Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][O:17][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Solvent: ClCCl
Product: CC1(C)CCC(N(C(=O)C(C)(C)COS(C)(=O)=O)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (300 mg, 0.76 mmol) prepared in Step B of Example A8 in DCM was added TEA (192 mg, 1.9 mmol), slowly added dropwise methanesulfonylchloride (104 mg, 0.91 mmol) at 0° C., and the solution was heated to rt, and stirred for 1 h. After the reaction finished, the solvent was concentrated in vacuo, and washed with water and EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/2) to give (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl){2,2-dimethyl-3-[(methylsulfonyl)oxy]propanoyl}amino]pyrrolidine (250 mg, 75%). A solution of this compound (200 mg, 0.42 mmol) in THF was added dropwise TBAF (in THF, 1.0M 0.5 ml, 0.5 mmol), and the solution was stirred at 80° C. for 3 h. After the reaction finished, the solvent was concentrated in vacuo, and extracted with 1N-HCl and EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/4) to give the title compound (147 mg, 89%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[P:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CCOCC>[C:5]1([CH2:4][CH2:3][P:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOP(Cl)OCC
Reactant: BrCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCOP(CCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4.13 g (0.172 mol) of magnesium in 45 ml of dry ether under argon was treated with a solution of 31.2 g (0.168 mol) of 1-bromo-2-phenylethane (Aldrich) in 90 ml of dry ether, added at a rate that maintained reflux. The reaction was stirred overnight at room temperature under argon, then filtered under argon, cooled to 10° C. and treated with 26.3 g (0.168 mol) of diethyl chlorophosphonite (Aldrich) dissolved in 60 ml of dry ether, added slowly to keep the temperature near 10° C. After addition, the reaction was refluxed for 1 hour, filtered under argon and distilled at 1 atm to remove ether. Vacuum distillation of the residue gave 20.6 g (54%) of the title A compound which distilled at 94°-96° C./0.55 mm Hg. The 1H-NMR and 13C-NMR of this material were both consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])c(C)c1

Procedure:
The product was prepared by the alkylation of 4-nitro-3-methylphenol (15.3 g) with ethyl bromoacetate (16.7 g) in DMF (150 mL) in the presence of potassium carbonate (13.8 g) to afford ethyl 4-nitro-3-methylphenoxyacetate; hydrogenation of the latter (7.18 g, 0.03 mol) in ethanol (250 mL) in the presence of 5% palladium on carbon (2.1 g) to afford 6.20 g (99%) of ethyl 4-amino-3-methylphenoxyacetate as a brown oil; and treatment of the latter (6.2 g, 0.0296 mol) in CH2Cl2 (100 mL) with pyridine (10 mL), followed by methanesulfonylchloride (3.73 g, 0.033 mol) to afford 6.54 g (76.9%) of N-[4-(ethoxycarbonylmethoxy)-2-(methyl)phenyl]methanesulfonamide, m.p. 93°-94 ° C., after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([O:19][C:20]1[O:24][C:23]([C:25]([OH:27])=O)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:28](OC1OC(C(O)=O)=CC=1)CCCCCCCCCCCCC>>[CH2:1]([O:19][C:20]1[O:24][C:23]([C:25]([CH3:28])=[O:27])=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(C)=O)o1

Procedure:
When in the procedure of Example 1(B) an appropriate amount of 5-(cis-9-octadecen-1-yloxy)-2-furoic acid is substituted for 5-(tetradecyloxy)-2-furoic acid, methyl 5-(cis-9-octadecen-1-yloxy)-2-furyl ketone is obtained.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:25])[C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:7]2=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:25][N:11]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]2=[CH:6][CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[N:8]2[CH2:9][CH2:10]1
Reactant: CC(=O)c1ccc2n1CCN(C)C21CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1ccc2n1CCN(C)C21CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 6-acetyl-2-methyl-Spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (300 mg, 0.86 mmol) and methylene chloride (1.7 mL) was added hydrogen chloride in dioxane (1.60 mL of 4 M, 6.40 mmol) The reaction was stirred at room temperature for 0.5 hours. The solvent was evaporated under reduced pressure to yield 1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl)ethanone dihydrochloride as a light green solid in quantitative yield. ESI-MS m/z calc. 247.2, found 248.2 (M+1)+; Retention time: 0.17 minutes (3 minute run).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)#[N:2].C(OCC)(=O)C>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Reaction time: 12 h
Yield: 99.2 %

Procedure:
The product of step B (100 mg, 0.201 mmol) was diluted with 7N ammonia/methanol (10 mL), followed by addition of ethyl acetate (10 mL). Once the material dissolved, Raney Nickel (1.72 mg, 0.0201 mmol) was added and the reaction was purged three times with a balloon of hydrogen. After stirring for 12 hours, the reaction mixture was filtered through a GF/F filter and concentrated. The residue was purified using a biotage 12i column eluting with methylene chloride:MeOH:NH4OH (90:9:1) to yield tert-butyl 2-(3-(aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate (100 mg, 99.2% yield) as a clear oil.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>>[CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCSCc3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCSCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyl-naphthalene there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzylsulphanyl-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless resin; MS: 598 (M+H)+.
Reaction SMILES: C(N)(C)C.[CH2:5]([NH2:8])[CH2:6][CH3:7].C(N[C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=3)[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)CC>>[CH2:5]([NH:8][C:16]1[C:17]2[C:18](=[O:29])[C:19]3[C:24](=[CH:23][C:22]([Cl:28])=[CH:21][CH:20]=3)[C:25](=[O:27])[C:26]=2[CH:13]=[CH:14][CH:15]=1)[CH2:6][CH3:7]
Reactant: CCCN
Reactant: CCCNc1cccc2c1C(=O)c1cc(Cl)ccc1C2=O
Solvent: CC(C)N
Product: CCCNc1cccc2c1C(=O)c1ccc(Cl)cc1C2=O

Procedure:
If the procedure indicated is followed but isopropylamine is replaced by propylamine, 22 g of 1-propylamino-7-chloroanthraquinone are obtained. The nitrobenzene/methanol mother liquor is concentrated and the residue is treated with methanol and with a little nitrobenzene. After working up, 8 g of 1-propylamino-6-chloroanthraquinone are obtained.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([N:19]5[CH2:23][CH2:24][CH2:25][S:26]5(=[O:28])=[O:27])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1c1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-ylamine (500 mg, 1.82 mmol) in DMF (10 mL) was added NaH (220 mg, 5.46 mmol) at 0° C. The mixture was allowed to warm to rt and then stirred for 30 min. A solution of 3-chloropropane-1-sulfonyl chloride (450 mg, 2.55 mmol) in DMF (2 mL) was added and the reaction mixture was stirred for 2 h. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (elute: 2% dichloromethane in methanol). This afforded 217 mg (31%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzothiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH:7]=[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[CH:19]1[C:10]2[CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8](=[CH:7][C:6]3[CH:5]=[C:4]([NH2:1])[CH:25]=[CH:24][CH:23]=3)[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(C=C2c3ccccc3C=Cc3ccccc32)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: Nc1cccc(C=C2c3ccccc3C=Cc3ccccc32)c1
Reaction time: 18 h
Yield: 78.1 %

Procedure:
Dissolve 5-(3-nitro-benzylidene)-5H-dibenzo[a,d]cycloheptene (120 mg, 0.4 mmol) in absolute ethanol. Add (10 ml tin chloride (416 mg, 2.0 mmol) and heat to reflux. After 18 h, cool and partition between 1N NaOH/EtOAc. Dry the organic layers (MgSO4) and concentrate to give 92.3 mg of a white solid. MS [EI+] 296 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Br)cs1
Temperature: 25 °C
Yield: 52 %

Procedure:
Anhydrous zinc chloride (0.150 g, 1.1 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (5 mL) was then added. To this mixture was added 3-(2-bromo-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.182 g, 0.55 mmol), acetic anhydride (0.156 mL, 1.65 mmol), and 2-methylthiazole-4-carboxaldehyde (0.209 g, 1.65 mmol in 3 mL of dioxane). The reaction was refluxed 3 hours, and was then cooled to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, then dried over magnesium sulfate and then concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.116 g (52% of 3-(2-bromo-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[N+:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)(=[O:31])=[O:32]
Reactant: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
To a solution of (R)-6-amino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (0.200 g, 0.709 mmol) and 3-nitro-benzenesulfonyl chloride (0.157 g, 0.709 mmol) in 10 mL of dichloromethane, was added triethylamine (0.5 mL, 3.544 mmol). After stirring at room temperature under N2 for 16 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 20-50% ethyl acetate/hexanes to give the title compound as light yellow semi-solid (0.128 g, 39% yield). LC-MS: tR=9.5 min; m/z 468 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][NH2:6])[CH2:3][NH2:4].[ClH:8].[NH2:9][C:10](N)=N>C(O)C>[ClH:8].[CH3:1][C:2]1([CH3:7])[CH2:5][NH:6][C:10]([NH2:9])=[N:4][CH2:3]1
Reactant: CC(C)(CN)CN
Reactant: N=C(N)N
Agent: Cl
Solvent: CCO
Product: CC1(C)CN=C(N)NC1
Yield: 104.9 %

Procedure:
2.5 g of 2,2-dimethylpropane-1,3-diamine and 2.17 g of guanidine hydrochloride are heated to 140° C. under argon for 4 h. After returning to RT, add ethanol and dry evaporate. 3.9 g (yield=95%) of 5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrochloride are obtained as a white powder used as such.
Reaction SMILES: [C:1]1([C@@:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:15]1[CH2:14][CH2:13][CH:12]([C@@:7]([OH:11])([C:8]([OH:10])=[O:9])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16]1
Reactant: O=C(O)[C@](O)(C1=CCCCC1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@](O)(c1ccccc1)C1CCCCC1
Reaction time: 18 h
Yield: 90.2 %

Procedure:
To a solution of (S)-Cyclohexenyl phenyl glycolic acid (1.11 g, 4.78 mmol) in methanol (16 mL) was added 10% Pd/C (0.11 g). The reaction was subjected to 1 ATM of Hydrogen and was allowed to stir for 18 h. The reaction mixture was filtered through a plug of celite and concentrated in vacuo to provide 1.01 g of (S)-CHPGA (91%, 98.3% e.e.).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[C:6]([C:21]([NH2:23])=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][O:14]C2CCCCO2)[C:9](=[O:11])[CH:10]=1.Cl>CCO.O>[F:1][C:2]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:3]=1[NH:4][C:5]1[C:6]([C:21]([NH2:23])=[O:22])=[CH:7][N:8]([CH2:12][CH2:13][OH:14])[C:9](=[O:11])[CH:10]=1
Reactant: NC(=O)c1cn(CCOC2CCCCO2)c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(=O)c1cn(CCO)c(=O)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-6-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,6-dihydro-3-pyridinecarboxamide (118 mg, 0.24 mmol) was dissolved in EtOH (8 mL), to which was added 1 M HCl (2 mL). This mixture was stirred at R.T. for 2 h., then diluted with water (80 mL). The resulting solution was extracted with EtOAc (3×40 mL), then the combined EtOAc fractions washed with water (2×50 mL) and brine (50 mL), then dried (Na2SO4). Removal of the solvent under reduced pressure afforded 4-(2-fluoro-4-iodoanilino)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (95 mg, 97%), m.p. (EtOAc/MeOH) 212-215° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.45 (s, 1H), 8.27 (s, 1H), 7.94 (br s, 1H), 7.74 (dd, J=10.1, 1.7 Hz, 1H), 7.57 (br d, J=8.6 Hz, 1H), 7.48 (br s, 1H), 7.29 (t, J=8.5 Hz, 1H), 5.55 (s, 1H), 4.93 (t, J=5.3 Hz, 1H), 3.85 (t, J=5.5 Hz, 2H), 3.60 (q, J=5.4 Hz, 2H). Anal. Calcd for C14H13FIN3O3: C, 40.3; H, 3.1; N, 10.1. Found: C, 40.4; H, 2.9; N, 9.8.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20](C)[C:21](=O)C)=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OCC)(=O)C>CO.[OH-].[Na+]>[CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)N(C)c1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 90 °C
Yield: 31.2 %

Procedure:
A mixture of (2-methyl-quinazolin-4-yl)-(N-methyl-4-acetamido-phenyl)-methylamine (103 mg, 0.321 mmol) in 3 mL of methanol and 3 mL of 2N NaOH was heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature and diluted 25 mL of ethyl acetate. It was washed with saturated NaHCO3, and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (40% ethyl acetate/hexane) to give the title compound (28 mg, 0.10 mmol, 31%). 1H NMR (CDCl3): 7.71 (m, 1H), 7.50 (ddd, J=8.4, 6.9, 1.5, 1H), 6.93-7.11 (m, 4H), 6.60 (m, 2H), 3.84 (s, broad, 1H), 3.57 (s, 3H), 2.87 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[NH:3][C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: Clc1nc2ncnc-2c(NCc2ccccc2)[nH]1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
189 mg of 2,6-dichloropurine, 4 ml of butanol and 0.12 ml (1.1 mol) of benzylarnine are mixed at room temperature and the medium is heated at a temperature of 75° C. for 5 hours and then it is left at room temperature overnight.
Reaction SMILES: [CH2:1]([C:3]([NH:8][C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1([CH2:4][CH3:5])[CH2:6][O:7][C:34](=[O:36])[N:8]1[C:9]1[S:10][C:11]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[N:23])[CH:18]=3)[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCC(CC)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1(CC)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
2-{[1-Ethyl-1-(hydroxymethyl)propyl]amino}-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (0.29 g, 0.89 mmol), prepared in the previous step, was dissolved in methylene chloride (10 mL) and diisopropylethyl amine (0.37 mL, 2.1 mmol) was added and the mixture was cooled to 0° C. Triphosgene (108 mg, 1.07 mmol) was added and the mixture was stirred for 2 h. The mixture was then diluted with methylene chloride and washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10%-15% ethyl acetate in hexane) afforded the title compound (230 mg, 73%) as a white solid. HRMS: calcd for C19H19N3O2S+H+, 354.12707. Found (ESI-FT/MS, [M+H]1+), 354.127; Analytical HPLC: purity 98.1% at 210-370 nm, 10.7 min.; 98.8% at 316 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([CH3:23])=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: Cc1ccnc2cc(O)ccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 90 %

Procedure:
Using a procedure analogous to that described for Example 10, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (130 mg, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 4-methyl-7-hydroxyquinoline (80 mg, 0.5 mol), (Chem. Ber. 1967, 100, 2077), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline (160 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[C:14]([Br:17])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: COc1ccc(N)c(CN2CCOCC2)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN2CCOCC2)c1

Procedure:
N-(2-Amino-3-bromo-5-methoxy-benzyl)-morpholine was prepared from N-(2-amino-5-methoxy-benzyl)-morpholine and bromine analogous to Exanple 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride): 3280 cm-1NH2 ; 3420 cm-1NH2 ; 2830 cm-1OCH3 ; 2810 cm-1N-alkyl; 1480 cm-1C= C; 1590 cm-1C=C.