Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:46]([O:50][C:51](=[O:60])[NH:52][C@H:53]([CH:55](O)[CH2:56][CH2:57][CH3:58])[CH3:54])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:55]([CH2:56][CH2:57][CH3:58])[C@@H:53]([NH:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:60])[CH3:54])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1
Reactant: CCCC(O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.3 %

Procedure:
4-nitrobenzoate (16.3 g), triphenylphosphine (32 g), and diisopropyl azodicarboxylate (40% toluene solution) (64 ml) were added dropwise to a tetrahydrofuran (50 ml) solution containing tert-butyl((2S)-3-hydroxyhexan-2-yl)carbamate (17 g) for 30 minutes, followed by stirring at room temperature for 14 hours. The solvent was distilled away from the reaction solution under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5.5:1), and a yellow solid of (2S)-2-((tert-butoxycarbonyl)amino)hexane-3-yl 4-nitrobenzoate (17 g) was thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)=[O:4].CO.[H][H]>[Pd]>[CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: [H][H]
Reactant: CN(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C1CCNCC1

Procedure:
Palladium (10.0 mg, 9.40E−6 mol) was added to a solution of benzyl 4-[(dimethylamino)carbonyl]piperidine-1-carboxylate (190.0 mg, 0.0006544 mol) in methanol (5.0 mL, 0.12 mol) under nitrogen. The mixture was hydrogenised with a balloon filled with hydrogen for 3 h. The mixture was filtered and the filtrate was concentrated to give the desired product.
Reaction SMILES: [N:1]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[N+]=[N-].C(N(CC)CC)C.Br.[Br:19][CH2:20][CH2:21]N>C(Cl)Cl>[C:4]([NH:1][CH2:21][CH2:20][Br:19])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCBr
Reaction time: 3 h

Procedure:
A mixture of t-butyl azidoformate (15.81 g) and triethylamine (30 ml) was added dropwise to a stirred suspension of 2-bromoethylamine hydrobromide (20.5 g.), in methylene chloride (100 ml.). The mixture was stirred for 3 hr., then filtered. The filtrate was concentrated to a small volume, and the residue was distributed between ether and water. The ether layer was dried, then distilled under reduced pressure, collecting the fraction b.p. 92°-94°/0.9 mm as N-carbo-t-butoxy-2-bromoethylamine (1.756 g.)
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][CH2:15][CH2:14]2.C(O)(=O)C>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH:16]([C:3]([O:6][CH3:7])=[O:8])[CH2:15][CH2:14]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A suspension of 24.0 g (0.60 mole) of sodium hydride (60% dispersion in mineral oil) and 49.5 ml (52.9 g; 0.59 mole) of dimethyl carbonate (freshly distilled from sodium hydride) in 240 ml of tetrahydrofuran under a nitrogen atmosphere was stirred and heated to reflux. Reflux was maintained while a solution of 29.7 g (0.17 mole) of 6-methoxy-1-tetralone in 105 ml of tetrahydrofuran was added dropwise over two hours. After addition was complete, the mixture was stirred at reflux for an additional 90 minutes, cooled in ice, and treated dropwise with 36 ml of glacial acetic acid, followed by 450 ml of ice water. The two-phase reaction mixture was extracted with ethyl acetate (4×250 ml), and the combined organic layers were washed with water (1×600 ml), 5% aqueous sodium bicarbonate solution (3×600 ml), and water again. The ethyl acetate extract was dried (anhydrous sodium sulfate and evaporated (vacuum). The residue was pulverized and stirred in 500 ml of hexane. Filtration yielded 37.9 g (96% yield) of the ester product, mp 79°-81°, suitable for further synthesis. A sample purified by bulb-to-bulb distillation followed by recrystallization from hexane/ethyl acetate was analytically pure, mp 82°-84° (a mp of 88°-89° is given by J. Jacques and A. Horeau, Bull. Soc. Chem. France, 512 (1950)).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10](=[O:18])OC3C=CC=CC=3)[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[S:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].O>CS(C)=O>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([S:39][C:30]4[C:29]5[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=5)[N:33]=[CH:32][N:31]=4)[CH:41]=3)=[O:18])[N:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C5CC5)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 40 °C
Yield: 47 %

Procedure:
A stirred mixture of phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example 353A (250 mg, 0.78 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (200 mg, 0.64 mmol) in DMSO (1 mL) was heated to 40° C. for 48 h. After cooling to rt, water (20 mL) was added. The resulting suspension was filtered and the collected solid purified via preparative silica gel thin-layer chromatography (eluting with a mixture of 10:10:1 ethyl acetate:dichloromethane:methanol) to give a solid which was triturated with diethyl ether (50 mL) to afford 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (162 mg, 47%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 7.77 (s, 1H), 7.22-7.51 (m, 10H), 6.15 (s, 1H), 3.99 (s, 6H), 1.86 (m, 1H), 0.85-0.91 (m, 2H), 0.65-0.68 (m, 2H); LC-MS (ESI) m/z 539 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH2:24])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:24][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:22])=[O:23]
Reactant: NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1cccc(Cl)c1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
2,3-Dichloroquinoxaline (1.00 g, 5.02 mmol), 2,3-dichlorobenzenesulfonamide (1.41 g, 5.02 mmol) and potassium carbonate (694 mg, 5.02 mmol) were suspended in dimethyl sulfoxide (30 mL) and the mixture was stirred at 150° C. for 3 hours. The reaction mixture was slowly added to a mixture (300 ml) of a 1% aqueous acetic acid solution and ice, and the mixture was stirred for 3 hours. The resulting solid was collected by filtration and washed with water. Then, slurry purification was performed using diisopropyl ether, to give 2,3-dichloro-N-{3-chloroquinoxalin-2-yl}benzenesulfonamide (Compound AA) (1.53 g, yield: 78%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:13]([N:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH:8]=[CH:7][C:6]2[CH:20]=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:3]=[CH:4][C:5]=2[CH2:12]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2ccccc21
Reactant: OB(O)c1ccccc1
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cnc(-c3ccccc3)cc2C=Cc2ccccc21
Yield: 46.8 %

Procedure:
Compound 41E (10.7 mg, 47%) was prepared from 41D (20 mg, 0.070 mmol) and phenylboronic acid (12.8 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.286 min; LCMS Found: (M+H)+=327.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27](OS(C)(=O)=O)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:7])[CH2:3][CH2:2]1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.12 g) in benzene (11 ml) is added morpholine (0.26 ml) under ice cooling, and the mixture is kept at 10° C. overnight. The reaction mixture is washed with water, dried, and evaporated under reduced pressure. Purification of the obtained residue (1 g) by chromatography over silica gel (10 g) using a mixture of benzene and ethyl acetate (1:2) gives p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido- 2-oxoazetidin-1-yl]-α-(1-morpholinoethylidene)acetate (602 mg). Foam.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([C:43]([CH:41]4[CH2:42][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]4)=[O:44])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of (5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) in DMF (1.5 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50.6 mg, 0.252 mmol), triethylamine (102 μl, 0.733 mmol), and (BOP) benzoltriazolyloxytris(dimethylamino)phosphomium-hexafluorophosphate (140 mg, 0.317 mmol). The reaction was stirred at rt overnight. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the organic was washed with H2O (20 mL). The combined aqueous layers were extracted with ethyl acetate (20 mL). The combined organics were washed with water (5×20 mL) to remove DMF, dried (Na2SO4), and evaporated. The crude material was purified by trituration with ether to yield 50 mg (35%) of the desired product. 1H NMR (300 MHz, Methanol-d6) δ 8.36 (s, 1 H), 7.85-7.81 (m, 2 H), 7.65 (s, 1 H), 7.40-7.20 (m, 4 H), 7.23 (d, 1 H), 6.67 (d, 1 H), 5.85 (s, 2 H), 4.20-3.90 (m, 3 H), 3.80-3.40 (m, 2 H), 3.30-3.10 (m, 4 H), 2.60-2.10 (m, 2 H), 1.33 (d, 9H); ES-MS m/z 579.0 [M+H]+, HPLC RT (min) 2.46.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[CH:34]=[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[F:44])[C:32]([O:45][CH3:46])=[CH:31][C:28]=1[CH:29]=[O:30]>O1CCCC1>[Cl:26][C:27]1[CH:34]=[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[F:44])[C:32]([O:45][CH3:46])=[CH:31][C:28]=1[CH:29]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1)[OH:30]
Reactant: COc1cc(C=O)c(Cl)cc1OCc1ccc(Cl)cc1F
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(Cl)cc1OCc1ccc(Cl)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68, 582.0 mg, 1.45 mmol, prepared as described in Example 22) was dissolved in tetrahydrofuran (10.0 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.79 mL) was added to the reaction. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 2-chloro-4-(4-chloro-2-fluoro-benzyloxy)-5-methoxy-benzaldehyde (140, 200 mg, 0.61 mmol) in tetrahydrofuran (7.0 mL) was added. The reaction was stirred for 1.5 hours during which time the temperature rose to 0° C. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, eluting with 0-20% ethyl acetate:hexanes, to provide the desired compound (141, 318 mg, 87%). MS (ESI): [M+H+]+=603.3, 605.3.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[O:11][C:6]2=[CH:5][CH:4]=1.CCN(CC)CC.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC#N>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=4)[O:11][C:6]3=[CH:5][CH:4]=2)[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=[N+]([O-])c1cccc(-c2nc3nc(CBr)ccc3o2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc([N+](=O)[O-])c4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Bromomethyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine (250 mg, 0.75 mmol) was dissolved in 5 mL of CH3CN along with Et3N (0.200 mL, 1.5 mmol) and 140 mg of Boc-piperazine. The reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and the resulting residue was mixed with 25 mL of CH2Cl2 and washed with brine. The organic layer was dried (Na2SO4) and concentrated to afford essentially quantitative yield of 4-[2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:40][C@@H:41]2[NH:45][C:44](=[O:46])[CH2:43][CH2:42]2)(=O)=O)=CC=1.CCOCC>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][C@@H:41]1[NH:45][C:44](=[O:46])[CH2:43][CH2:42]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.3 %

Procedure:
To a suspension of 7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (1.36 g, 4.24 mmol), (prepared as described in Example 49), in DMF (70 ml), was added potassium carbonate (2.34 g, 17.0 mmol, 4 eq.) followed by (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.25 g, 4.66 mmol, 1.1 eq.), (prepared as described for the starting material in Example 317), and the resulting yellow suspension heated at reflux. After 4 hours, some starting material remained, and a further addition of (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (0.57 g, 2.12 mmol, 0.5 eq.) was made. The reaction was heated at reflux for a further 2 hours resulting in consumption of starting material. The reaction was cooled to ambient temperature, the inorganic residue filtered off and the filtrate evaporated in vacuo to leave a brown oil which was purified by column chromatography (methylene chloride/methanol, (100/0 to 90/10)) to give a light brown oil. Trituration with ether afforded a thick oil, which upon chromatography eluting as above gave a yellow oil. Trituration of this oil with ether gave an initial crop of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (5 mg) as an off-white solid (ca. 90% pure by nmr). Chromatography of the residues (eluting as above) followed by ether trituration gave further crops of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline as a white solid (180 mg, >95% pure by nmr), as an off-white solid (800 mg, ca. 95% pure by nmr).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22](NC2C=CC(OC3C=CN=CC=3)=CC=2)=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:44]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)[CH:42]=[CH:41][C:40]=1[NH2:53]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([NH:53][C:40]2[CH:41]=[CH:42][C:43]([O:45][C:46]3[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=3)=[CH:44][C:39]=2[F:38])=[O:23])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Reactant: Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Product: COCCOc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1

Procedure:
The title compound was prepared in the same manner as described for 1-{5-tert-butyl-2-[4-(2-methoxyethoxy)phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea, replacing 4-(pyridin-4-yloxy)phenylamine with 2-fluoro-4-(2-methyl-pyridin-4-yloxy)phenyl-amine. 1H-NMR (DMSO-d6) δ 8.96 (s, 1H), 8.74 (s, 1H), 8.29 (d, J=6.0 Hz, 1H), 8.14 (t, J=9.3 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.0 Hz, 1H), 7.08 (dd, J=11.7, 2.4 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.73 to 6.70 (m, 1H), 6.34 (s, 1H), 4.16 to 4.12 (m, 2H), 3.68 to 3.65 (m, 2H), 3.30 (s, 3H), 2.38 (s, 3H), 1.24 (s, 9H); MS LC-MS [M+H]+=534, RT=2.39 min.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]#[N:15]>>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([CH2:13][C:14]#[N:15])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: N#CCBr
Product: N#CCN1CCN(C2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Cyclopentyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=194.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.45-2.20 (m, 9H), 1.80-1.20 (m, 8H).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].Cl.[CH3:15][C:16]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH2:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:15][C:16]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH:22][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC1(C)CCCC1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)CCCC1CNC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.) solution of 4-formylcinnamic acid (345 mg, 1.96 mmol) and 2,2-dimethylcyclopentylmethylamine, hydrochloride (321 mg, 1.96 mmol; title B compound of Example 1) in DMF (5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (954 mg, 2.16 mmol) and N-methylmorpholine (0.47 mL, 4.31 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl and saturated NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated in vacuo to yield a light amber gum. MS: (ESI), (M+H)+ 286.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].[C:12](Cl)([Cl:14])=[O:13].C1(C)C=CC=CC=1>C1COCC1>[C:12]([Cl:14])(=[O:13])[O:11][CH2:10][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: N#Cc1cc(Cl)cc(CO)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(COC(=O)Cl)c1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
3-Chloro-5-(hydroxymethyl)benzonitrile (25 g, 145 mmol) was dissolved in THF (200 mL). The resulting yellow solution was cooled to 10° C. in an ice bath and treated dropwise with phosgene in toluene (152 mL, 289 mmol). The reaction mixture was stirred at ambient temperature for 16 hrs. The mixture was concentrated under reduced pressure and the crude material was diluted with toluene (200 ml) and re-concentrated under reduced pressure. The residue was purified by chromatography on silica (Redisep 340 g column on a Biotage system), eluting with EtOAc/iso-hexane to give 3-chloro-5-cyanobenzyl carbonochloridate as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([OH:10])([CH3:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:6]1[S:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(C(C)(C)O)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(C(C)(C)O)sc1Br

Procedure:
2-(4-Methylthiazol-2-yl)propan-2-ol (321 mg 2.04 mmol) and NBS (404 mg 2.25 mmol) was stirred in DMF (10 mL) at room temperature for 2 hours under nitrogen. The mixture was diluted with EtOAc (50 mL) and washed with water (2×20 ml), then brine, dried over sodium sulfate and concentrated to give an oil which was purified by ISCO CombiFlash® chromatography eluting with Heptane:EtOAc (100:0 to 0:100 over 20 CV) to the product as a pale yellow oil (296 mg 61%).