Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[F:37][C:38]1[C:39]([NH:48][CH:49]2[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]2)=[C:40]([CH:44]=[C:45](I)[CH:46]=1)[C:41]([OH:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC(N(C)C)=O.O>[F:37][C:38]1[C:39]([NH:48][CH:49]2[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]2)=[C:40]([CH:44]=[C:45]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)[CH:46]=1)[C:41]([OH:43])=[O:42]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(O)c1cc(I)cc(F)c1NC1CCC(O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC4CCC(O)CC4)c(C(=O)O)c3)cc12
Temperature: 100 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.24 g, 3.27 mmol), 3-Fluoro-2-(4-hydroxy-cyclohexylamino)-5-iodo-benzoic acid (1.65 g, 3.27 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (66 mg, 0.08 mmol) in dimethylacetamide (20 mL) and aqueous solution of sodium carbonate (2M, 4.9 mL) was stirred at 100° C. for 14 h. The cooled reaction mixture was poured into 150 mL of water acidified with 6 N hydrochloric acid and filtered. The solids were redissolved in a mixture of dichloromethane and ethanol and filtered again. The filtrate was concentrated and the brown residue was purified by flash silica gel chromatography using a gradient of a solution of 90 parts ethyl acetate, 10 parts methanol, and one part acetic acid and hexanes afforded 1.5 g of a light brown solid (2.38 mmol, 76% yield). MS: m/z 630 [MH+]
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Br
Yield: 84.9 %

Procedure:
To a solution of diethyl (2-bromo-4,5-difluorobenzoyl)malonate (75.6 g) in water (100 ml) is added p-toluenesulfonic acid (0.3 g), and the mixture is refluxed for 3 hours. After cooling, the reaction mixture is extracted with dichloromethane. The dichloromethane layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue is distilled to give ethyl (2-bromo-4,5-difluorobenzoyl)acetate (52.0 g), b.p. 105°-115° C. (0.15 mmHg).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=1.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:9][C:10]#[N:11])[S:16][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC=Cc1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
A solution of diethyl(cyanomethyl)phosphonate (2.1 mL, 12.9 mmol) in anhydrous THF (50 mL) was cooled to 0° C. under nitrogen and treated with KN(TMS)2 (11 mmol of a 0.5 M solution in toluene). After stirring for 15 min at 0° C., a solution of 4-bromo-2-thiophenecarboxaldehyde 63 (Aldrich, Wis.) (1.9 g, 10 mmol) in anhydrous THF (50 mL) was added and the resulting mixture was stirred for 30 min at 0° C. Saturated aqueous NH4Cl solution was added and the crude product extracted three times with diethylether. The ether extracts were dried over Na2SO4, filtered, and evaporated, and the product was purified by flash chromatography on a silica gel column (eluent: 5% EtOAc in hexane). The major fractions were combined and concentrated to give 76 (2.1 g) in 9.3 to 1 ratio of trans to cis isomers as a white solid; For trans isomer: 1H NMR (400 MHz, d6-DMSO) δ: 7.90 (s, 1H), 7.77 (d, J=16.5 Hz, 1H), 7.57 (s, 1H), 6.28 (d, J=16.5 Hz, 1H); For cis isomer: 1H NMR (400 MHz, d6-DMSO) δ 7.97 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=11.1 Hz, 1H), 5.82 (d, J=11.7 Hz, 1H). MS (EI) m/z [(M+H+) (79Br)] 214 and [(M+H+) (81Br)] 216.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CS(O[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)(=O)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C(=O)Nc1ccc(C(C)C)cc1)CCC2
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Product: COc1ccc(CCCN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1
Yield: 57.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-3-(4-methoxyphenyl)propane (0.40 g) as starting materials, N-(4-isopropylphenyl)-N-[3-(4-methoxyphenyl)propyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C@@H:13]1[CH2:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][C@H:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[CH:24]1)(=[O:11])[CH3:10]>CN(C)C=O>[C:9]([O:12][C@@H:13]1[CH2:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][C@H:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[C:24]1[Br:1])(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)C1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1C[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)C1
Temperature: 70 °C

Procedure:
N-Bromosuccinimide (4.54 g, 25.5 mmol) was added to a solution of (±)-(1R*,2R*,4S*)-4-(acetoxymethyl)-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclopentyl acetate (8.95 g, 23.2 mmol) in dry N,N-dimethylformamide (46 mL). The solution was maintained at ca. 70° C. (oil bath) for 5 hours. Volatiles were removed in vacuo and the residual orange syrup chromatographed on silica gel. Title compound was eluted with chloroform as a pale yellow solid (5.14 g, 48%), m.p. 122°-125° C.; 1H-NMR (DMSO-d6) δ: 8.16 (s, 1, benzimidazole H7), 7.95 (s, 1, benzimidazole H4), 5.60-5.55 (m, 1, OCH), 5.12-5.03 (m, 1, NCH), 4.15 (d, J=6.3 Hz, 2, OCH2), 2.66-2.60 (m, 1, CHCH2), 2.29-2.14 (m, 3, CH), 2.06 (s, 3, CH3CO), 1.93 (s, overlapped by m, 4, CH3CO+CH); mass spectrum (CI): 469 (5.8), 467 (37.5), 465 (95), 463 (54, M+1), 199 (100, M-B).
Reaction SMILES: C1COC2(N)N(C(NC3C=CC4OC(CO)=CC=4C=3)=NC=C2F)O1.[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([C:42](OC)=[O:43])=[CH:36]3)=[N:30][CH:31]=1.CC(C[AlH]CC(C)C)C>>[F:25][C:26]1[C:27]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[N:28][C:29]([NH:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([CH2:42][OH:43])=[CH:36]3)=[N:30][CH:31]=1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Agent: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Product: OCc1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine was reduced with DIBALH to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.81 (d, 1H, J=4.2 Hz), 7.23 (d, 1H, J=1.8 Hz), 7.28–7.23 (m, 2H), 7.19 (t, 1H, J=2.4 Hz), 7.12 (dd, 1H, J=1.8 and 9.0 Hz), 7.07 (t, 1H, J=8.4 Hz), 6.52 (ddd, 1H, J=1.2 and 8.1 Hz), 6.30 (s, 1H), 4.71 (s, 2H); 19F NMR (CD3OD): −47971; LCMS: ret. time: 15.36 min.; purity: 100%; MS (m/e): 366 (MH+).
Reaction SMILES: [CH2:1]([O:8]CC(N)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]1([C:16]2[N:20]([CH3:21])[C:19]([CH:22]=[O:23])=[CH:18][N:17]=2)CC1>>[CH2:1]([O:8][CH2:13][C:16]1[N:20]([CH3:21])[C:19]([CH:22]=[O:23])=[CH:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)COCc1ccccc1
Reactant: Cn1c(C=O)cnc1C1CC1
Product: Cn1c(C=O)cnc1COCc1ccccc1

Procedure:
2-Benzyloxymethyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from 2-benzyloxy-acetamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.[SH:20][C:21]1[NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][NH:27][C:25]=2[N:26]=1>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][S:20][C:21]3[NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][NH:27][C:25]=4[N:26]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=c1[nH]c(S)nc2[nH]ccc12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSc2nc3[nH]ccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In DMF (20 ml) was dissolved 2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (836 ml) followed by addition of 1N-sodium hydroxide (5 ml). Then, under ice-cooling, a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in DMF (5 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, at the end of which time it was poured in ice-water (200 ml). The resulting precipitate was collected by filtration, rinsed with water, and dried. This precipitate was purified by flash column chromatography (3-5% ethanol-containing chloroform) to provide the title compound (1.33 g). 1H-NMR (DMSO-d6) δ: 4.52(2H,s), 6.34-6.37(1H,m), 6.91-6.95(1H,m), 7.61(2H,d,J=8.4Hz), 7.65(2H,d,J=8.4Hz), 7.70(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 11.42(1H,s), 11.95(1H,s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH:28]([C:30]1[O:31][C:32](=[O:47])[C:33]2[C:38]([C:39]=1[CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:29]>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([CH:28]([C:30]3[O:31][C:32](=[O:47])[C:33]4[C:38]([C:39]=3[CH2:40][N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:29])[N:11]=[C:10]([C:4]3[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:18]=12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1CN1CCOCC1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3CN3CCOCC3)c3ncnc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
3-(3-Fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate G1, 0.135 g, 0.521 mmol) and potassium carbonate (0.206 g, 1.498 mmol) were mixed in DMF (5 ml) and stirred at r.t. for 10 min. Then a solution of 3-(1-bromoethyl)-4-(morpholinomethyl)-1H-isochromen-1-one hydrobromide (intermediate C48, 0.215 g, 0.496 mmol) in DMF (5 ml) was added and the mixture was heated at 70° C. for 3 hrs. The reaction was quenched by the addition of 1M HCl (2 ml) and the solvent was removed under vacuum. The crude was purified by reverse phase flash chromatography on C18 Biotage cartridge (H2O:CH3CN=80:20 to 100% CH3CN, with 0.1% HCOOH) to afford 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (0.033 g).
Reaction SMILES: C(O[P:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])C.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:6]([O:5][P:4]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8])[CH3:7]
Reactant: CCOP(=O)(OCC)c1ccc(Cl)cc1
Reactant: CCCCCBr
Product: CCCCCP(=O)(OCC)c1ccc(Cl)cc1

Procedure:
3.5 g (15 mmol) of diethyl(4-chlorophenyl)-phosphonate and 3 ml (24.7 mmol) of n-pentylbromide are heated to 150° C. for 90 minutes with stirring. The cooled clear solution is chromatographed on silica gel and eluted with cyclohexane/ethyl acetate (7:3 to 1:1).
Reaction SMILES: C([S:11][CH:12]1[N:15]([C:16](=[C:30]([OH:33])[CH2:31][Br:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:34])[CH:13]1[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(OCC1C=CC=CC=1)=O.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[SH:11][CH:12]1[N:15]([C:16](=[C:30]([OH:33])[CH2:31][Br:32])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:34])[CH:13]1[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1SC(=O)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of p-nitrobenzyl α-[4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (480 mg) in methylene chloride (5 ml) containing 20% of nitromethane is added a solution of aluminum chloride (270 mg) in methylene chloride containing 20% of nitromethane (4 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into diluted hydrochloric acid, and is extracted with methylene chloride. The extract solution is washed water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (376 mg). Yield: 99.5%.
Reaction SMILES: [NH:1]([CH2:8][CH:9]([OH:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28](OCC)=[O:29].CN(C)C=O>O.C(OCC)(=O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH:9]2[CH2:8][N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:27][C:28](=[O:29])[O:19]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: OC(CNc1ccccc1)COc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CN(c2ccccc2)CC(COc2ccc(Cl)cc2)O1
Yield: 56.8 %

Procedure:
Two grams (0.0072 moles) of 1-anilino-3-(p-chlorophenoxy)-2-propanol [prepared in part (1)], 1.2 g (0.0087 moles) of K2CO3 and 2.9 g (0.0174 moles) of ethyl bromoacetate were added to 20 ml of N,N-dimethylformamide. The resulting mixture was refluxed for 5 hr with stirring. Concentration of the reaction mixture and addition of ethyl acetate and water to the residue gave a solid. The solid was collected by filtration and washed with ethyl acetate and water and dried (0.5 g). The filtrate was acidified with 10% aqueous hydrochloric acid and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After the evaporation of ethyl acetate, 20 ml of acetic acid was added to the residue and refluxed for 3 hr. The reaction mixture was concentrated under reduced pressure, and 1.3 g of the solid was obtained by crystallizing the residue from ether. Recrystallization of the combined solids (1.8 g) from benzene gave 1.3 g (57%) of crystals, m.p.142°-144°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH2:37][OH:38])=[CH:31][CH:30]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]=[O:38])=[CH:31][CH:30]=1
Reactant: OCC#Cc1ccc(-c2ncccn2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=CC#Cc1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of the Dess-Martin reagent (1.59 g, 3.75 mmol) and 3-[4-(2-pyrimidinyl)phenyl]-2-propyn-1-ol (525 mg, 2.50 mmol, prepared as described in Reference Example 239) in dichloromethane (15 mL) was stirred at room temperature for 30 min. Aqueous 10% Na2S2O3 (25 mL) and aq. sat. NaHCO3 (15 mL) were added, the mixture was stirred for 5 min, the layers were separated, and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were dried (MgSO4) and concentrated to provide 465 mg (89%) of the title compound as a yellow solid. MS 209 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+].[OH-].[Na+]>O.C(O)(=O)C>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([C:21](=[O:29])[C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2c(=O)n(CCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccc2c(=O)n(CCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To a stirred and cooled (5° C.) solution of 0.205 parts of 7-amino-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione in 50 parts of an acetic acid solution 1N was added a solution of 0.1725 parts of sodium nitrite in 2 parts of water. The whole was stirred for 20 minutes at 5° C. A solution of 0.1625 parts of sodium azide in 2 parts of water was added and stirring was continued for 20 minutes at 5° C. in vacuo. 5.5 Parts of a sodium hydroxide solution 10N were added whereupon the product solidified. The product was filtered off and crystallized from acetonitrile. The product was filtered off and dried, yielding 0.120 parts (55%) of 7-azido-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)quinazolinedione; mp. 193.7° C. (28).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH3:16])([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:3][C:4]([CH3:16])([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: CSc1ccc(C(=O)C(C)(C)O[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)C(C)(C)O)cc1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 40 mg (0.14 mmol) of 2-trimethylsilyloxy-4'-(methylthio)isobutyrophenone in 2 mL THF was added 0.2 mL of 1M n-Bu4NF in THF. The resulting mixture was stirred for 30 min and then quenched with 10 mL of NH4OAc buffer. The product was extracted with EtOAc, dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 4:1 hexane/EtOAc to give 25 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CN(Cc1ccc(Cl)cc1C(=O)O)c1ccc(Cl)cn1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2CN(C)c2ccc(Cl)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-{[(5-chloropyridin-2-yl)(methyl)amino]methyl}benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:21]=12>CN1CCCC1=O>[CH2:1]([O:8][C:16]1[N:17]=[N:18][CH:19]=[C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:21]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(C)cc3cnnc(Cl)c32)cc1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2c(C)cc3cnnc(OCc4ccccc4)c32)cc1
Yield: 80 %

Procedure:
5.63 g (52 mmol) of benzyl alcohol, 90 ml of N-methylpyrrolidone, 9.75 g (87mmol) of potassium tert-butoxide, 0.46 g (1.74 mmol) of [18]crown-6 and 5.0 g (17 mmol) of 7-chloro-1-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine are reacted at room temperature for 2 h. Purification: crystallization from ethyl acetate, concentration of the mother liquor and chromatography on silica gel (eluent: toluene/dioxane =9:1). Yield: 80%, m.p.: 152°-156° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:10]3[CH:9]=[C:8]([CH:25]=[CH:24][CH:23]=3)[CH:7]=[C:4]3[CH2:5][CH2:6][N:1]([C:33]([NH:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:34])[CH2:2][CH2:3]3)=[N:13][CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCCC3)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(N4CCCC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.2 %

Procedure:
To a solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(pyrrolidin-1-yl)pyridine (0.119 g, 0.354 mmol) in DMSO (2 mL) was added phenyl pyridin-3-ylcarbamate (0.076 g, 0.354 mmol) followed by triethylamine (0.049 mL, 0.354 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The residue was purified by silica gel column chromatography (32% acetone/hexane) to give the title compound (0.11 g, 68.8% yield). 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H), 8.24 (s, 1H), 8.12 (d, J=7.3 Hz, 1H), 7.58 (s, 1H), 7.28 (m, 1H), 6.83 (m, 6H), 6.37 (s, 1H), 3.62 (m, 2H), 3.51 (m, 2H), 3.27 (m, 4H), 2.58 (m, 2H), 2.44 (m, 2H), 2.02 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 156.57, 154.53, 153.74, 143.38, 141.54, 140.80, 138.66, 137.47, 136.49, 130.41, 129.30, 127.70, 124.96, 123.66, 122.73, 119.38, 117.18, 113.11, 47.83, 45.70, 44.75, 41.01, 35.74, 29.71, 29.15, 25.39; m/z (456.2, MH+); HPLC: 97.0%.