Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH2:12][C:13](O)=O)=O)C1C=CC=CC=1.NC1C=CC=CC=1O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:26]=1[NH2:38].C(OC(NCC(N[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C1)=O)=O)(C)(C)C.C(OC([NH:73][CH2:74][C@@H:75]1[CH2:79][N:78](C(OC(C)(C)C)=O)[C@@H:77]([C:87]([OH:89])=O)[CH2:76]1)=O)(C)(C)C>>[NH2:73][CH2:74][C@@H:75]1[CH2:79][NH:78][C@@H:77]([C:87]([NH:11][CH2:12][C:13]2[NH:38][C:26]3[CH:27]=[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:29]=[CH:30][C:25]=3[N:24]=2)=[O:89])[CH2:76]1
Reactant: Nc1ccc(Cc2ccccc2)cc1N
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Nc1ccccc1O
Product: NC[C@@H]1CN[C@@H](C(=O)NCc2nc3ccc(Cc4ccccc4)cc3[nH]2)C1

Procedure:
This compound was prepared as in Compound M77, replacing N-(Benzyloxycarbonyl)-D-homophenylalanine with N-(Benzyloxycarbonyl)glycine, 2-aminophenol with 1,2-diamino-4-benzylbenzene and trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline with trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-D-proline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[K].CCN([CH2:17][CH3:18])CC.[CH2:19](Cl)Cl>CC(O)C.O.CCOCC>[CH2:19]=[C:17]([C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1)[CH3:18]
Reactant: CC(=O)c1cncc(Br)c1
Reactant: ClCCl
Reactant: CCN(CC)CC
Agent: [K]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: C=C(C)c1cncc(C(C)=O)c1
Temperature: 25 °C
Yield: 3170.7 %

Procedure:
A stirred solution of 1-(5-bromopyridin-3-yl)ethanone (600 mg, 3.0 mmol), potassium isopopenyltrifluoroborate (148 mg, 3.0 mmol), and Et3N (1.25 mL, 9.0 mmol) in iPrOH (20 mL) and H2O (10 mL) was degassed with argon for 10 min and then PdCl2 (dppf).CH2Cl2 (74 mg, 0.09 mmol) was added and the reaction mixture was heated to reflux for 5 h. The solution was cooled to room temperature and diluted with Ether and H2O. The layers were separated and the aqueous layer was extracted with Ether (2×50 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc in hexanes) to provide 460 mg of 1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanone.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[C:37]([CH:38]=O)=[CH:36][NH:35][N:34]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:37]4[C:33]([CH3:32])=[N:34][NH:35][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: Cc1n[nH]cc1C=O
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]nc4C)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 3-methyl-1H-pyrazole-4-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH:12]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.O1CCCC1>[CH2:1]=[C:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:24]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A suspension of methyl triphenylphosphonium bromide (31.22 g; 87.3 mmol) in 500 mL of ether was added at -30° C. 10M n-butyllithium in hexane (8.73 mL; 87.3 mmol) and the mixture was allowed to stir at room temperature for 1/2 h. To the above mixture was added 15 g (83.2 mmol) of 9-fluorenone in 50 mL of tetrahydrofuran and the mixture was refluxed for 1 h. The above mixture was cooled to 0° C., filtered, and concentrated to yield 11.3 g (76.3%) of 9-methylene-fluorene (Formula III: R3 =R4 =H; R5 =R6 together form a 9-fluorene ring).
Reaction SMILES: NS(C1C=CC(CCN[C:14]([C:16]2[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[O:15])=CC=1)(=O)=O.CC1N=CC([C:30](O)=[O:31])=NC=1>CO>[CH3:30][O:31][C:14]([C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:15]
Reactant: Cc1cnc(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)cn1
Reactant: Cc1cnc(C(=O)O)cn1
Solvent: CO
Product: COC(=O)c1cnc(C)cn1

Procedure:
A process for the preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of the formula I: ##STR21## consisting of: i) treating 5-methylpyrazine-2-carboxylic acid of the formula VIII: ##STR22## with methanol under reflux to obtain 5-methylpyrazine-2-carboxylic acid methyl ester of the formula VIII A: ##STR23## ii) reacting 5-methylpyrazine-2-carboxylic acid methyl ester of the formula VIII A with 2-phenylethylamine of the formula II: ##STR24## at 100° to 200° C. to obtain 5-methylpyrazine 2-(2-phenylethyl) carboxamide of the formula IX: ##STR25## iii) chlorosulfonating the 5-methylpyrazine-2-(2-phenylethyl)carboxamide of the formula IX with chlorosulfonic acid at 0°-45° C. to obtain [N-[2-[4-(chlorosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide] of the formula X: ##STR26## iv) and treating the [N-[2-[4-(chlorosulfonyl)phenyl]ethyl]-5-methyl purazinecarboxamide] of the formula X with ammonia to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the formula I.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.C(Br)C1C=CC=CC=1.C([O:46][C:47](=[O:58])[C:48](SC1SC(N)=NC=1)([CH3:50])[CH3:49])C>>[CH2:4]([O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][C:48]([CH3:50])([CH3:49])[C:47]([OH:58])=[O:46])=[CH:14][N:15]=1)[C:3]1[CH:2]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: BrCc1ccccc1
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using benzyl bromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.[C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[CH:16][CH2:15][CH2:14]2)#[N:10].O>CS(C)=O.C(Cl)Cl>[C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[CH:16][CH2:15][CH2:14]2)(=[O:2])[NH2:10]
Reactant: N#Cc1ccc2c(c1)CCC=C2n1ccnc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc2c(c1)CCC=C2n1ccnc1
Reaction time: 24 h

Procedure:
Potassium carbonate and 30% aqueous H2O2 solution are added several times, within a period of 24 hours, to 6-cyano-1-(1-imidazolyl)-3,4-dihydronaphthalene (Example 1) in DMSO and CH2Cl2. Finally, water is added and the solid is filtered off, yielding the title compound.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:29])[CH2:18][C@@H:19]1[C@@H:22]([C:23]([O:26][CH3:27])([CH3:25])[CH3:24])[C:21](=[O:28])[NH:20]1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[O:29]=[C:17]1[CH2:18][C@H:19]2[N:20]([C:21](=[O:28])[C@@H:22]2[C:23]([O:26][CH3:27])([CH3:24])[CH3:25])[C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COC(C)(C)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 4-nitrobenzyl 2-diazo-4-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxo-azetidin-2-yl]-3-oxobutanoate (56.5 mg) and a catalytic amount of rhodium (II) acetate (ca. 1 mg) in dry benzene (5.6 ml) was refluxed for 30 minutes. After cooling to ambient temperature, the mixture was filtered and evaporated in vacuo to give 4-nitrobenzyl (2R, 5R, 6S)-3,7-dioxo-6-(1-methoxy-1-methylethyl)-1-azabicyclo[3.2.0]-heptane-2-carboxylate (50.0 mg) as an amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]3[O:20][CH2:21][O:22][C:15]=13)=[CH:10][C:9]([O:23][CH3:24])=[C:8]([O:25][CH2:26][C@@H:27]1[O:29][CH2:28]1)[CH:7]=2)#[N:2].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:28][C@@H:27]([OH:29])[CH2:26][O:25][C:8]2[CH:7]=[C:6]3[C:11]([C:12]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]5[O:20][CH2:21][O:22][C:15]=45)=[C:3]([C:1]#[N:2])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:23][CH3:24])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OC[C@H]1CO1
Product: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OC[C@H](O)CN1CCN(C(C)=O)CC1
Yield: 35 %

Procedure:
Using an analogous procedure to that described in Example 11, 3-cyano-7-[(2R)-2,3-epoxypropoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinoline was reacted with 1-acetylpiperazine to give the title compound in 35% yield; NMR Spectrum: (DMSOd6) 1.96 (s, 3H), 2.34-2.54 (m, 6H), 3.35-3.45 (m, 4H), 3.94 (s, 3H), 4.0-4.1 (m, 2H), 4.13-4.21 (m, 1H), 4.94 (d, 1H), 5.97 (s, 2H), 6.80-6.92 (m, 3H), 7.23 (s, 1H), 7.76 (s, 1H), 8.4 (s, 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 520.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])=[CH:18][NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:27]=1.[C:28]([Cu])#[N:29]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[C:15]([C:13]2[S:12][C:11]3[C:5]4[CH:4]=[CH:3][C:2]([C:28]#[N:29])=[CH:27][C:6]=4[O:7][CH2:8][CH2:9][C:10]=3[CH:14]=2)=[N:16][NH:17][CH:18]=1
Reactant: Clc1ccccc1-c1c[nH]nc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: N#C[Cu]
Product: N#Cc1ccc2c(c1)OCCc1cc(-c3n[nH]cc3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedure of Example 53, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-1H-pyrazole and CuCN gave 275. MS: (ESI+) 404.1
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+]>CO>[N:14]([CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(O)C1CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
To a solution of 8-(oxiran-2-yl)-1,4-dioxaspiro[4.5]decane (205 mg, 1.11 mmol), prepared in the previous step, in methanol (5 mL) water (0.5 mL) was added sodium azide (361 mg, 5.56 mmol) and ammonium chloride (119 mg, 2.22 mmol). The mixture was stirred, heating to 80° C. under argon overnight and then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ether) to afford the product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.[C:25]1(O)[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:33]1([O:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)[C:34]2[CH2:25][CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Reactant: Oc1cccc2c1CCCC2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3cccc4c3CCCC4)c3ccccc23)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.302 mmol) was dissolved in THF (6 mL). 5,6,7,8-Tetrahydronaphthalen-1-ol (0.067 g, 0.454 mmol) was added, and after 25 min di-tert-butyl azodicarboxylate (0.105 g, 0.454 mmol) was added. The reaction mixture was stirred at 40° C. for 5 h. The solvent was removed in vacuo. The crude product was flash chromatographed (9:1 hexane:EtOAc) and tert-butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate was obtained in 22% yield. tert-Butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.028 g, 0.061 mmol) was dissolved in EtOAc (5 mL). 4N HCl in dioxane (2 mL) was added. The reaction mixture was stirred at rt under N2 for 20 h. The solvent, was removed in vacuo. The crude product was dissolved in EtOAc (2 mL) and Et2O (3 mL) was added dropwise. The precipitate was collected by filtration, wash with Et2O and dried in vacuo at reduced pressure to yield 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride in 73% yield. 1H NMR (400 MHz, CD3OD) δ 1.66-1.72, 2.35-2.39, 2.65-2.72, 3.20-3.23, 3.36-3.50, 4.23-4.28, 4.61-4.64, 6.51, 6.63, 6.93, 7.10, 7.18, 7.44, 7.50; MS (ESI+) for C24H28N2O m/z 361.1 (M+H)+.
Reaction SMILES: C[C:2]1[N:3]([C@H:29]2[C@H:33]([OH:34])[C@H:32]([OH:35])[C@@H:31]([C:36]([NH:38][CH2:39][CH3:40])=[O:37])[O:30]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:7]=[C:6]([C:26]([NH2:28])=[O:27])[N:5]=2.[CH2:41](N)[CH2:42][NH2:43]>ClCCl>[NH2:43][CH2:42][CH2:41][NH:28][C:26]([C:6]1[N:5]=[C:4]2[C:9]([N:10]=[CH:2][N:3]2[C@H:29]2[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@@H:31]([C:36]([NH:38][CH2:39][CH3:40])=[O:37])[O:30]2)=[C:8]([NH:11][CH2:12][CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1)=[O:27]
Reactant: NCCN
Reactant: CCNC(=O)[C@H]1O[C@@H](n2c(C)nc3c(NCC(c4ccccc4)c4ccccc4)nc(C(N)=O)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@H]1O
Temperature: 105 °C
Yield: 86.1 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 9) (1.1 g, 2 mmol) and 1,2-ethylenediamine (1.1 g, 18.3 mmol) was heated at 105° C. for 2.5 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.99 g, 86%)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>CN(C)C(=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:26]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=1
Reactant: N#Cc1c(F)cccc1Oc1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(-c2ccccc2)nc2cccc(Oc3ccccc3)c12
Temperature: 150 °C
Yield: 12.3 %

Procedure:
A mixture of 2-fluoro-6-phenoxybenzonitrile (2.7 g, 13 mmol), benzamidine hydrochloride (Aldrich) (3.0 g, 19 mmol) and sodium acetate (1.6 g, 19 mmol) in 60 ml of N,N-dimethylacetamide was heated at 150° C. under nitrogen for 6.5 hours. After cooling to room temperature the reaction mixture was evaporated under reduced pressure. The product was suspended in 20 ml of ethanol and water (100 ml) and concentrated ammonium hydroxide (10 ml) was added. The precipitate was isolated by filtration, washed with water, dried and recrystallized twice from 60 ml of 2-propanol at 4° C. The precipitate was collected by filtration, washed with 2-propanol and dried at 50° C. in vacuo to give 4-amino-2-phenyl-5-phenoxyquinazoline (0.5 g, 12%, m.p. 190-191° C.):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9]
Reactant: OO
Reactant: COc1ccccn1
Solvent: CC(=O)O
Product: COc1cccc[n+]1[O-]
Temperature: 80 °C

Procedure:
This compound, originally prepared by H. J. Den Hertog and M. Van Ammers, Rec. Trav. Chim. 1955, 74, 1160, was synthesized using a different procedure. To a solution of 21.83 of 2-methoxypyridine (0.2 mol) in glacial acetic acid (80 ml), was cautiously added 30% hydrogen peroxide (20 ml). The stirred mixture was heated to 80° C. for 3 hrs, and cooled to room temperature. An additional 20 ml of 30% H2O2 was added, and the clear solution was heated at 80° C. for 12 hrs. The solution was concentrated to half the original volume under vacuum, and 100 ml of water was added. The solution was reconcentrated, and the process was repeated two times (2×100 ml H2O). The syrup was placed under vacuum to remove remaining water and acetic acid. After time, a white solid formed. The material obtained in quantitative yield was used without further purification; M.P. 128°-130° C.; IR (KBr) 3447, 1613, 1570, 1508 1447, 1316, 1214, 1015, 764 cm-1 ; 1H NMR (CDCl3) δ 4.05 (s, 3H), 6.91 (d, 1H, J=8.0 Hz), 6.92 (m, 1H), 7.33 (dt, 2H, J=8.0, 1.6 Hz), 8.3 (dd, 1H, J=6.3, 1.6 Hz). HRMS Calcd. for C6H7NO2 : 125.0477. Found: 125.0474.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:16])[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CN(Cc2ccc(Br)cc2)C1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
1-(4-Bromobenzyl)imidazolidine-2,4-dione (1B4) (1.86 mmol, 500 mg) was dissolved in DMF (7 ml) and potassium carbonate (5.57 mmol, 770 mg) and iodomethane (1B5) (1.86 mmol, 0.116 ml, 264 mg) were added and the reaction mixture was stirred at 50° C. under nitrogen. The reaction was monitored by TLC and after 48 h of heating some starting material remained. An additional 2 equivalents of iodomethane (3.72 mmol, 0.232 ml, 528 mg) was added and the mixture stirred at 75° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, filtrated and concentrated, then purified on silica eluting with heptane/EtOAc/EtOH 5/4/1 to give 1-(4-bromobenzyl)-3-methylimidazolidine-2,4-dione (1B6) 438 mg, (83%); 1H NMR (400 MHz, CDCl3) 7.51 (d, 2H) 7.15 (d, 2H) 4.53 (s, 2H) 3.74 (s, 2H) 3.06 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].ClC(=O)CC(OC)=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N)(=O)CCC(N)=O>>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][C:2]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Reactant: COC(=O)CC(=O)CCl
Agent: NC(=O)CCC(N)=O
Product: COC(=O)CCC(=O)Nc1ccccc1

Procedure:
Using the same reaction conditions as described in Example 20-step a except that methyl 4-chloro-3-oxobutyrate replaced methyl 3-chloro-3-oxopropionate, aniline (2.33 g, 25 mmol) was converted to the succinamide compound (5.18 g, 100%) after purification by chromatography over silica gel. 1H NMR (400 MHz, CDCl3) δ: 7.70 (s, 1H), 7.50 (d, 2H), 7.30 (t, 2H), 7.09 (m, 1H), 3.70 (s, 3H), 2.73–2.65 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>CN(C)C=O>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([S:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-ol (0.99 g), N,N-dimethylformamide (40 mL), potassium carbonate (0.60 g) and bromoacetic acid methyl ester (0.32 mL) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue diluted with water and this mixture was extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) gave title compound as a white solid, 0.26 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16]C)=[N:14][CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.N1C=CC=CC=1>ClCCl.O>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(Oc2ncc(Cl)cc2Cl)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cn1
Temperature: 200 °C

Procedure:
A mixture of 5-(3,5-dichloro-pyridin-2-yloxy)-2-methoxy-pyridine (2.39 g, 8.82 mmol) and pyridine hydrochloride (7.00 g, 60.6 mmol) was heated in a kugelrohr apparatus at 200° C. for 25 minutes. After cooling to room temperature dichloromethane and water were added. The solid material, which was insoluble in dichloromethane and water, was isolated by suction and dried in a vacuum oven at 45° C., yielding the title compound, which was used without further purification.