Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:18][NH2:19])=[O:17].C(N(CC)CC)C.[C:33](Br)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(N(C)C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:18][NH:19][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:17]
Reactant: O=C(Br)c1ccccc1
Reactant: NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[(2-naphthyl)methoxy]-5-nitrobenzhydrazide (0.30 g, 0.89 mmol) and triethylamine (0.14 mL, 0.98 mmol) in DMA (25 mL) at room temperature was added benzoyl bromide (0.11 mL, 0.89 mmol), and stirring was continued overnight. Yellowish solution was poured onto ice-water (50 g) and set aside for 24 h. Precipitate formed was filtered, washed with water, and air-dried. Off-white solid, yield 0.34 g (87%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.92 (s, 1H); 10.66 (s, 1H); 8.12-7.89 (m, 8H); 7.67-7.50 (m, 6H); 5.53 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:32])[C@@H:5]([CH3:31])[CH2:6][CH:7]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>>[C:27]([CH2:26][CH2:25][C:24]([NH:23][CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)[CH2:6][C@H:5]([CH3:31])[C:4]([OH:32])=[O:3])=[O:30])([OH:29])=[O:28]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2ccccc2OC)cc1)NC(=O)CCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1-c1ccc(CC(C[C@H](C)C(=O)O)NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-4-(3-carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester was added 1M NaOH (2 ml) and stirred at room temperature for 2 hours. Then, to the mixture was added 2 ml of 1M HCl and concentrated under reduced pressure. The obtained residue was purified by RP-HPLC(H2O(0.1% TFA)/CH3CN) to afford 110 mg of white powder. HPLC Retention time 0.86 minutes (condition A): MS 414.1 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 3H) 1.28-1.48 (m, 1′-1) 1.66-1.84 (m, 1H) 2.24-2.39 (m, 5H) 2.63-2.75 (m, 2H) 3.75-4.02 (m, 4′-1) 6.97-7.04 (m, 1H) 7.09 (d, J=7.58 Hz, 1H) 7.16-7.22 (m, 2H) 7.24-7.29 (m, 1H) 7.29-7.35 (m, 1H) 7.35-7.41 (m, 2H) 7.77 (d, J=8.59 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:29]([N:31]([CH2:41][C:42]1[C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[S:45][CH:46]=1)[C@@H:32]([CH3:40])[CH:33]([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[O:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[S:45]1[CH:46]=[C:42]([CH2:41][N:31]([C@@H:32]([CH3:40])[CH:33]([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])[C:29](=[O:30])[C@@H:20]([NH:19][C:14](=[O:16])[CH2:13][N:11]([CH3:12])[NH:10][C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 88 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)-((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:35]([NH:34][C:26]2[C:25]([CH:22]([CH3:23])[CH3:24])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:31]([CH3:33])[CH3:32])=[O:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN(C)c1ccc(CNc2ccc(C(C)(C)C)cc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-tert-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.7 g) and 2,6-diisopropylphenyl isocyanate (0.59 mL) as starting materials, N-(4-tert-butylphenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.29 g) was obtained. melting point: 154–155° C.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.S(OC)(O[CH3:31])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]=[C:16]2[O:26][CH3:31])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCn1c(=O)sc2cc(F)c(-n3c(OC)nc(C(F)(F)F)cc3=O)cc21
Reaction time: 1.5 h

Procedure:
A mixture of 27.50 g of 3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzothiazolinyl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (see Example 1), 10.80 g of dimethyl sulphate and 9.08 g of sodium carbonate in 250 ml of acetone is heated at the boiling temperature while stirring for 1.5 hours. After cooling the solid constituent is filtered off under suction and washed with acetone. The filtrate is then evaporated to dryness under reduced pressure, the residue is dissolved in 350 ml of ethyl acetate and the solution is washed three times with 300 ml of water each time. Subsequently, the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure, and the resinous residue is purified by chromatography on 1.5 g of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. The first fraction is recrystallized from ethyl acetate/diethyl ether (1:1), whereby there is obtained 6-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-3-(2-propynyl)-2-benzothiazolinone, m.p. 191°-192° C. The 2nd fraction is recrystallized from diethyl ether/n-hexane (1:1) and there is thus obtained 3-[6-fluoro-2-oxo-3-(2-propynyl)-5-benzothiazolinyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 190°-192° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(OCC)(=O)C>[F:21][C:17]1[CH:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)n1cnc2c(Nc3cccc(F)c3)nc(Cl)nc21
Reactant: NCCO
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cccc(F)c3)nc(NCCO)nc21

Procedure:
0.2 g (0.63 mmol) of 2-chloro-9-isopropyl-6-(3-fluoro-phenyl-amino)-9H-purine (prepared according to Stage 91.1) is stirred in 1 ml of ethanolamine at 150° C. for 5 h, and the mixture is then allowed to cool and is diluted with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate. On concentration of the solvent, 6-(3-fluoro-phenyl-amino)-2-(2-hydroxy-ethyl-amino)-9-isopropyl-9H-purine is obtained as a crystalline mass. This is filtered off and dried; m.p. 142° C.; FAB-MS: (M+H)+=330; Rf=0.6 (CH2Cl2:methanol 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:15])[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([NH:15][C:11]1[S:12][C:13]([CH3:14])=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:22]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(-c2nc(N)sc2C)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2C)cc1
Yield: 63.5 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-methyl-thiazol-2-ylamine prepared in Example 52 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1) to obtain a product as a white solid in a yield of 63.5%, mp: 174-175 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.51 (3H, s, ArCH3), 3.83 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.95 (3H, s, OCH3), 6.82˜6.92 (3H, m, ArH), 7.42˜7.56 (4H, m, ArH), 10.83 (1H, br, CONH); EI-MS m/e (%): 384.0 (M+, 66), 165.0 (100); HREI-MS Calcd. for C20H20N2O4S: 384.1144. found: 384.1143. Anal. Calcd. for C20H20N2O4S: C, 62.48; H, 5.24; N, 7.29. found: C, 62.30; H, 5.19; N, 7.30.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1C1C=CC=CC=1B(O)O>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C:9]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1-c1ccc(F)cc1F
Reactant: O=Cc1ccc(OCCOc2cccc(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCCOc2cccc(-c3ccc(F)cc3F)n2)cc1
Yield: 73.1 %

Procedure:
To a toluene (80 mL) solution containing 4-{2-[(6-bromo-2-pyridinyl)oxy]ethoxy}benzaldehyde (1 g) and tetrakis(triphenylphosphine)palladium (0.18 g), a 2M aqueous solution (4 mL) of sodium carbonate and a solution of 2,4-difluorophenylbenzeneboronic acid (0.64 g) in ethanol (4 mL) were added. The resultant mixture was refluxed for four hours. After completion of reaction, the reaction mixture was poured into saturated saline, and the thus-obtained toluene layer of the resultant mixture was separated. The separated layer was dried over magnesium sulfate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was purified by means of a silica gel column, to thereby yield 0.71 g of the title compound as colorless crystals (yield 64.5%).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][Cl:42])=[CH:37][CH:36]=3)[CH:31]=2)[C:12]([N:15](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:13][CH:14]=1>ClCCl>[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][Cl:42])=[CH:37][CH:36]=3)[CH:31]=2)[C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Trifluoroacetic Acid (2.500 mL) was added to a solution of tert-butyl N-[5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (500 mg, 0.8836 mmol) in dichloromethane (20.00 mL) and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated in vacuo to give 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine (323.1 mg, assumed 100% yield) which was used as such in next step. LC/MS m/z 365.4 [M−H]− Step 2: 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine was dissolved in ethanol, methanamine in ethanol (2.495 g, 3.300 mL, 26.51 mmol) was added and the mixture was stirred at 70° C. in a microwave. The reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. Combined organic extract was dried (MgSO4) and concentrated in vacuo yielding 5-bromo-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine as an oil that was used without further purification.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9]O)[OH:8])[OH:6])[OH:4].O.[NH2:12][NH2:13]>CO>[CH:9](=[N:12][NH2:13])[C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8]
Reactant: NN
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CO
Product: NN=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A solution of 4.0 g of D-arabinose in 10 ml of methanol and 10 ml of hydrazine hydrate was stirred overnight, then evaporated to dryness in vacuo. The residue was triturated with 25 ml of methanol and the solid was collected, giving 3.5 g of D-arabinose hydrazone.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:22]>>[BrH:22].[OH:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C2CNCc3ccc(C)cc32)cc1OC
Agent: Br
Product: Cc1ccc2c(c1)C(c1ccc(O)c(O)c1)CNC2

Procedure:
To 450 mg of 4-(3,4-dimethoxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline, was added 9 ml of 48% hydrobromic acid, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction solution was cooled, and the crystals which separated out were collected by filtration, giving 390 mg of 4-(3,4-dihydroxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:21]#[N:22])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:1][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:21]#[N:22])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:7]=2[O:6]1
Reactant: Cc1ccccc1-c1cc(C#N)cc2c1OC(CN=[N+]=[N-])C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccccc1-c1cc(C#N)cc2c1OC(CN)C2
Yield: 53 %

Procedure:
Treatment of 3-bromo-4-hydroxybenzonitrile (10.0 g, 50.0 mmol) with potassium carbonate (27.9 g, 200 mmol) and allyl bromide (7.96 g, 66.0 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromo-4-hydroxybenzonitrile. Treatment of 3-allyl-5-bromo-4-hydroxybenzonitrile (4.63 g, 19.0 mmol) with 3-chloroperoxybenzoic acid (6.2 g, 35.93 mmol, 77%) followed by potassium carbonate (6.56 g, 47.5 mmol) generally according to the procedure described for Intermediate 9 afforded 1.30 g (426) of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile (1.3 g, 5.0 mmol) with p-toluenesulfonyl chloride (1.02 g, 5.4 mol) generally according to the procedure described for Intermediate 10 gave 1.5 g (72%) of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.3 g, 2.20 mmol) generally according to the procedure described for Intermediate 35 afforded 0.33 g, (99%) of (±)-[5-cyano-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.26 g, 4.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (74%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of the azide with polymer-supported triphenylphosphine (0.24 g, 0.67 mmol) according to the procedure described in Example 154 afforded 0.118 g (53%) of (±)-2-(aminomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile as a white solid, hydrochloride salt. mp 127-129° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Brc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Br
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 58 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (10.0 g, 69.9 mmol, 1 eq) and 4-bromopyridine HBr (16.2 g, 83.7 mmol, 1.2 eq) were dissolved in n-butanol (120 ml) and DIPEA (23 ml, 139.8 mmol, 2.0 eq) and refluxed for 14 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 3% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 58% (9.0 g, 40.9 mmol).
Reaction SMILES: CO[C:3]([O:13][CH3:14])(OC)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.OC[C:17]([CH2:22][CH2:23][CH3:24])([CH2:20][SH:21])[CH2:18][SH:19]>>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]23[S:21][CH2:20][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][S:19]2)[CH2:14][O:13]3)=[CH:9][CH:8]=1
Reactant: CCCC(CO)(CS)CS
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Product: CCCC12COC(c3ccc(Br)cc3)(SC1)SC2

Procedure:
1-(4-Bromophenyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo[2,2,2]octane was prepared from trimethyl 4-bromo-orthobenzoate and 2-hydroxymethyl-2-n-propyl-propan-1,3-dithiol.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N:24]1([C:23]2[C:6]3[C:5]4[CH:4]=[C:3]([C:1]#[N:2])[N:11]=[CH:10][C:9]=4[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=3[N:20]=[CH:21][CH:22]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CCNCC3)ccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)piperazine-1-carboxylate (440 mg, 0.8 mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid (0.6 mL, 8.0 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium carbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-10% methylene chloride in methanol) to afford the title compound as a white foam, which was used in the next step without any further purification (200 mg, 60%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[NH:12][C:11](=[O:13])[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O-].[Na+].CI>CO>[CH3:14][N:12]1[C:11](=[O:13])[O:10][N:9]=[C:8]1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(Cc2ccccc2)no1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1c(Cc2ccccc2)noc1=O
Temperature: 0 °C

Procedure:
35.2 g. (0.2 moles) of 3-(phenylmethyl)-1,2,4-oxadiazol-5(4H)-one obtained in Example 1 (a) are dissolved in 100 ml of methanol and 110 ml. (0.22 moles) of 2N sodium methylate solution are added. The solution is evaporated to dryness and the residue is dissolved in 200 ml. of anhydrous dimethylformamide. 35.5 g. (0.25 moles) of methyl iodide are added dropwise while cooling with ice water and stirring. The reaction mixture warms slightly and is stirred overnight at room temperature. The reaction mixture is concentrated and the residue is treated with water and acidified with 2N hydrochloric acid. The crystals are filtered under suction, triturated with sodium bicarbonate solution while still moist, again filtered under suction, and washed with water. 33.6 g. of 4-methyl-3-(phenylmethyl)-1,2,4-oxadiazol-5(4H)-one are obtained, m.p. 105°-107°. After recrystallizing twice from isopropanol the m.p. is 110°-112°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(Cl)(=O)C(Cl)=O.[CH2:21]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24]>C(N(CC)CC)C>[CH2:21]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:12]([C:4]2[C:5]3[O:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=[C:2]([Cl:1])[CH:3]=2)=[O:14])[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN1CCC(CN)CC1
Reactant: Cc1nc2cc(Cl)cc(C(=O)O)c2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)cc3nc(C)oc23)CC1

Procedure:
5-Chloro-2-methylbenzoxazole-7-carboxylic acid (Ger. Offen. 2,225,544) is converted to its acid chloride by treatment with oxalyl chloride. The acid chloride is treated with N-(1-butyl-4-piperidinyl)methylamine in the presence of triethylamine to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:4]3[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=3[O:2][CH3:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: COc1cc(C)ccc1O
Product: COc1cc(C)ccc1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared starting from 2-methoxy-4-methylphenol (162 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 mmol; prepared in Example 52, Step 2) to give 233 mg (67%) of a yellow solid. HRMS m/z calcd for C18H24N4O3 (M)+ 344.1848, found 344.1839.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=O.Cl.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][NH2:29])=[N:20][N:19]=1>O1CCOCC1>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2=[N:28][N:29]=[C:13]([C:9]3[O:8][CH:12]=[CH:11][CH:10]=3)[N:20]2[N:19]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1nn2c(-c3ccco3)nnc2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
Triethylamine (1.46 ml, 10.5 mmol) and 2-furoyl chloride (1.03 ml, 10.4 mmol) were added to a stirred solution of 1-chloro-4-hydrazinophthalazine hydrochloride (2.0 g, 8.7 mmol) in dioxane (200 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 2 h and then heated at reflux for 6 h. The mixture was cooled to room temperature, the solvent evaporated in vacuo and the residue partitioned between dichloromethane (800 ml) and water (200 ml). The organic layer was separated, washed further with water (4×200 ml) and brine (x 1), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with a 0.5-2% methanol/dichloromethane gradient, to afford the title-product (0.665 g, 28%); 1H NMR (250 MHz, CDCl3) 6.68 (1H, q, J=1.7 Hz, Ar—H), 7.56 (1H, m, Ar—H), 7.73 (1H, m, Ar—H), 7.91 (1H, m, Ar—H), 8.05 (1H, m, Ar—H), 8.31 (1H, d, J=7.5 Hz, Ar—H), 8.76 (1H, m, Ar—H).