Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][O:3]1.[CH3:9][C:10](=[CH2:14])[CH2:11][CH2:12]O>CCCCCC>[CH3:14][C:10](=[CH2:9])[CH2:11][CH2:12][O:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][O:3]1
Reactant: C=C(C)CCO
Reactant: CC1CCOC(O)C1
Solvent: CCCCCC
Product: C=C(C)CCOC1CC(C)CCO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A 300-ml three-necked flask equipped with condensor, stirrer and thermometer was charged with 70 g (0.60 mole) of 2-hydroxy-4-methyltetrahydropyran, 52.46 g (0.61 mole) of 3-methyl-3-buten-1-ol, 150 ml of hexane and 3 g of active clay, and the mixture was stirred at 60° C. for 1 hour. Thereafter, the reaction mixture was analyzed by gas chromatography. The chromatogram showed no peak for 2-hydroxy-4-methyltetrahydropyran but showed a new peak. The active clay was filtered off from the reaction mixture, then, the hexane was distilled off and the residue was distilled under reduced pressure to give 105 g (98% yield) of tetrahydro-2-(3-methyl-3-butenoxy)-4-methyl-2H-pyran as a fraction boiling at 89.5°-90.0° C./10 mm Hg. A nuclear magnetic resonance (NMR) spectrum (in CDCl3) and an infrared absorption spectrum (liquid film-NaCl method) each obtained with the above product are shown in FIG. 1 and FIG. 2, respectively. The NMR spectrum suggested this product was a mixture of 70% of ##STR16## and 30% of ##STR17## Field desorption ionization (FD) mass spectrometry of this product gave M+ =184.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)#[N:32].C(=O)(O)[O-].[Na+]>ClCCl>[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=2)=[O:38])=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C#N)cc3)cc2)c2ccccc12
Yield: 48.5 %

Procedure:
Ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (176 mg, 0.569 mmol) and triethylamine (173 mg, 1.71 mmol) were dissolved in dichloromethane (15 mL), and in an ice bath dichloromethane solution (10 mL) of 4-cyanobenzoyl chloride (95 mg, 0.574 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 121 mg, at a yield of 48.5%.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[NH3:18]>O1CCOCC1.O>[C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8]([NH2:18])(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
2-Phthalimidoethanesulfonyl chloride (2.0 g) was added portion wise to a solution of 0.5 M of ammonia in dioxane (15 ml) and the solution obtained this way was stirred at room temperature. After 48 hours the reaction mixture was poured in water (50 ml) causing the title compound to precipitate. The product was collected by filtration. Yield: 1.52 g (83%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 7.92-713 (m, 4H), 7.06 (s, 2H), 6.88-3.93 (m, 2H), 3.37-3.30 (m, 2H).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:6][C:4]1([CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7])[O:13][CH2:12][CH2:11][O:5]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1(C)OCCO1

Procedure:
In a flask equipped by a Dean-Stark trap, a mixture of ethyl levulinate (28.83 g; 200 mmol), ethylene glycol (37.24 g; 600 mmol) and a catalytic amount of pyridinium para-toluenesulfonic acid in toluene (200 mL) was heated at reflux until the theoretical amount of water was distilled off. After cooling, the mixture was washed with a saturated solution of sodium hydrogen carbonate. The basic layer was extracted with diethylether and the organics were combined, then washed with brine and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate as a colorless oil. ESI/APCI(+): 189 (M+H). 1H NMR (CDCl3): δ 4.12 (q, J=7.14 and 14.25 Hz, 2H, CO2CH2CH3); 3.93 (m, 4H, OCH2CH2O); 2.37 (m, 2H, CH2); 2.02 (m, 2H, CH2); 1.32 (s, 3H, CH3); 1.25 (t, J=7.14 Hz, 3H, CO2CH2CH3).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:13]=[C:9]([CH:10]=[N:11]O)[C:8]([OH:14])=[C:7]([I:15])[CH:6]=1)([CH3:4])[CH3:3].ClC(Cl)(Cl)C(N=C=O)=O.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([I:15])[C:8]2[O:14][N:11]=[CH:10][C:9]=2[CH:13]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(I)c(O)c(C=NO)c1
Agent: O=C([O-])[O-]
Agent: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(I)c2oncc2c1
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
To a solution of 3.19 g of 5-(1,1-dimethylethyl)-3-iodosalicylaldoxime in 10 ml of tetrahydrofuran is added 2.0 g of trichloroacetylisocyanate in tetrahydrofuran (5 ml) at room temperature followed by addition of 1.52 g of potassium carbonate. The mixture is stirred for an additional 20 minutes before it is poured into 400 ml of water. The precipitate so obtained is crystallized from methanol to afford 1.4 g (46.5%) of 5-(1,1-dimethylethyl)-7-iodo-1,2-benzisoxazole, m.p. 106°-109° C.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38]>>[OH:41][CH2:40][CH2:39][N:35]([CH2:36][CH2:37][OH:38])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:8](=[O:29])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=2[F:25])[C:11]=1[C:26]([NH2:27])=[O:28]
Reactant: NCCCCN(CCO)CCO
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(CCO)CCO)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]-ethanol by the procedure analogous to Example 6. HPLC ret. time: 3.1 minutes. 1H NMR (400 MHz, CD3OD) δ 7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm; MS (APCI, m/z): 502 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=1
Reactant: NCCCc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccccn1
Product: Clc1c(CCCNCc2ccccn2)ccc2ccccc12
Yield: 67 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and pyridine-2-carbaldehyde in 67% yield as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.CO[C:33](OC)([N:35](C)C)[CH3:34].[NH2:40]N>>[Br:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][C:5]2[N:11]=[C:10]3[NH:40][NH:35][C:33]([CH3:34])=[C:9]3[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: COC(C)(OC)N(C)C
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Br)c(OCCCN3CCOCC3)cc2N1
Reactant: NN
Product: CC1=C2N=C(c3ccccc3Cl)c3cc(Br)c(OCCCN4CCOCC4)cc3N=C2NN1

Procedure:
7-bromo-5-(2-chlorophenyl)-1,2-dihydro-8-(3-(4-morpholinyl)propoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVj) was prepared by reacting 0.0011 moles of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-thione (IIj) with 1,1 -dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=530.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:20]C.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.32 g, 1.07 mmol) with pyridinium HCl (7 g) at 190° C. according to method B to yield 0.12 g (41%) of an off white solid: mp 222-224° C. (dec.);
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:13]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=1[O:12][CH2:1][C:3]1[CH:11]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Yield: 115.1 %

Procedure:
A mixture of 5-formylsalicylic acid (4.98 g, 30 mmol), benzyl bromide (15.39 g, 90 mmol), potassium carbonate (16.59 g, 120 mmol), and methyl ethyl ketone (350 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1), suspended and washed with isopropyl ether under heating at reflux to give the title compound (5.98 g, 57.5%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].O.Cl>ClCCl>[N:1]1([CH2:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)CCl
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.27 g (14.6 mmol) of morpholine are added to a solution of 1.0 g (6.64 mmol) of methyl 4-chloroacetoacetate in 10 ml of dichloromethane, and the mixture is stirred at room temperature for 4 hours. Water is then added and the mixture is neutralized with 2N hydrochloric acid. The organic phase is dried over sodium sulfate and concentrated, and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (10:1→4:1→1:1) as mobile phase.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][CH:7]=1)[CH2:3][OH:4].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]([CH3:42])([CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][CH:7]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution in methylene chloride (15 mL) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy) phenyl)propan- -ol (0.4 g, 0.72 mmol), prepared as in step 1, and DMSO (0.17 g, 2.17 mmol) was added oxalyl chloride (0.14 g, 1.08 mmol) and the reaction mixture was stirred for 0.5 hours. Triethylamine (0.37 g, 3.6 mmol) was added via syringe, the ice bath was removed, and the reaction was allowed to warm to room temperature. The mixture was concentrated in vacuo and triturated with dry THF. The THF solution was filtered and washed with additional THF. The THF solution and washings were combined and concentrated in vacuo to give crude 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propanal which was used without further purification for oxime formation.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH:28]1([CH2:34][NH2:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:34][NH:35][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NCC1CCCCC1
Product: CN(C(=O)Oc1ccc(C(=O)NCC2CCCCC2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and C-cyclohexyl-methylamine. The crude product was used without further purification (84%, oil). HPLC-MS: m/z=367.3 (M+1); Rt: 4.28 min.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:13]([CH3:23])[CH2:12][C@@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:31][C:32]1[N:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][C:33]=1[F:41]>CCOC(C)=O>[Si:1]([O:8][C@H:9]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C@H:13]([CH3:23])[CH2:12][C@@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:38](=[O:39])[C:36]2[CH:35]=[CH:34][C:33]([F:41])=[C:32]([Br:31])[N:37]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: C[C@@H]1C[C@@H](c2ccncc2N)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 9, 4-((1R,3R,4S,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, N-(4-((1R,3R,4S,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-yl)-6-bromo-5-fluoropicolinamide was obtained. LCMS (m/z): 652.5, 652.4 (MH+); LC Rt=5.82 min.
Reaction SMILES: CO[C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[CH3:30][O-:31].[Na+]>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]1[C:7]2[N:8]=[C:9]([O:31][CH3:30])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]1=[O:29]
Reactant: COC(=O)/C=C/c1c(Nc2ccccc2Cl)nc(SC)nc1-c1ccccc1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(-c2ccccc2F)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2-chloro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 8-(2-chloro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.70 (s, 3H), 6.59 (d, 1H, J=9.7 Hz), 7.01-7.20 (m, 3H), 7.40 (m, 2H), 7.56 (m, 4H); LC MS (m/e)=382 (MH+). Rt=2.24 min
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16](=[CH:19]OCC)[C:17]#[N:18])[CH3:13]>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][CH:19]=[C:16]([C:17]#[N:18])[C:15]([O:14][CH2:12][CH3:13])=[O:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1ccc2ccccc2n1
Product: CCOC(=O)C(C#N)=CNc1ccc2ccccc2n1

Procedure:
Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958), reports the condensation of 2-aminoquinoline and ethylethoxymethylenecyanoacetate to give ethyl 2-quinolylaminomethylenecyanoacetate which when distilled under reduced pressure afforded 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carbonitrile. The compound demonstrated antischistosomal action.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[C:25]([NH:27][CH:28]=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30](OCC)=[O:31])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1>CCCCCC>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]=[CH:23][C:24]3[C:30](=[O:31])[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:28][NH:27][C:25]=3[N:26]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)C(=CNc1ccnc(N2CCN(C)CC2)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2nc(N3CCN(C)CC3)ncc2c1=O
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a 50 ml of diphenyl ether heated at 210° - 220°C was added with stirring 7.0 g of diethyl N-[2-(4-methyl-1-piperazinyl)-4-pyrimidinyl]aminomethylenemalonate, and heating was continued for 1 hour. To the resulting mixture, after being cooled, was added 50 ml of n-hexane. The resulting precipitate was collected, washed with ethanol, and recrystallized from dimethylformamide to yield 6.3 g of the product, m.p. 266° - 268°C.
Reaction SMILES: N1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2N=CC=[CH:9]3)C=CC=1.[C:15]([O-:18])([O-])=O.[Cs+].[Cs+].I[C:22]1[CH:27]=CC=C[C:23]=1C>[Cu]I.C(O)CCC>[CH2:15]([O:18][C:13]1[CH:14]=[CH:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH2:23][CH2:22][CH3:27]
Reactant: Cc1ccccc1I
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCCCO
Product: CCCCOc1ccccc1C
Temperature: 110 °C
Reaction time: 23 h
Yield: 484 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), Cs2CO3 (456 mg, 1.4 mmol), 2-iodotoluene (127 μL, 1.0 mmol) and n-butanol (1.0 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with ethyl acetate. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane) provided 159 mg (97% yield) of the title compound as a colorless oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])([O-:8])=[O:7].[CH2:18]1COC[CH2:19]1>>[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([C:2]1[CH:19]=[CH:18][CH:5]=[CH:4][CH:3]=1)=[O:12])([O-:8])=[O:7]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: [Li]CCCC
Reactant: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C

Procedure:
1-Scheme 1 (1.0 g, 1.0 mmol) was suspended in THF (10 mL) and cooled to -78° C. Added n-BuLi (1.6M in Hexanes, 1.6 mmol) and allowed to react for 2 h. The mixture was warmed to -65° C.; 2-nitrobenzoyl chloride (1 mL, 7 mmol) was added, and the mixture was allowed to warm to room temperature overnight. Filtration followed by washing with methanol (3×25 mL), water (2×25 mL, methylene chloride (2×25 mL and finally with methanol (50 mL) gave the resin which was dried at 60° C. in vacuo. Recovered (1.0 g). IR 1740, 1520 cm-1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>C(O)C>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2nc(NCCN3CCOCC3)sc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2nc(NCCN3CCOCC3)sc2c1
Yield: 77.6 %

Procedure:
A mixture of (2-morpholin-4-yl-ethyl)-(6-nitro-benzothiazol-2-yl)-amine (Example 26, 250 mg, 0.81 mmol) and tin(II) chloride dihydrate (914 mg, 5 eq.) in ethanol (30 mL) was heated at reflux for 6 hours. The reaction mixture was concentrated, treated with 1.0 N NaOH solution (50 mL), and extracted with ethyl acetate (2×100 mL). The organic layer was dried over MgSO4, concentrated and subjected to silica gel chromatography (10% 2M ammonia/methanol in CH2Cl2) to give the desired amine (175 mg, 77%). LCMS analysis (acetonitrile water, C18 silica) reveals 99.9% purity. MS (M+1, 279).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([N:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Reactant: C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)N2CCNCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid was reacted with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3243.