Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:18])[N:4]2[CH2:3][CH2:2][O:1][C:6]3[C:5]2=[C:10]([CH:9]=[CH:8][CH:7]=3)[C:22]=1[OH:23])=[O:15])[CH3:12]
Reactant: c1ccc2c(c1)NCCO2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccc3c2n(c1=O)CCO3
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-dihydro-2H-1,4-benzoxazine (6 g) and tri(ethoxycarbonyl)methane (9.4 ml) was stirred at 150° C. for 1 hour and at 200° C. for 1 hour. The mixture was cooled and the solid was washed with ether to give pale brown crystals of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (9.6
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:37]1[N:42]=[CH:41][C:40]([Br:43])=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:28][CH:29]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:37]1[N:42]=[CH:41][C:40]([Br:43])=[CH:39][N:38]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC2CCCC2)cc1
Reactant: Brc1cnc(Br)nc1
Product: CCOC(=O)c1cc2cc(-c3ncc(Br)cn3)ccc2n1-c1ccc(OC2CCCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(b), from 1-(4-cyclopentoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (d) above) and 2,5-dibromopyrimidine (see step (f) above).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](OC)(=O)C(OC)=O.CC(C)([O-])C.[K+]>CN(C=O)C.O>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of indole product from Example 38, Step F (182 mg, 0.694 mmol) and dimethyl oxalate (90 mg, 0.76 mmol) in DMF (5 mL), potassium tert-butoxide (86 mg, 0.76 mmol) was added in one portion at room temperature under nitrogen. The reaction mixture was warmed to reflux under nitrogen for 30 min and then was cooled to room temperature. The mixture was diluted with water (50 mL) and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/hexanes, 1:1) to afford the N-methyl indole product, Example 37, as a white solid (180 mg, 92%): mp 106-108° C.; 1H NMR (500 MHz, CDCl3) δ 7.19-7.28 (m, 5H), 7.05 (d, J=8.5 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 6.41 (dd, J=3.0, <1 Hz, 1H), 4.37 (t, J=6.3 Hz, 1H), 4.00 (d, J=15.1 Hz, 1H), 3.85 (d, J=15.1 Hz, 1H), 3.75 (s, 3H), 3.08 (dd, J=11.4, 5.4 Hz, 1H), 2.66 (dd, J=11.4, 8.1 Hz, 1H), 2.50 (s, 3H); CI MS m/z=277 [C19H20N2+H]+; IR (KBr) 3050, 2939, 2783, 1487, 1451 cm−1; Anal. Calcd for C19H20N2-0.1 H2O: C, 82.04; H, 7.32; N, 10.07. Found: C, 82.06; H, 7.50; N, 9.85.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:20]O>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]([NH2:11])[C:8]([O:10][CH3:20])=[O:9])=[CH:5][CH:4]=1
Reactant: NC(C(=O)O)c1ccc(C(F)(F)F)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)c1ccc(C(F)(F)F)cc1
Yield: 69 %

Procedure:
4-Trifluoromethyl-α-carboxybenzylamine (1.4 g, 1.83 mmol) and thionylchloride were added to methanol (8 ml) and the mixture was refluxed for 2 h. The solvent was evaporated under reduced pressure. The residue was suspended in diethyl ether and the product was filtered off, washed with ether and dried to give the title compound 0.34 g (69%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P(=O)(O)(O)[OH:16]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: O=P(O)(O)O
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Yield: 72 %

Procedure:
In another experiment, a slurry of 2-amino-4,6-dichloro-5-{[(dimethyl-amino)methylene]amino}-pyrimidine (Example 2, 25.0 g, 0.107 mol) in 1.5 M aqueous potassium phosphate buffer (300 mL, prepared as above) was gently refluxed for 4 hours. pH was maintained at 3.2 by addition of 85% phosphoric acid, as required, throughout this period. The precipitate was filtered, washed with water (3×10 mL), methanol (2×10 mL), and dried (50° C., 25 mm Hg) to give the title compound as an off-white powder (16.0 g, 72%) with purity identical to that of the characterized sample described above (elemental analysis and 1H-NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](O)=O.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH2:17]([C:14]1[CH:15]=[CH:16][C:2]2[N:1]=[C:10]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)[C:6]3=[CH:7][CH:8]=[CH:9][N:5]3[CH2:4][C:3]=2[CH:13]=1)[CH3:18]
Reactant: CCc1ccc(N)c(Cn2cccc2C(=O)O)c1
Reactant: OCCN1CCNCC1
Product: CCc1ccc2c(c1)Cn1cccc1C(N1CCN(CCO)CC1)=N2

Procedure:
In the manner described in Example 5, reaction of 1-(2-amino-5-ethylbenzyl)-2-pyrrolecarboxylic acid with N-(β-hydroxyethyl)piperazine provides the title compound after cyclization.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][NH2:23]>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:23][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH3:13])=[O:12])[CH2:2]2
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNC(=O)CC1CN2CCC1CC2
Yield: 15 %

Procedure:
Using general procedure I, (1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (200 mg, 1.20 mmol) and 2-(2-methoxy-phenyl)-ethylamine gave the title compound as a white solid (60 mg, 15%). 1H NMR (400 MHz, CD3OD) δ 7.17 (t, J=7.2 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.84 (t, J=7.6 Hz, 1H), 3.89 (s, 3H), 3.35-3.45 (m, 3H), 3.21-3.31 (m, 3H), 2.76-2.83 (m, 3H), 2.29-2.45 (m, 3H), 1.82-2.01 (m, 3H), 1.72-1.81 (m, 2H) ppm. 13C NMR (400 MHz, CD3OD) δ 172.0, 158.0, 130.4, 127.8, 127.2, 120.2, 110.4, 54.6, 52.0, 46.4, 45.9, 39.1, 38.3, 30.7, 30.2, 23.8, 17.9 ppm. Purity: 92.4% HPLCMS (210 nm); retention time 1.59 min; (M+1) 303.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[F:19][CH:20]([F:24])[C:21](Cl)=[O:22]>O1CCOCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[CH:20]([F:24])[F:19])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Reactant: O=C(Cl)C(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(Cl)ccc1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 1 g of 2-amino-5-chlorobenzenesulphonamide (obtained in accordance with J. Chem. Soc. Perkin I 1979, 1043-1047) dissolved in 4 ml of dioxane there are added, in the cold state (+5° C.), 0.6 ml of pyridine and 0.6 ml of difluoroacetic acid chloride. The flask is hermetically closed immediately and subjected to vigorous stirring at ambient temperature for 10 minutes. The solvents are then removed under reduced pressure. The solid residue is taken up in water (12 ml), and the insoluble material is collected by filtration, washed with water and dried to yield the expected compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8](=[O:24])[N:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:10]=1)=[O:5])C.O.O.[OH-].[Li+]>O1CCCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]2=[O:24])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)[nH]c2=O)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
tert-Butyl 4-(4-(ethoxycarbonyl)-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (400 mg, 1.179 mmol) was dissolved in tetrahydrofuran (10 mL). Water (10 mL) was added to the mixture followed by lithium hydroxide hydrate (180 mg, 4.29 mmol). Mixture was warmed to 70° C. and held with stirring for 16 hours. Mixture was cooled to room temperature. Reaction was quenched with 4.5 mL 1N hydrochloric acid. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 98% yield. MS (M−H)−=310.2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:24]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:18][C:19]1[C:24]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5](=[CH:4][CH:3]=2)[N:6]=[CH:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]3)=[CH:21][N:20]=1
Reactant: CN(C)S(=O)(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: Brc1ccc2ncc(-c3ccncc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1cc(-c2ccc3ncc(-c4ccncc4)nc3c2)cnc1N
Temperature: 100 °C
Yield: 47.2 %

Procedure:
A mixture of 7-bromo-2-(4-pyridinyl)quinoxaline (0.245 mmol), 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide (0.245 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.0196 mmol), 2M aqueous potassium carbonate (2 mL) and anhydrous 1,4-dioxane (6 mL) was heated at 100° C. for 4 h in a sealed pressure vessel. After cooling to room temperature, the organic layer was separated and purified directly on silica gel, eluting with 0-10% methanol in ethyl acetate followed by a second purification by HPLC (eluting with acetonitrile: 0.1% TFA in H2O) to afford the title compound as a bright yellow solid (47 mg, 47% yield). MS(ES)+ m/e 407.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1.C(OCC)(=O)C>C(O)(=O)C>[Br:8][C:7]1[C:2]2[N:1]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[NH:11][C:3]=2[C:4]([O:9][CH3:10])=[CH:5][CH:6]=1
Reactant: COc1ccc(Br)c(N)c1NC(=O)c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Br)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Yield: 81.7 %

Procedure:
A solution of 1.44 g (3.97 mmol) N-(2-amino-3-bromo-6-methoxy-phenyl)-4-isopropyl-benzamide in 25 ml glacial acetic acid is stirred at 100° C. for 3 h. The reaction mixture is cooled to room temperature 200 ml ethyl acetate is added. The solution is washed with 4N NaOH (2×) and with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 1.12 g of the title compound as slightly reddish solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Product: COC(=O)c1c(CNC(=O)c2cccc(OC)c2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
7-Methoxy-3-[(3-methoxy-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 3-methoxybenzoyl chloride. MS calcd. for C27H24N2O6 [(M+H)+] 473.2, obsd. 473.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH2:25](I)[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:25][CH3:26])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CCI
Product: CCN(c1c(C)cc(C)cc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Yield: 100 %

Procedure:
In the same manner as described in Example 9, 0.30 g (0.860 mmol) of the product of Example 62 was alkylated with ethyl iodide to give 0.324 g (100%) of the desired product as a white solid. Electrospray Mass Spec: 378 (M+H).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].I[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])=[CH:10][CH:9]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(Cl)(Cl)Cl>[CH3:4][Si:3]([C:1]#[C:2][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: C#C[Si](C)(C)C
Reactant: CC(NC1CC1)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Product: CC(NC1CC1)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
Ethynyl(trimethyl)silane (80 mg), PdCl2(PPh3)2 (29 mg), CuI (16 mg), and TEA (0.25 g) were added to a chloroform (5.0 mL) solution of N-[1-(4-iodophenyl)ethyl]cyclopropylamine (0.23 g) as obtained in Example 14-(1), and the mixture was stirred in a nitrogen atmosphere for 24 hours at room temperature. Further, stirring was continued for 2 hours at 45° C., and then PdCl2(PPh3)2 (29 mg) was added. After the system was refluxed in a nitrogen atmosphere for 5 hours, the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=85/15) to obtain N-(1-{4-[(trimethylsilyl)ethynyl]phenyl}ethyl)cyclopropylamine (brown oil) (0.14 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:12].N([O-])=O.[Na+].[BrH:18]>O.[Cu]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:18])=[CH:6][C:5]=1[Cl:12]
Reactant: Br
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(Cl)cc(Br)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
4-Amino-2,6-dichlorobenzoic acid methyl ester (1.00 g) was suspended in 40% aq. HBr and the mixture was cooled lto 0-5° C. After NaNO2 (376 mg) was added in small portions, the mixture was stirred for about 5 min. Copper (100 mg) was added and the mixture was warmed up to 100° C. The mixture was then stirred at 100° C. for 30 min, diluted with water and extracted with AcOEt. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane and AcOEt 50:1) to give 4-bromo-2,6-dichlorobenzoic acid methyl ester (1.07 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@H:7]2[CH2:12][C@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.CCO.C(#N)C>C(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Agent: O=C=O
Solvent: CC#N
Solvent: CCO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(F)cc1
Yield: 30.3 %

Procedure:
Trans-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.268 g, 0.8 mmol) was subjected to chiral preparative HPLC (Column: Chiralcel OJ (250×30), 5 μm particle size, mobile phase: 10% EtOH in CO2 (175 bar), flow rate 150 mL/min) to yield (2S,4S)-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (81 mg, 30%), Chiral purity 99.8% ee, Optical rotation [α]D20=+29.3 (acetonitrile, c=1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1cccc(Cl)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(Cl)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-chlorobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C-]#N.[K+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:19]=1.[CH3:20][N:21](C)C=O>O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[CH2:11][C:10]3[CH:19]=[C:6]([CH2:5][C:20]#[N:21])[CH:7]=[CH:8][C:9]=3[O:18][C:13]=12
Reactant: CN(C)C=O
Reactant: ClCc1ccc2c(c1)Cc1cccnc1O2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1ccc2c(c1)Cc1cccnc1O2
Reaction time: 2 h

Procedure:
A solution of 7.8 g of potassium cyanide in 20 ml of water is added dropwise to a mixture of 23 g of 7-chloromethyl-5H-[1]benzopyrano[2,3-b]-pyridine and 200 ml of dimethylformamide, and the whole mixture is allowed to stand at 55°-60°C for 2 hours. The reaction mixture is poured into a large amount of water, and the crystalline precipitate is filtered off, washed with water and recrystallized from aqueous dioxane to give 20 g of 5H-[1]-benzopyrano[2,3-b]pyridin-7-yl-acetonitrile melting at 166°-167°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].N[C:37](N)=[O:38]>O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[NH:35][C:37](=[O:38])[N:8]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c2c(Cl)ncnc2n1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 49.9 %

Procedure:
7.5 Parts of 6-chloro-N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine and 3.6 parts of urea were heated together till about 220° C. during 10 minutes. The resulting melt was cooled and suspended in water. The solid was filtered off, washed with water and ethanol and recrystallized from a mixture of N,N-dimethylacetamide, ethanol and water, yielding 3.9 parts (49.9%) of 6-chloro-9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-7,9-dihydro-8H-purin-8-one; mp. 266.2° C. (compound 144).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:3]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccn(-c2ccc(C(=O)O)cc2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)Cl)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a suspension of 4-(3-methylpyrazol-1-yl)benzoic acid (1.84 g) in dichloromethane (25 ml) was added oxalyl chloride (1.16 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. Dichloromethane was added, the solution filtered, and the solvent evaporated under reduced pressure to yield 4-(3-methylpyrazol-1-yl)benzoyl chloride as a yellow oil (1.76 g), which was utilized without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>N1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:24])/[CH:21]=[CH:22]/[CH3:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
A solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.57 ml of trans-crotonoyl chloride in 6 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid recrystallized from n-butanol to give 0.69 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(E)-2-butenamide: mp=153-160° C., mass spectrum (m/e): M+H 383, 385.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][OH:45])[CH2:41][CH2:42]4)[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1cccc(N2CCN(CCO)CC2)c1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCN(CCO)CC4)c3)nn12
Yield: 23.9 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (150.0 mg, 0.0005220 mol), N,N-Diisopropylethylamine (0.136 mL, 0.000783 mol) and 2-[4-(3-Amino-phenyl)-piperazin-1-yl]-ethanol (231.0 mg, 0.001044 mol) were dissolved in 2-Methoxyethanol (3.66 mL) and the The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 55.38 mg of 2-(4-{3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanol as a lyophilated powder. (M+H)=445.21. 1H NMR (400 MHz, DMSO, d6) δ 9.16 (s, 1H), 8.94 (s, 1H), 7.72 (d, 1H, J=5.85 Hz), 7.44 (t, 1H, J=7.64 Hz), 7.26 (s, 1H), 7.19 (d, 1H, J=7.68 Hz), 7.08 (m, 2H), 7.01 (t, 1H, J=7.80 Hz), 6.90 (q, 2H, J=4.61 Hz), 6.46 (d, 1H, J=6.89 Hz), 3.76 (s, 3H), 3.53 (m, 4H), 3.04 (m, 2H), 2.87 (m, 2H), 2.67 (m, 2H), 2.44 (m, 2H).