Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([O:28]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]#[N:45])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:44]([CH:41]1[CH2:42][CH2:43][N:38]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:39][CH2:40]1)#[N:45]
Reactant: N#CC1CCNCC1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1

Procedure:
115 mg (0.22 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 2.5 ml of DMF, and 74 mg (0.67 mmol) of piperidine-4-carbonitrile and 31 mg (0.22 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 71 mg (65% of theory)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[I-].[Na+]>C(#N)C>[C:23]1([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Temperature: 60 °C
Reaction time: 0.02 h
Yield: 28.5 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indazole-7-carboxamide (Intermediate 22) (18 mg, 0.039 mmol) in acetonitrile (2 mL) was added K2CO3 (25 mg, 0.156 mmol), pyrrolidine (19 uL, 0.196 mmol) and sodium iodide (0.7 mg, 0.0039 mmol). The reaction mixture was heated to 60° C. overnight. The solution was filtered and concentrated. The residue was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (5.5 mg, 28%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:28][OH:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(C=O)=C1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(CO)=C1C(=O)OCC
Reaction time: 0.17 h

Procedure:
To a solution of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.70 g) in ethanol (100 ml) was gradually added at 4° C. sodium borohydride (445.2 mg) and the resultant mixture was stirred at 4° C. for 1.5 hours under ice-cooling. The reaction mixture was acidified with 50% acetic acid and ethanol was removed. To the residue was added water and the aqueous mixture was stirred for 10 minutes. The powder was collected by filtration and washed with water to give crude crystals (4.49 g), which were recrystallized from methanol to give yellow crystals of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-hydroxymethyl-1,4-dihydropiridine-3,5-dicarboxylate, m.p. 124° to 126° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+]>CO.O>[Cl:11][C:10]1[N:9]([CH2:12][CH2:13][O:14][CH3:15])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(CCOC)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCn1ncc(C(=O)O)c1Cl
Yield: 92.5 %

Procedure:
To a solution of 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (8.51 g, 36.6 mmol) in methanol (37 mL) and water (37 mL) was added lithium hydroxide (1.21 g, 50.4 mmol). The reaction mixture was stirred at reflux for 3 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid as a white solid (6.93 g, 92%). Mass spectrum: m/z: 205.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([NH2:15])[NH:5][N:4]=1)[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]2[NH:15][C:25](=[O:26])[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[N:5]2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CCc1n[nH]c(N)c1-c1ccc(C)cc1
Solvent: c1ccncc1
Product: CCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
3-Ethyl-4-(4-methylphenyl)-1H-pyrazol-5-amine (200 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (250 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 280 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](=[O:16])[CH3:15])[CH2:10]1.[Br:17]Br>ClCCl>[Br:17][CH2:15][C:14]([C:11]1[CH2:10][CH:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:16]
Reactant: CC(=O)C1=NOC(c2c(F)cccc2F)C1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Temperature: 33 °C
Reaction time: 0.17 h

Procedure:
A 500-mL flask equipped with a mechanical stirrer, thermometer, addition funnel and scrubber was charged with 1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e. the product of Step B) (60.0 g, 0.27 mmol) and dichloromethane (130 mL). The reaction mixture was heated at 33° C., and a solution of bromine (39.2 mL, 0.24 mol) in dichloromethane (100 mL) was added dropwise via the addition funnel. After about 5 mL of the bromine solution had been added, the addition was stopped and the reaction mixture was stirred at 33° C. for about 10 minutes, during which time the color of the reaction mixture changed from red to yellow. The reaction mixture was cooled to 5° C., and the remaining bromine solution was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was washed with aqueous sodium bisulfite solution (3.5 g in 100 mL of water), the layers were separated and the organic layer was concentrated under reduced pressure. Hexanes were added to the resulting residue, and the mixture was filtered rinsing with hexanes to provide the title compound as a brown solid (73 g), which was used without further purification.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>C(O)C.[Pd]>[OH:1][C@H:2]1[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][NH:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](Oc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CNC[C@H]1Oc1ccccc1

Procedure:
28.2 g (0.09 mol) of trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-pyrrolidine are dissolved in 280 ml of ethanol and hydrogenated in the presence of 3 g of a 5% strength palladium-on-charcoal catalyst under normal pressure and at room temperature. After the absorption of hydrogen has ceased, the catalyst is filtered off by means of diatomaceous earth and the filtrate is evaporated under a water pump vacuum. The residue is crystallised from methanol/ether and gives trans-3-hydroxy-4-phenoxy-pyrrolidine with a melting point of 120°-122°. The crystalline neutral fumarate with a melting point of 145°-146° is obtained by reacting the base with a solution of fumaric acid in methanol/ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1.[Na]>C1(C)C=CC=CC=1>[NH:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH2:4][CH2:5][CH2:6]1
Reactant: NCCCc1cccnc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: c1cnc2c(c1)CCCN2
Yield: 30 %

Procedure:
The final step in the process of the present invention is the cyclization of compound (II) to elaborate the final product (I). This intramolecular transformation is efficiently carried out by an optimized Chichibabin-type reaction (for a discussion of Chichibabin aminations, see H. Vorbrüggen, Adv. Heterocyclic Chem., 49, 1990, 117-192). Intramolecular nucleophilic cyclizations of 3-substituted pyridylalkylamines have previously been described. Thus, treatment of 3-(3-pyridyl)propylamine with two equivalents of sodium in boiling toluene afforded 1,2,3,4-tetrahydro-[1,8]-naphthyridine in 30% yield (E. M. Hawes and H. L. Davis, J. Heterocyclic Chem., 1973, 39-42). 1,2,3,4-Tetrahydro-3-phenyl-[1,8]-naphthyridine has been similarly prepared in 54% yield (E. M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315-321). The substrate for the Chichibabin-reaction of the present invention has two nucleophilic amino groups presenting complicating issues of regioselectivity and intramolecular vs. intermolecular reactivity.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: NCCOCCO
Product: N#Cc1ccccc1NCCOCCO

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 2-(2-aminoethoxy)ethanol.
Reaction SMILES: [OH-].[Na+].ClC1C=CC([C:10]2[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=C(OC)C=1>CO>[CH2:12]([C:10]1[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1Cc1ccccc1
Temperature: 60 °C
Yield: 170.4 %

Procedure:
A solution of sodium hydroxide 10N (0.300 mL; 3.0 mmol) was added to a mixture of methyl 2-(4-(4-chloro-2-methoxyphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.095 g; 0.254 mmol) in methanol (3 mL). The mixture was heated at 60° C. in a sealed tube for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate formed. The precipitate was collected by filtration and dried under reduced pressure over phosphorus pentoxide to afford 0.078 g (84%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[CH:14]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([N:30]3[CH2:31][CH2:32][C:27]([F:33])([F:26])[CH2:28][CH2:29]3)=[O:12])=[C:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: Cc1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Reactant: FC1(F)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC(F)(F)CC2)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Yield: 99.1 %

Procedure:
In a flask were mixed together the above prepared 5-chloro-6-(1-isopropyl-piperidin-4-yloxy)-3-methyl-benzofuran-2-carboxylic acid (0.200 g, 0.406 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.077 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.216 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.166 mL) in 4 mL of abs. THF and stirred over night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) yielded 0.183 g of the title compound as white solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH:20]=O>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Product: O=c1cc(N2CCN(Cc3cc(Cl)ccc3[N+](=O)[O-])CC2)nc[nH]1

Procedure:
6-[4-(5-Chloro-2-nitro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chloro-2-nitrobenzaldehyde. Mass spectrum (ES) MH+=350.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH2:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=S.C(N(C(C)C)CC)(C)C>>[OH:1][CH2:2][CH:3]([NH:11][C:13]1[S:12][CH2:18][C:16](=[O:17])[N:15]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NC(CO)Cc2ccccc2)=N1

Procedure:
Similar procedure as described in example 1f was used, starting (R)-1-hydroxymethyl-2-phenyl-ethylamine, rhodanine (2-thioxo-thiazolin-4-one) and DIEA (diisopropylethyl-amine) to give 2-(1-hydroxymethyl-2-phenyl-ethylamino)-thiazol-4-one. LC-MS m/e 251 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)=[CH:10][N:6]2[N:7]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)nn1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Yield: 727.3 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (0.842 g, 0.0065 mol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (2.03 g, 0.65 mmol) in acetonitrile (37.34 mL) is heated at 90° C. for 48 hr. The reaction mixture is concentrated and purified by silica gel chromatography (CH2Cl2 to EtOAc) to give the title compound (1.62 g, 73% yield). LCMS m/z=343.3 [M+H]+, tR=3.15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3ccc(Cl)cc3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)c3ccc(Cl)cc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-chlorophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:31]=[C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][C:39]5[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[CH2:41][C:40]=5[C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=5)[CH2:34][CH2:33]4)[CH:29]=[CH:28][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([C:26]#[N:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:54]1CCCC1.OO.[OH-].[Na+]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:31]=[C:30]([N:32]4[CH2:33][CH2:34][N:35]([CH2:38][C:39]5[CH2:44][CH2:43][C:42]([CH3:46])([CH3:45])[CH2:41][C:40]=5[C:47]5[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=5)[CH2:36][CH2:37]4)[CH:29]=[CH:28][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([C:26](=[O:54])[NH2:27])[CH:20]=3)(=[O:17])=[O:18])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N)c(C#N)c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(N)c(C(N)=O)c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 45 °C

Procedure:
To a solution of EXAMPLE 70B (90 mg) in ethanol (2 mL) was added tetrahydrofuran (2 mL), hydrogen peroxide (30%, 1 mL) and 1M sodium hydroxide solution (0.48 mL), followed by an additional 2 mL of tetrahydrofuran. The reaction was heated to 45° C. for 30 minutes, cooled, and then quenched with 5% HCl solution and extracted twice with dichloromethane. The extracts were combined and concentrated to obtain the product.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]=1[C:19]([O:21]C)=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28].O>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[NH:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[C:19](=[O:21])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:3]2=[O:23])([CH3:16])([CH3:17])[CH3:18]
Reactant: NC1CCC(=O)NC1=O
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1C(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C

Procedure:
Diusopropylethylamine (3.20 g, 25 mmol) was added to a stirred suspension of methyl-3-[(t-butoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (8.00 g, 25 mmol) and aminoglutarimide hydrochloride (4.07 g, 25 mmol) in DMF (60 ml). The mixture was heated to 120° C. for 24 hours and then cooled to room temperature. The mixture was poured into cold water (300 ml) and extracted with ethyl acetate (4×100 ml each). The combined ethyl acetate extracts were washed with water (2×50 ml), brine (50 ml) and dried. Solvent was removed in vacuo and the product purified by flash chromatography (dichloromethane/ethyl acetate 8 to 2) to yield 4.66 g of recovered starting material and 3.31 g (82%) of the product as a white solid: mp 180–182° C.; 1H NMR (CDCl3) δ 8.51 (s, 1H), 7.81–7.67 (m, 3H), 5.54 (b, 1H), 5.03–4.96 (dd, J=5.2 and 11.2 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.95–2.74 (m, 3H), 2.18–2.14 (m, 1H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 170.99, 168.08, 167.95, 167.07, 155.86, 139.17, 135.00, 134.61, 132.15, 128.22, 122.82, 79.81, 49.21, 40.53, 31.33, 28.32, 22.58; Anal. Calcd for C19H21N3O6: C, 58.91; H, 5.46; N, 10.85. Found: C, 59.08; H, 5.51; N, 10.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:18]2[CH2:17][CH2:16][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:20][CH2:19]2)=[O:31])=[CH:25][CH:24]=1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: O=C=Nc1ccc(CCl)cc1
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CCl)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
In 10 ml of toluene was suspended 593.5 mg (2.16 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 362.6 ml (2.16 mmol) of 4-(chloromethyl)phenyl isocyanate was added thereto, followed by stirring at room temperature for 3 hours. After the reaction mixture was filtered, the obtained crystals were washed with diisopropyl ether and dried under reduced pressure to give 916.8 mg (2.08 mmol, 96%) of N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide. In 10 ml of dimethylformamide was dissolved 422.9 mg (0.96 mmol) of the obtained N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide, and 0.28 ml (2.83 mmol) of piperidine was added thereto, followed by stirring at room temperature for 7 hours. Then, the reaction mixture was poured into water and the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 430.9 mg (0.88 mmol) of the desired compound as colorless crystals.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[C:14]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl>[C:14]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[O:1][C:5]=3[CH2:6]2)=[O:27])=[CH:29][CH:30]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Reaction time: 8 h

Procedure:
To a solution of 72 mg (0.40 mmol) of methyl 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-carboxylate, 0.11 g (0.48 mmol) of 4-benzoylbenzoic acid and 0.11 ml (0.79 mmol) of triethylamine in 30 ml of dichloromethane, 0.07 ml (0.48 mmol) of diethyl cyanophosphonate was added dropwise at room temperature, followed by overnight stirring. After the reaction mixture was evaporated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.