Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)[CH:4]=[C:3]1[C:24]([O:26]CC)=O.P(Cl)(Cl)(Cl)=O.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[NH:42][NH2:43].C(=O)([O-])[O-].[K+].[K+]>>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[N:42]1[C:24](=[O:26])[C:3]2=[CH:4][N:5]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:17][CH:18]=3)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:43]1
Reactant: NNc1c(F)cccc1F
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4-dihydroquinoline-3-carboxylate (0.10 g, 0.27 mmol) was dissolved in phosphorus oxychloride (0.75 mL, 8.0 mmol, 30 equiv) and stirred vigorously for 1 hour at ambient temperature. The mixture was concentrated in vacuo and the residue was concentrated from toluene (3×10 mL). The resulting 4-chloro-3-[(ethyloxy)carbonyl]-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}quinolinium salt was dissolved in N,N-dimethylformamide (3 mL) and treated with (2,6-difluorophenyl)hydrazine (92 mg, 0.64 mmol, 2.5 equiv) and potassium carbonate (0.18 g, 1.3 mmol, 5 equiv). The mixture was placed into an oil bath preheated to 80° C. for 1 hour, cooled to ambient temperature and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (82:20 to 5:95; water containing 0.05% trifluoroacetic acid:acetonitrile containing 0.05% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.18 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.18 (1H, dd, J=7.9, 1.3 Hz), 7.83 (2H, d, J=8.7 Hz), 7.78 (1H, d, J=9.0 Hz), 7.72 (1H, d, J=1.6 Hz), 7.66-7.57 (2H, m), 7.53 (1H, t, J=7.4 Hz), 7.48 (2H, d, J=8.5 Hz), 7.34 (2H, t, J=8.3 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.78 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 453.9 [(M+H)+; calculated for C26H18F2N5O: 454.1].
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28]Br>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1cccc(CCBr)c1
Product: Cc1ccc(N(CCc2cccc(F)c2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 3-fluorophenethylbromide (1.38 g, 6.7 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: CN(C)CCNCc1ccccc1
Product: CN(C)CCN(Cc1ccccc1)c1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 3.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 448 using 6 (200 mg, 0.87 mmol) and N′-benzyl-N,N-dimethylethane-1,2-diamine (0.67 ml, 3.47 mmol) to provide 450 (11 mg, 3% yield) as a white powder. LC-MS (M+H=373, obsd.=373). 1H NMR (400 MHz, DMSO-D6) δ 11.61 (s, 1H), 9.88 (m, 1H), 8.76 (d, J=7.5, 1H), 8.45 (d, J=3.4, 1H), 8.08 (d, J=9.0, 1H), 7.57 (s, 1H), 7.20 (m, 6H), 7.10 (d, J=7.0, 1H), 4.86 (s, 2H), 4.02 (m, 4H), 2.89 (d, J=4.7, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1.C1O[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:19](Cl)[CH2:20][CH3:21])[O:17]C1>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]([CH2:19][CH2:20][CH2:21][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][O:7]3)[CH2:3][CH2:2]2)=[O:17])=[CH:28][CH:27]=1
Reactant: CCC(Cl)C1(c2ccc(F)cc2)OCCO1
Reactant: c1ccc2c(c1)COC21CCNCC1
Product: O=C(CCCN1CCC2(CC1)OCc1ccccc12)c1ccc(F)cc1

Procedure:
Reaction of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine] and α-chloro-p-fluorobutyrophenone ethylene ketal by the method described in Example 6 provides 1,3-dihydro-1'-[3-(4-fluorobenzoyl)propyl]spiro[isobenzofuran-1,4'-piperidine] as a solid, hydrochloride salt, m.p. 215°-217°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:33][CH2:32][N:31]([CH:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[C:42]([NH2:45])[CH:43]=[CH:44][C:37]=4[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH2:24][CH2:23]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:45][C:42]2[CH:43]=[CH:44][C:37]3[CH2:36][CH2:35][CH:34]([N:31]4[CH2:32][CH2:33][CH:28]([N:25]5[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]5)[CH2:29][CH2:30]4)[CH2:40][CH2:39][C:38]=3[CH:41]=2)=[N:3][CH:4]=1
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(C2CCN(C3CCc4ccc(N)cc4CC3)CC2)CC1
Product: CN1CCN(C2CCN(C3CCc4ccc(Nc5ncc(Cl)c(Nc6c(F)cccc6OCC#N)n5)cc4CC3)CC2)CC1

Procedure:
The title compound was prepared by combining [2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-phenoxy]-acetonitrile (Example N?, 31.3 mg, 0.100 mmol) and 7-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (Example N?, 25.2 mg, 0.074 mmol) in an analogous manner described in Example 151d. The title product was isolated as described in Example 1475b as a white foam (33 mg, 66%) that had the following properties: m.p: 110-116° C.; LC/MS (m/e): 620 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.10 (s, 1H), 7.36 (dd, J=14.7, 7.8 1H), 7.14 (s, 1H), 7.05 (d, J=6.9, 1H), 7.01 (d, J=8.7, 1H), 6.94-6.90 (m, 2H), 6.88 (s, 1H), 6.50 (s, 1H), 4.73 (s, 2H), 2.90-2.80 (m, 2H), 2.75-2.35 (m, 10H), 2.30 (s, 3H), 2.30-2.18 (m, 2H), 2.10-2.00 (m, 2H), 1.85-1.65 (m, 4H), 1.65-1.45 (m, 2H) 1.40-1.20 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=23)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C(OCC)(=O)C>[F:22][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:2]=1[NH:1][C:32]([NH:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[F:23])=[O:33])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=12
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: COC(=O)c1cc2nccc(Oc3ccc(N)c(F)c3)c2s1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.62 g, 5.1 mmol) was taken up in 55 mL of ethyl acetate followed by the dropwise addition of 2-fluoro-5-methylphenyl isocyanate (0.85 g, 5.6 mmol) in 5 mL ethyl acetate. The solution afforded a lavender solid after stirring at room temperature for overnight. The solid was collected by filtration and washed with diethyl ether to give methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate as an off white solid. Yield: 1.75 g (73%); MS [M+H]+ 470.1; 1HNMR (DMSO-d6) δ: 9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H, 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 3.9 (s, 3H), 2.1 (s, 3H) ppm.
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].C(N(S(F)(F)[F:27])CC)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[F:27][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:20]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
A well stirred suspension of 10 g (0.03 mol) of 3-hydroxy-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one and 500 ml of methylene chloride was cooled to -70°. Diethylaminosulfur trifluoride (25 ml, 0.2 mol) was then added dropwise with exclusion of moisture and air. On completion of the addition the dry-ice acetone bath was removed, the contents of the flask were allowed to warm up in about 25 minutes to -10° and the reaction then immediately quenched by pouring into a beaker containing 400-500 ml of ice water. (If the reaction mixture is allowed to warm to 25°, none of the desired product is obtained.) Vigorous stirring of the ice water mixture continued for 7 to 10 minutes. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure to give a light orange powder. The product was dissolved in hot benzene, treated with decolorizing charcoal and filtered hot. On addition of heptane to the benzene solution, followed by cooling in ice, 3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one crystallized out as a white powder, 8.19 g (82%): mp 190°-192° (decom.); 19F nmr (DMSO-d6) δ -161.5 ppm (d, d, J = 56, 4 Hz, 1H), 1H nmr (DMSO-d6) δ 7.2-7.8 (m, 8H), δ 5.72 (d, J = 56 Hz, 1H), δ 11.0 ppm (N-H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH2:41][C:42](O)=[O:43])[CH:39]=2)[CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][C:38]3[CH:39]=[C:40]4[C:35]([CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:36][CH:37]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: O=C(O)Cc1ccc2cccnc2c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc4cccnc4c3)c2)c2cncnc21

Procedure:
Prepared according to the method described for Example 1 using (5-aminopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Preparation 38), and 2-quinolin-7-ylacetic acid with DIPEA as base.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](=O)[CH2:7][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:1][C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1CC(=O)S2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(F)c2sccc12
Temperature: 35 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 7-fluoro-4-methoxy-1-benzothiophen-2(3H)-one (1.06, 5.4 mmol) in dichloromethane (10 mL) at 0° C. was added slowly a solution of diisobutylaluminium hydride in dichloromethane (1 M, 8.04 mL, 8.0 mmol). After 30 mins the reaction was quenched by careful addition of aqueous hydrochloric acid (6 N, 25 mL). The mixture was concentrated to remove the dichloromethane, the aqueous residue was then stirred at 35° C. for 2 h. The aqueous solution was extracted with diethyl ether (3×50 mL), washed with aqueous sodium hydroxide (2 N, 50 mL), brine (50 mL) then dried (MgSO4) and the solvent evaporated in vacuo to give the title compound (0.86 g, 87%) as a purple oil; δH 7.44–7.38 (1H, m, ArH), 7.36–7.24 (1H, m, ArH), 6.88–6.80 (1H, m, ArH), 6.57–6.49 (1H, m, ArH) and 3.82 (3H, s, OCH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[O:28][C:27]([CH2:29][OH:30])=[CH:26][CH:25]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[O:28][C:24]([C:23]([F:32])([F:22])[F:31])=[CH:25][CH:26]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: OCc1ccc(C(F)(F)F)o1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)o4)cc3=O)cn12
Temperature: 100 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a suspension of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (120 mg) and (5-(trifluoromethyl)furan-2-yl)methanol (87 mg) in toluene (2 ml) was added potassium tert-butoxide (117 mg) at room temperature, and the mixture was stirred at 100° C. for 1 h. The mixture was quenched with water, and the precipitate was collected by filtration and washed with IPE to give the title compound (75 mg) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH:15]([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:23][CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: CCC(NC(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(O)cccc3C2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OCc4ccccc4)cccc3C2C1
Temperature: 80 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-hydroxy-pyrazino[2,1-a]isoindol-6(2H)-one (30 mg, 0.10 mmol) from Example 72, Step B, in N,N-dimethylformamide (1.5 mL) was added benzyl bromide (0.017 L, 0.15 mmol) and potassium carbonate (41 mg, 0.29 mmol). The resulting mixture was warmed to 80° C. After 4 h the reaction was cooled to room temperature, diluted with ethyl acetate, washed with 50% saturated aqueous sodium chloride, and the the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (30% ethyl acetate in hexanes) to give the desired product as a clear residue (31 mg, 80%). MS (ESI) 395.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:23][C:24]3[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:33])=[N:19][CH:20]=2)[N:15]([CH3:34])[C:14]1=[O:35].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:33])[C:24]=1[NH:23][C:18]1[N:17]=[C:16]2[N:15]([CH3:34])[C:14](=[O:35])[N:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])[CH2:22][C:21]2=[CH:20][N:19]=1
Reactant: COc1cc(OC)c(Cl)c(N2Cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3N(C)C2=O)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(N2Cc3cnc(Nc4c(C)cccc4N)nc3N(C)C2=O)c1Cl
Temperature: 70 °C
Reaction time: 6 h
Yield: 9.9 %

Procedure:
A mixture of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(2-methyl-6-nitrophenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (290 mg, 0.56 mmol) in ethanol (10 mL) and water (2 mL) was stirred at 70° C. for 20 mins before iron powder (320 mg, 5.60 mmol) and ammonium chloride (250 mg, 2.79 mmol) were added. The reaction mixture was stirred at 70° C. for another 6 h. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated. The residue was dissolved by ethyl acetate (30 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give the title compound (27 mg, 10%) as a white solid. MS (ES+) C22H22Cl2N6O3 requires: 488, 490. found: 489, 491 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ ppm 7.89 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.69 (d, 2H, J=7.5 Hz), 6.60 (s, 1H), 4.53 (s, 2H), 3.94 (s, 6H), 3.34 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[CH:7]=1)[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])[CH:7]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)Cc1cccc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester and (3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)([O-:26])=[O:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg (0.37 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 17 mg (0.44 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 76 mg (0.44 mmol) of 4-nitrobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[H][H]>O=[Pt]=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:6][NH:7][C:8]1[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: COc1cc(CNc2ccccc2[N+](=O)[O-])ccc1CN1CCCC1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1cc(CNc2ccccc2N)ccc1CN1CCCC1

Procedure:
The title compound was prepared by the addition of Adam's catalyst (160 mg, 10% wt.) to a degassed solution of N-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-2-nitroaniline (1.6 g, 4.69 mmol) in absolute ethanol (25 mL). The atmosphere was replaced with hydrogen then the reaction was stirred vigourously at ambient temperature until all of the nitro compound had been consumed as determined by tlc (9:1 CHCl3:MeOH, 1% TEA). The reaction mixture was filtered through a bed of diatomaceous earth, then the solvent was removed under reduced pressure to give the diamine as a brown yellow oil (1.46 g, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8]NCC(O)C)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:16][CH:17]([CH2:38]OC1C2C(=CC=CC=2)C=CC=1)[CH2:18][NH:19][C:20]1[C:21]2[N:22]=[CH:23][N:24]([C:34]=2[N:35]=[CH:36][N:37]=1)[C@@H:25]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]1[OH:27]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:38][CH:17]([OH:16])[CH2:18][NH:19][C:20]2[C:21]3[N:22]=[CH:23][N:24]([C:34]=3[N:35]=[CH:36][N:37]=2)[C@@H:25]2[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]2[OH:27])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCC(O)COc4cccc5ccccc45)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)c1ccc(ONCC(C)O)cc1
Product: CC(=O)c1ccc(OCC(O)CNc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1

Procedure:
By substituting (4-acetylphenoxy)-2-hydroxypropylamine (3.65 g, 0.017 mole) for the 2-hydroxy-(1-naphthalenyloxy)propylamine of Example 1 and following the method of Example 1, N6 -[3-(4-acetylphenoxy)-2-hydroxypropyl]-adenosine was obtained.
Reaction SMILES: [C:1]([C:6]1[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]([OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19].P(Cl)(Cl)Cl>C1(C)C(C)=CC=CC=1>[C:1]([C:6]1[CH:14]=[C:10]([C:11]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[CH3:16])=[O:13])[C:9]([OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCC(C)(C)c1ccc(O)c(C(=O)Nc2ccc([N+](=O)[O-])cc2C)c1
Temperature: 70 °C
Yield: 55 %

Procedure:
A mixture of 10.4 g of 5-tert-amylsalicylic acid and 7.6 g of 2-methyl-4-nitroaniline in 100 ml of xylene is heated at 70° C and to the mixture is added a solution of 2.6 g of phosphorus trichloride in 10 ml of xylene. The whole mixture is refluxed for two and a half hours. The hot reaction solution is decanted. The supernatant solution is cooled on an ice bath. The crystalline precipitate is collected by filtration. Recrystallization from methanol gives 9.4 g of the title compound as pale yellow crystals, melting at 150°-151° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[F:15])#[N:2].[OH-:16].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[CH3:14][C:10]1([CH3:13])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([F:15])=[C:3]([C:1]([NH2:2])=[O:16])[C:12]=2[O:11]1
Reactant: CC1(C)C=Cc2ccc(F)c(C#N)c2O1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)C=Cc2ccc(F)c(C(N)=O)c2O1
Yield: 48.8 %

Procedure:
A stirred solution of 5.0 grams (0.025 mole) of 8-cyano-2,2-dimethyl-7-fluoro-2H-1-benzopyran and 5.1 grams (0.091 mole) of potassium hydroxide in 60 mL of tert.-butanol was maintained at reflux for one hour and then poured into an aqueous solution saturated with sodium chloride. The mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 2.7 grams of 2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-ylcarboxamide. The NMR spectrum was consistent with the proposed structure.