Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][CH:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1.[S:27]1(=[O:39])(=[O:38])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][NH:30][CH2:29][CH2:28]1.FC(F)(F)C(O)=O.NCC1(NC(=O)OC(C)(C)C)CC1>>[O:39]=[S:27]1(=[O:38])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][N:30]([C:2]2[N:11]=[C:10]([NH:14][CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=2)[CH2:29][CH2:28]1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: CC(C)(C)OC(=O)NC1(CN)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NC3CCNC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 135-1 in Scheme 70 by using 2,4-dichloro-6-methylquinazoline, tert-butyl 3-aminopyrrolidine-1-carboxylate, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid instead of 2,4-dichloro-6-methylquinazoline, tert-butyl [1-(aminomethyl)cyclopropyl]carbamate, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and trifluoroacetic acid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.82 (m, 2 H), 7.78 (br. s., 1 H), 7.69-7.56 (m, 2 H), 7.48 (t, J=7.53 Hz, 1 H), 7.34 (dd, J=8.53, 1.25 Hz, 1 H), 7.22 (d, J=6.78 Hz, 1 H), 5.08 (br. s., 2 H), 4.47 (br. s., 2 H), 3.48-2.54 (m, 7 H), 2.33 (s, 3 H), 2.25-2.00 (m, 1 H), 1.81-1.68 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.[Cl:21]C(OCC)=O.[CH2:27]([N:29]1[CH2:33][CH:32]([NH2:34])[CH2:31][N:30]1[CH2:35][CH3:36])[CH3:28].C(OC(C)C)(C)C>C(Cl)Cl>[ClH:11].[ClH:21].[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:34][CH:32]2[CH2:31][N:30]([CH2:35][CH3:36])[N:29]([CH2:27][CH3:28])[CH2:33]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CCN1CC(N)CN1CC
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CN1CC
Product: Cl
Reaction time: 0.5 h

Procedure:
To an ice-sodium chloride chilled stirring suspension of 46.34 g. (0.23 mole) of 4-amino-5-chloro-2-methoxybenzoic acid in 400 ml. of methylene chloride was added 23.23 g. (0.23 mole) of triethylamine. After the temperature had fallen to 0° C., 24.96 g. (0.23 mole) of ethyl chloroformate was added dropwise while maintaining a temperature of 0°-5° C. by ice bath cooling. The mixture was stirred at this temperature for 1 hour. To this was added dropwise at 0°-5° C. a solution of 32.26 g. (0.23 mole) of 1,2-diethyl-4-pyrazolidinamine in methylene chloride and stirring was continued for 0.5 hour at this temperature. The resulting mixture was washed with a dilute solution of sodium bicarbonate and the methylene chloride dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in 2-propanol, filtered, and made acidic to litmus by bubbling hydrogen chloride gas through the solution. The product was recrystallized from a mixture of ethanol, 2-propanol and isopropyl ether. A yield of 34.6 g. of product which melted at 182°-185° C. was obtained. To the filtrate was added additional isopropyl ether and after chilling, 15.35 g. of product which melted at 179°-185° C. was obtained. The combined yield was 49.95 g. (50%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19]O)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[CH2:58]([Cl:60])[Cl:59]>>[NH3:1].[CH2:58]([Cl:60])[Cl:59].[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][C:9]=1[CH3:14])[CH3:16]
Reactant: Cc1cc(N2CCCCC2)ccc1O
Reactant: CCN(CC)CCO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(N2CCCCC2)cc1C
Product: N
Reaction time: 2 h

Procedure:
A suspension of the product of Example 17 (176 mg), 2-Diethylamino-ethanol (0.12 mL), and polymer supported triphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5 mL) was treated with di-tert-butylazodicarboxylate (316 mg). After 2 h, the resulting mixture was filtered, and the filtrate was evaporated. Chromatography of the residue (3% 2 M methanolic ammonia/DCM) gave the title compound as a pale yellow oil (37 mg). 1H NMR (400 MHz, CDCl3): 7.20 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.40 (s, 2H), 2.87 (t, J=6.5 Hz, 2H), 2.63 (q, J=7.0 Hz, 4H), 2.35 (br s, 4H), 1.59–1.52 (m, 4H), 1.46–1.37 (m, 2H), 1.07 (t, J=7.1 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([CH2:14][C@H:15]([N:19]2[C:23](=[O:24])[C@H:22]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:21][C:20]2=[O:32])[C:16](O)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([CH2:14][C@H:15]([N:19]2[C:23](=[O:24])[C@H:22]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[NH:21][C:20]2=[O:32])[C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: Nc1ccccn1
Product: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O

Procedure:
By using the conditions described in Step (iv) of Example 17, 2-aminopyridine was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd for C24H34N4O3 (M+) 427.2709, found 427.2706.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C1CCCCC1.[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20].CI>O1CCCC1>[CH2:19]([O:21][C:22]([C:24]1([CH3:1])[CH2:25][CH2:26][N:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)C1(C)CCN(c2ccc(C(C)(C)C)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (113 μL, 0.81 mmol) was diluted with tetrahydrofuran (1 mL). The resulting solution was cooled to 0° C., and a solution of n-butyllithium in cyclohexane (400 μL, 2M, 0.80 mmol) was then added. The mixture was stirred at 0° C. for 30 min. The mixture was then cooled to −78° C., and a solution of the 1-(4-Tert-butyl-phenyl)-piperidine-4-carboxylic acid ethyl ester (118 mg, 0.41 mmol, prepared in accordance with Example 48) in tetrahydrofuran (3 mL) was added. After 30 min, methyl iodide (57 μL, 0.41 mmol) was added. Afterward, the mixture was maintained at −78° C. for 1 hr. The mixture was then allowed to increase to room temperature, and maintained at that temperature for 1 hr. The mixture was then quenched with saturated aqueous ammonium chloride (15 mL). The organic phase was extracted with ethyl acetate (20 mL). The organic phase was then dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as an oil (155 mg, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[C:5]([Cl:23])=[C:4]([Cl:24])[N:3]=1.[C:25](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:20])[F:21])[CH3:25])[C:5]([Cl:23])=[C:4]([Cl:24])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Nc2c(Cl)c(Cl)nc(Cl)c2Cl)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CN(c1ccc([N+](=O)[O-])cc1C(F)(F)F)c1c(Cl)c(Cl)nc(Cl)c1Cl
Reaction time: 2 h

Procedure:
N-(2,3,5,6-Tetrachloro-4-pyridyl)-N-(4-nitro-2-trifluoromethylphenyl)amine (2.0 grams; 0.005 mole), 30 ml. of acetone, 6.0 grams of sodium carbonate and 6 ml. of dimethyl sulfate were mixed and refluxed. After 2 hours, TLC showed no evidence of product. After 8 hours, TLC showed evidence of some product formation. After about sixteen hours, the reaction mixture was quenched by adding water, heating for one hour, and then allowing to cool. Product precipitated and was separated by filtration. It was purified by passing it through a silica gel column with toluene as eluent. Yield was 0.31 gram, m.p. 152°-155° C. Elemental analysis showed
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[C:12]([F:20])=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.CCO.O.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>[F:19][C:14]1[CH:13]=[C:12]([F:20])[C:11]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: O=Cc1cc(Br)c(F)cc1F
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=Cc1cc(-c2cncnc2)c(F)cc1F
Temperature: 100 °C
Yield: 51.4 %

Procedure:
A mixture of bis(triphenylphosphine)palladium(II) chloride (0.56 g, 0.80 mmol), pyrimidin-5-ylboronic acid (0.99 g, 8.0 mmol), 5-bromo-2,4-difluorobenzaldehyde (0.88 g, 3.98 mmol), cesium carbonate (2.59 g, 7.96 mmol) in DME (13 mL), EtOH (7 mL) and water (7 mL) was heated at 100° C. for 45 min, and the crude reaction mixture was subjected to HPLC separation eluting with 0-100% A/B (A: 95% H2O/5% MeCN, 10 MM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 30 min period to give the title compound as a white solid (450 mg, 51% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ 10.40-10.33 (m, 1H), 9.28 (s, 1H), 8.94 (d, J=1.2 Hz, 2H), 8.06 (dd, J=8.4, 7.8 Hz, 1H), 7.15 (t, J=9.9 Hz, 1H), 10.37 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](O)(=[O:13])C.C1N2CN3CN(C2)CN1C3>O>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH:11]=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc[nH]c2n1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: Cc1ccc2c(C=O)c[nH]c2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
6-Methyl-1H-pyrrolo[2,3-b]pyridine (0.066 g, 0.50 mmol) was successively added with acetic acid (0.2 mL), water (0.4 mL), and hexamethylenetetramine (0.098 g, 0.70 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and then the precipitated solid was collected by filtration to obtain 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.054 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][NH2:13]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:13][CH3:12])=[O:5]
Reactant: CN
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1F

Procedure:
A solution of 2,4-difluoro-benzoylchloride D in a solution of methylamine and tetrahydrofuran (THF) is allowed to react to produce 2,4-difluoro-N-methylbenzamide M (quantitative yield). The 2,4-difluoro-N-methylbenzamide M is mixed with in a solution of acetonitrile and 4-methoxy-benzenemethanamine and heated in a microwave for 20 minutes at 190° C. to produce 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S (yield of 40%). The 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S is reacted in a solution of dichloromethane and trifluoroacetic acid to produce 2-fluoro-4-amino-N-methylbenzamide T (yield greater than 95%). The 2-fluoro-4-amino-N-methylbenzamide T is reacted with a solution of sodium cyanide and cyclobutanone to produce 4-(1-cyanocyclobutylamino)-2-fluoro-N-methylbenzamide B.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)=O.[C:16]([O:20][C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:1][C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)=[O:37])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)c1cccnc1C=O
Reactant: Cc1cnc(CNCCCCNC(=O)OC(C)(C)C)c(C)c1
Product: CC(=O)OC(C)(C)c1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1ncc(C)cc1C

Procedure:
Using general procedure B with acetic acid 1-(2-formyl-pyridin-3-yl)-1-methyl-ethyl ester and {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester gave acetic acid 1-(2-{[(4-tert-butoxycarbonylamino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester was obtained as a colorless oil. 1H NMR (CDCl3) δ 1.35 (m, 2H), 1.43 (s, 9H), 1.55 (m, 2H), 1.76 (s, 6H), 1.95 (s, 3H), 2.13 (s, 3H), 2.26 (s, 3H), 2.60 (t, 2H, J=6.0 Hz), 2.98 (m, 2H), 3.79 (s, 2H), 3.96 (s, 2H), 5.29 (br s, 1H), 7.16 (dd, 1H, J=6.0, 3.0 Hz), 7.20 (s, 1H), 7.65 (d, 1H, J=9.0 Hz), 8.17 (s, 1H), 8.50 (d, 1H, J=3.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[C:30](=[O:47])[N:31]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]([CH3:38])=[N:33]2>CN(C=O)C>[O:46]=[C:40]1[CH:39]([N:31]2[C:30](=[O:47])[C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[CH2:27][NH:26][C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=3)[N:33]=[C:32]2[CH3:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(CC(=O)O)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1F
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of (3-fluoro-4-methyl-phenyl)-acetic acid (0.25 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.27 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-Dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide as a yellow solid (500 mg, 74% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.10 min (99.3%); mp, 264-266° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 4H, CHH and CH3Ar), 2.57-2.91 (m, 6H, CHCH2, CH3), 3.51 (s, 2H, ArCH2), 4.73-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 6.99-7.72 (m, 6H, Ar), 8.34 (t, J=6 Hz, 1H, CH2NH), 11.01 (s, 1H, NH; 13C NMR (DMSO-d6) δ 13.76 (d, JC-F=3 Hz), 20.73, 23.27, 30.59, 41.60, 41.72, 56.48, 115.43 (d, JC-F=22 Hz), 117.69, 121.98 (d, JC-F=17 Hz), 124.82 (d, JC-F=7 Hz), 124.83, 125.59, 131.23 (d, JC-F=5 Hz), 133.80, 136.12 (d, JC-F=8 Hz), 140.64, 148.44, 154.80, 160.38 (d, JC-F=242 Hz), 160.91, 169.49, 169.90, 172.58. LCMS MH=451; Anal Calcd For C24H23N4O4F: C, 63.99; H, 5.15; N, 12.44; F, 4.22. Found: C, 63.61; H, 5.19; N, 12.33; F, 4.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19](I)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:20]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1

Procedure:
N-tert-Butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.74) (0.37 g, 0.86 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.33 g, 1.29 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.2 g) which was subsequently deprotected.
Reaction SMILES: O1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:18]=[CH:19][N:20]=4)[CH:14]=[C:15](Br)[N:16]=3)[CH:8]=[CH:9][C:4]=2N=C1.S(O)(O)(=O)=O.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.[NH2:36][C:37]1C=C(B(O)O)C=CC=1.C([O-])([O-])=[O:47].[Na+].[Na+]>COCCOC>[NH2:26][C:27]1[CH:28]=[C:29]([C:15]2[N:16]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[O:47][CH:37]=[N:36][C:5]=4[CH:6]=3)[C:12]3[N:13]([CH:18]=[CH:19][N:20]=3)[CH:14]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cn2ccnc2c(Nc2ccc3ncoc3c2)n1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4ocnc4c3)n2)c1
Temperature: 95 °C

Procedure:
A quantity of 0.33 g (1 mmole) of benzooxazol-6-yl-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine is dissolved in 10 mL ethylene glycol dimethyl ether and the solution purged for 15 minutes with N2. Catalytic tetrakis(triphenylphosphine)palladium (10 mol %) is added and the solution purged with N2 for 5 minutes with vigorous stirring. 3-Aminophenylboronic acid hemisulfate (0.23 g, 1.25 mmole) is added to the reaction, followed by 4 mL of 1.0N Na2CO3 and the reaction heated to 95° C. overnight in a sealed tube. The reaction is then cooled to rt, and the bilayer partitioned between ethyl acetate and water. The water layer is further extracted with ethyl acetate, and the organic extracts are pooled and washed with brine. After drying the organic extracts with solid sodium sulfate, the solvents are removed in vacuo to afford the [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzooxazol-5-yl-amine, which is purified by silica chromatography.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH3:32]>>[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29])[CH3:32]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: CCN(CC)CCCCN
Product: CCN(CC)CCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-diethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCI, ml) 488 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH:10]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=3)[NH:25][CH:24]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:8][CH2:9][CH:10]1[CH2:18][NH:19][CH2:20][CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=2)[NH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(CNCCCc2c[nH]c3ccc(F)cc23)Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]cc(CCCNCC3CNc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
The title compound was prepared in a 19% yield by reacting {[3-(5-fluoro-1H-indol-3-yl)-propylamino]-methyl}-3,4-dihydro-benzo [1,4]oxazine-4-carboxylic acid tert-butyl ester (0.49 g, 1.1 mmol) with trifluoroacetic acid (20 mL) in methylene chloride (20 mL). The reaction mixture was stirred at room temperature for two hours and then poured into saturated sodium carbonate and extracted with methylene chlloride. The organic layer was dried over anhydrous sodium sulfate, filtered and chromatographed (5% MeOH in methylene chloride) afforded 0.06 g (19%) of product as an oil. The oxalate salt was prepared in ethanol: mp 168-170° C.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14](/[CH:19]=[N:20]/[OH:21])[CH:15]=[C:16]([Br:18])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:22]=[C:23]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.C(OCC)(=O)C.O>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]2[CH2:22][C:23]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[O:21][N:20]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O/N=C/c1cc(Br)cc(OCc2ccccc2)c1
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(Br)cc(OCc3ccccc3)c2)=NO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.2 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 7.92 g) was added dropwise to a solution of (E)-1-(3-(benzyloxy)-5-bromophenyl)-N-hydroxymethanimine (1.48 g) and di-tert-butyl 2-methylenesuccinate (1.171 g) in THF (15 mL) at 0 C, and the obtained mixture was stirred at 0 C for 2 hours and subsequently at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and water was added thereto. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.67 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N(CC)CC)C.ClC(OCC)=O.[C:26]1([N:32]2[C:36]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:35](=[O:42])[NH:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.CN1CCOCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:39]1[CH2:38][CH2:37][C:36]2([N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][NH:34][C:35]2=[O:42])[CH2:41][CH2:40]1)=[O:12]
Reactant: O=C(O)C1=Cc2ccccc2C1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(C1=Cc2ccccc2C1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Indene-2-carboxylic acid (12.8g) is dissolved in dry tetrahydrofuran (300 ml), cooled to 0° C, treated with N-methylmorpholine (40 drops), triethylamine (12 ml) and ethyl chloroformate (8.6g) and stirred for 30 minutes. To this mixture is added a suspension of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (20.0g) in dry tetrahydrofuran (200 ml) and the mixture is stirred at 0° C for 30 minutes. The mixture is allowed to warm to room temperature and stirred for 16 hours. The precipitated solids are filtered off, washed with additional tetrahydrofuran, and the filtrate is concentrated. The semi-solid residue is dissolved in chloroform, washed with water and saturated sodium bicarbonate solution, dried, and concentrated to give the crude product.