuran. 1.11 g (4.0 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were then added to the suspension, after which 0.71 ml (4.37 mmole) of 95% diethyl cyanophosphonate and 2.0 ml (14.56 mmole) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 15 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by medium pressure column chromatography through silica gel (using ethyl acetate as the eluent), to afford 1.43 g of the title compound as a colourless amorphous product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[CH3:48][S:49]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(OS(C)(=O)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 2.5 h
Yield: 26.3 %

Procedure:
4-(4-Hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (178 mg, 0.330 mmol) was suspended in dichloromethane (14 mL), and the suspension was added with triethylamine (0.092 mL, 0.66 mmol) and methanesulfonyl chloride (0.031 mL, 0.40 mmol) under ice-cooling, followed by stirring for 2.5 hours. The reaction mixture was filtered, and the filtrate was added with water and extracted with ethyl acetate and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=10/0.5/0.5) to obtain 4-(4-methanesulfonyloxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (53.4 mg, yield 26%).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[OH:18][CH:19]([CH2:22][OH:23])[CH2:20][NH2:21]>CO>[OH:18][CH:19]([CH2:22][OH:23])[CH2:20][NH:21][C:3]([C:4]1[CH:9]=[C:8]([CH:10]([OH:13])[CH2:11][OH:12])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)=[O:17]
Reactant: NCC(O)CO
Reactant: COC(=O)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(NCC(O)CO)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
3-Nitro-5-(1,2-dihydroxyethyl)benzoic acid methyl ester (0.40 g, 1.69 mmol) and 2,3-dihydroxypropylamine (0.17 g, 1.86 mmol) were dissolved in methanol (2 ml) and the solution was stirred at 75° C. for 1 h. The pressure was then reduced to 200 mm Hg and stirring was continued at 95° C. for 2 h . The crude reaction mixture was purified by preparative HPLC. Yield: 0.40 g (78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=2)[CH:28]=[CH:29][CH:30]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:2]3[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]4[CH:15]=[CH:14][C:13]([CH2:16][N:17]5[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]5)=[CH:12][CH:11]=4)[CH:5]=[CH:6][CH:7]=3)[N:32]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nccc(-c2cccc(Cl)c2F)n1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Nc2nccc(-c3cccc(Cl)c3F)n2)c1)c1ccc(CN2CCCCC2)cc1
Temperature: 150 °C

Procedure:
A mixture of N-(3-bromophenyl)-4-(piperidin-1-ylmethyl)benzamide (20 mg, 0.054 mmol) and 4-(3-chloro-2-fluorophenyl)pyrimidin-2-amine (18 mg, 0.080 mmol), KOBut (12 mg, 0.11 mmol), Pd2(dba)3 (2.5 mg, 0.027 mmol) and Xantphos (2.5 mg, 0.043 mmol) in a microwave reaction vessel was suspended in 0.6 mL of toluene. The reaction mixture was heated in a microwave at 150° C. for 1 h. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder. MS (ESI+) m/z 516.2 [M+H]+.
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.N1C=CC=CC=1.Cl.[CH2:42]1C[O:45][CH2:44][CH2:43]1.CN(C=O)C>>[ClH:1].[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:44](=[O:45])[CH:43]=[CH2:42])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: C1CCOC1
Reactant: Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Temperature: 0 °C
Yield: 45 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.1 mmol) was added to a solution of 6-amino-4[(3-(trifluoromethyl)phenyl)-amino]quinazoline (153 mg, 0.5 mmol) acrylic acid (73 mg, 1.0 mmol) and pyridine (206 mg, 2.5 mmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 15 minutes the reaction mixture was stirred at 25° C. for 1 hour, and then recooled to 0° C. Dilute hydrochloric acid (0.5 M, 10 mL) was added, and after 15 minutes the precipitate was collected by Buchner filtration. The residue was rinsed with water (5 mL) and ether (2×5 mL) and dried in a vacuum oven at 75° C. overnight to give N-[4-[(3-(trifluoromethyl)phenyl)amino]quinazolin-6-yl]acrylamide hydrochloride (87 mg, 45%) as a light greenish solid, mp 195-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[C:27]([NH:29][C:30](=[N:38][CH2:39][CH2:40][S:41][CH2:42][C:43]1[N:44]=[C:45]([NH:48][C:49]([NH2:51])=[NH:50])[S:46][CH:47]=1)OC1C=CC=CC=1)#[N:28]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30]([NH:29][C:27]#[N:28])=[N:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[N:44]=[C:45]([NH:48][C:49]([NH2:51])=[NH:50])[S:46][CH:47]=2)[CH3:20])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (1.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine and 0.7 g (1.9 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=655 ([M+H]+ 2), 230 (18), 154 (100); IR (KBr): 2161 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 150° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[NH:9][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[C:17]([F:23])[CH:16]=1>O1CCCC1>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][C:17]=1[F:23])=[O:11]
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reactant: NCc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Yield: 79.9 %

Procedure:
A mixture of 7-chloro-2H-3,1-benzoxazine-2,4(1H)dione (18.4 g) and 4-bromo-2-fluorobenzylamine (26 g) in tetrahydrofuran (200 ml) was refluxed for 15 minutes. After cooling, tetrahydrofuran was evaporated to give a residue. Recrystallization from isopropyl ether gave 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide (26.6 g).
Reaction SMILES: [OH:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.CN(C=O)C.[CH:19](B(O)O)=[CH2:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C:2]1[C:12]([CH:19]=[CH2:20])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: C=CB(O)O
Reactant: CCOC(=O)c1cnc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)OCC)cnc1O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
Ethyl 6-hydroxy-5-iodonicotinate (200 mg, 0.682 mmol) was added with N,N′-dimethylformamide (4.1 mL) and water (1.4 mL). The resultant mixture was then added with tetrakis triphenylphosphine palladium (79 mg, 0.0682 mmol), vinylboronic acid (417 μL, 2.46 mmol) and sodium carbonate (433 mg, 4.09 mmol), and stirred at 80° C. for 20 minutes. Subsequently, the resultant mixture was further added with tetrakis triphenylphosphine palladium (79 mg, 0.0682 mmol) and vinylboronic acid (417 μL, 2.46 mmol), and stirred at 80° C. for 20 minutes. The reaction solution was filtered using celite and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (chloroform/acetone) and concentrated in vacuo. Ethyl 6-hydroxy-5-vinylnicotinate (95 mg, yield 72%) was obtained as a yellow oil.