Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:6]([CH:21](OCC)OCC)([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH3:20])[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:30][C:31]([NH2:33])=[NH:32]>C(O)C>[NH2:33][C:31]1[N:32]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=2[CH3:20])=[CH:21][N:30]=1
Reactant: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)cc1C)C(OCC)OCC
Reactant: N=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C)c(Cc2cnc(N)nc2N)cc1OC

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(4,5-dimethoxy-2-methylphenyl)propionitrile (3.9 g, 0.01 mol) and an equivalent amount of potassium hydroxide in ethanol (70 ml) was heated at reflux for one hour. A solution of guanidine (0.035 mol) in ethanol (50 ml) was added, and reflux was resumed. Ethanol was boiled off until the reaction temperature reached 85° C. After 20 hours at reflux the mixture was allowed to cool, and the product was filtered and washed with ethanol giving 2.57 g (94%) of nearly white solid. After purification as described in Example 5, the product was dried under reduced pressure giving a white solid, m.p. 231°-233° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([CH3:19])=[C:12]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:22][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([CH3:19])=[C:12]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: Cc1c(C(=O)N(C)C)sc2ncn(CCO)c(=O)c12
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1c(C(=O)N(C)C)sc2ncn(CCCl)c(=O)c12
Yield: 83 %

Procedure:
29.9 g (106 mM [sic]) of 3-(2-hydroxyethyl)-5-methyl-6-dimethylcarbamoylthieno [2,3-d]pyrimidin-4-one in 200 ml of 1,2-dichloroethane were heated to reflux (slow dissolution) and then 12.7 ml (175 mM [sic]) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After refluxing for 1 h, the reaction mixture was cooled and concentrated. The crude product was partitioned between methylene chloride and water at pH=9. Drying and concentration of the organic phase resulted in isolation of 44.1 g (83%) of product as a dark oil which was purified by column chromatography (silica gel, eluent ethyl acetate). 23.8 g (76%) of product were isolated with melting point 120-122° C.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[C:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: OB(O)c1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccccc2OCc2ccccc2)c1N
Temperature: 110 °C
Yield: 70 %

Procedure:
A flask containing a mixture of methyl 3-amino-2,6-dibromoisonicotinate (3.00 g, 9.68 mmol), 2-benzyloxybenzeneboronic acid (2.52 g, 11.1 mmol), tetrakistriphenylphosphine palladium (0) (0.533 g, 0.461 mmol) and Na2CO3 (2.64 g, 24.9 mmol) was flushed with nitrogen. Toluene (24 mL) and methanol (8 mL) were added and the reaction was heated at 110° C. for 23 h. This was partitioned between EtOAc and aq. sat. sodium bicarbonate solution. The organic phase was washed with sat. aq. sodium bicarbonate solution and brine and then dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (step gradient elution with hexane containing 0 to 15% EtOAc afforded methyl 3-amino-2-(2-(benzyloxy)phenyl)-6-bromoisonicotinate (2.80 gm, 6.78 mmol, 74% yield) as a solid. This was quickly dissolved in TFA (40 mL) and the yellow solution cooled in an ice-bath. Sodium nitrite (0.935 g, 13.6 mmol) was added with stirring to give a dark red mixture. After 30 min, solid sodium azide (4.40 g, 67.8 mmol) was added over 5 min followed by Et2O (40 mL). This was stirred in the ice-bath for 30 min and then partitioned between H2O and EtOAc. The organic phase was separated and most of the solvent was removed. The residue was diluted with EtOAc, washed with aq. sat. NaHCO3 solution and brine and then dried over sodium sulfate. The solution was concentrated to about 50 ml volume and the solid was with EtOAc, to leave methyl 3-azido-2-(2-(benzyloxy)phenyl)-6-bromoisonicotinate (2.70 gm, 4.39 mmol, 65% yield) as a solid. 1,2-Dichloroethane (3 mL), rhodium octanoate dimer (0.171 g, 0.220 mmol), and crushed 4A° molecular sieves (2.70 g) were added and the mixture was heated at 80° C. for 48 h. It was diluted with a mixture of 25% MeOH in DCM and filtered. The solid was washed with additional 25% MeOH in DCM and the solvents removed from the combined filtrates. The residue was suspended in MeOH and filtration followed by washing with MeOH left methyl 9-(benzyloxy)-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (1.84 g, 97% yield) as a solid. MS (ESI) m/z 411.0 (M+H). 1H NMR (500 MHz, chloroform-d) d ppm 9.63 (1H, br. s.), 7.98 (1H, s), 7.77 (2H, d, J=7.32 Hz), 7.48 (3H, m), 7.34 (1H, m), 7.16 (1H, d, J=7.93 Hz), 6.85 (1H, d, J=7.93 Hz), 5.48 (2H, s), 4.09 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][SH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:18](OCC)[CH2:19][Br:20])C.FC(F)(F)C(O)=O>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[CH:18]([CH2:19][Br:20])[S:14][CH2:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCCS)cc1OC
Reactant: CCOC(CBr)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1OC)C(CBr)SCCC2
Reaction time: 8 h

Procedure:
A mixture of 0.67 g of 3-(3,4-dimethoxyphenyl)-1-propanethiol, 1.0 g of bromoacetaldehyde diethylacetal, 0.16 ml of trifluoroacetic acid, and 25 ml. of nitromethane as solvent is stirred at room temperature for 1 hour, stored overnight in the freezer, and then heated at 70° for 2 hours after an additional 0.05 ml trifluoroacetic acid is added. After cooling, the reaction mixture is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is taken to dryness, and the residue is chromatographed one time on silica gel with methylene chloride as eluent and a second time with 10% ethyl acetate/Skellysolve B as eluent to yield 7,8-di-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)[N:5]=1)[CH3:3].C(N(CC)CC)C.[Cl:26][C:27]1[CH:28]=[N:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32](Cl)=[O:33]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[N:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32]([NH:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([CH2:11][N:6]2[C:7]([CH2:9][CH3:10])=[CH:8][C:4]([CH2:2][CH3:3])=[N:5]2)[CH2:17][CH2:16]1)=[O:33]
Reactant: CCc1cc(CC)n(C[C@H]2CC[C@H](N)CC2)n1
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(CC)n(C[C@H]2CC[C@H](NC(=O)c3cc(Cl)cnc3C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-4-(3,5-diethyl-pyrazol-1-ylmethyl)-cyclohexylamine hydrochloride (Intermediate B) (65 mg, 0.238 mmol) was placed in a flask with DCM (5 ml) and triethylamine (72 mg, 0.714 mmol). 5-Chloro-2-methylnicotinoyl chloride (Intermediate C) (54 mg, 0.238 mmol) was added portionwise. After addition of the acid chloride, the reaction mixture was stirred at RT for 1 hour and partitioned between DCM and sat. NaHCO3. The organic phase was passed through a phase separator and the solvent was removed in vacuo. The crude product was triturated in EtOAc:iso-hexane—1:1, filtered and dried to afford the title compound; 1H NMR (d6-DMSO, 400 MHz) δ 8.52 (1H, d), 8.39 (1H, d), 7.79 (1H, d), 5.82 (1H, s), 3.76 (2H, d), 3.67 (1H, m), 2.57 (2H, q), 2.47 (5H, m), 1.89 (2H, m), 1.72 (1H, m), 1.57 (2H, m), 1.23 (10H, m); LC-MS Rt 2.35 mins, [M+H]+ 389; Method LowpH_v002.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.O1C2C=CC=CC=2N=C1>O>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1nc2ccccc2o1
Agent: c1ccc2ocnc2c1
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To a solution of 15.4 g. (0.1 mole) of 2-chlorobenzoxazole in 200 ml. of tetrahydrofuran was added dropwise a solution of 16.1 g. (0.1 mole) of p-aminobenzotrifluoride in 100 ml. of tetrahydrofuran with vigorous agitation. Following the addition, the reaction mixture was heated on a steam bath under reflux for 16 hours. Then the reaction mixture was cooled to about 25° C., and about 500 ml. of water was added. The tetrahydrofuran solvent was removed by distillation under vacuum, leaving an aqueous slurry of the reaction product. The solids were filtered off and dried. The dried residue was dissolved in a minimum amount of warm benzene. Then about 200 ml. of hexane was added to the benzene solution to crystallize the reaction product. The crystals were filtered off and dried, yielding 19.2 g. of 2-[4-trifluoromethyl)anilino]benzoxazole having a melting point of 180°-182° C.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]1[CH:10]=[C:9]([C:11]([CH2:13][CH2:14][CH2:15][Cl:16])=O)[S:8][CH:7]=1>CO.Cl.O>[Cl:16][CH2:15][CH2:14][CH2:13][C:11](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[C:9]1[S:8][CH:7]=[CH:6][CH:10]=1
Reactant: O=C(CCCCl)c1cccs1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCCCl)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution 4-chloro-2'-butyrothienone (16.2 mL, 0.1 mol) in 350 mL of methanol plus 27 mL 1N HCl plus 25 mL of water. After stirring at room temperature for approximately 2 hours, all of the solid had dissolved. The reaction was then stirred at room temperature for 24 hours (overnight). By TLC starting material remained. An additional 27 mL of 1N HCl was added and the reaction stirred at room temperature for 6 hours. The solid formed was removed by filtration and dried under high vacuum to give 14.87 g (57%) of the title compound as a brown solid, mp 120-122° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:17])([Cl:16])[CH:13](O)[OH:14]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH:13]([OH:14])[C:12]([Cl:17])([Cl:16])[Cl:11])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC(O)C(Cl)(Cl)Cl)cc1
Reaction time: 12 h
Yield: 87.9 %

Procedure:
A mixture of p-toluamide (11.0 g, 81.3 mmol) and 2,2,2-trichloro-1,1-ethanediol (16.6 g, 100 mmol) in benzene (175 mL) was stirred at reflux in a Soxhlet extraction device charged with molecular sieves (20 g). After 12 hours, the extraction thimble of molecular sieves was replaced with a fresh portion of molecular sieves (20 g), and the reaction was allowed to heat at reflux for an additional 12 hours. Concentration in vacuo provided a heavy syrup which was dissolved in ethyl acetate (15 mL) and diluted with hexanes (175 mL). Refrigeration at 8° C. facilitated precipitation of a white solid that was collected by filtration and washed with hexanes to provide 20.2 g of the desired product.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=O.O.[NH2:33][NH2:34]>C(O)(=O)C>[C:25]1(=[O:26])[N:21]([CH2:20][CH2:19][CH2:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([C:2]3[CH2:3][CH2:4][C:5](=[O:7])[NH:33][N:34]=3)=[CH:10][CH:11]=2)(=[O:16])=[O:17])[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]12
Reactant: NN
Reactant: COC(=O)CCC(=O)c1ccc(S(=O)(=O)CCCN2C(=O)c3ccccc3C2=O)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(c2ccc(S(=O)(=O)CCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Temperature: 0 °C

Procedure:
34 g (78.2 mmol) of methyl 4-oxo-4-[4-(3-phthalimidopropylsulphonyl)phenyl]butyrate are refluxed for two hours in a solution of 6 ml (120 mmol) of hydrazine hydrate (99%) in 350 ml of glacial acetic acid. Then the mixture is poured onto 2.5 liters of ice water, the product precipitated is suction filtered and dried in a circulating air dryer at 80° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[CH:30]=[CH:31][O:32]CC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31](=[O:32])[CH3:30])[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)c1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.220 g, 0.000543 mol), tributyl-ethoxyvinyl-tin (0.202 mL, 0.000597 mol), and bis(triphenylphosphine)palladium(II) chloride (0.0190 g, 0.0271 mmol) was degassed with N2. The reaction was heated to 100° C. overnight. The crude was hydrolyzed with 10% HCl and extracted 3 times with ethyl acetate. The organic layers were combined, dried with MgSO4 and concentrated. The crude was loaded as a solid onto silica and purified by flash chromatography (45-100% ethyl acetate in hexanes) to give 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethanone as a white solid (126 mg). MS(ESI+) 369.2
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)(=[O:34])[CH3:33]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5-hydroxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) are added acetic anhydride (4.0 ml) and pyridine (0.5 ml), and the mixture is stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution is poured into ice-water and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-acetyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.43 g) as colorless needles, m.p. 155°-156° C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:22])([F:21])[C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10]C1CCCCO1.CN(C)CCN(C)C.CN(C)[CH:33]=[O:34]>C(OCC)C.O>[OH:10][C:9]1[C:8]([C:7]([F:6])([F:21])[F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH:33]=[O:34]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccccc1OC1CCCCO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1cccc(C(F)(F)F)c1O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 192.1 %

Procedure:
A n-butyl lithium-1.58M n-hexane solution (65.9 ml, 104 mmol) was added dropwise to a solution of 2-[2-(trifluoromethyl)phenoxy]tetrahydro-2H-pyrane (21.4 g, 86.8 mmol) which was synthesized according to the method described in literature (Miller, J. A. et al., J. Org. Chem. 1993, vol. 58, pp. 2637-2639) and N,N,N′,N′-tetramethylethylenediamine (15.7 ml, 104 mmol) in diethyl ether (230 ml) at −20° C. over 10 minutes. After the reaction mixture was stirred at −20° C. for 30 minutes, it was further stirred at room temperature for 40 minutes. After the reaction mixture was cooled to −30° C. and N,N-dimethylformamide (13.5 ml, 174 mmol) was added thereto, the mixture was further stirred at room temperature for 1 hour. After the reaction mixture was carefully poured into cooled water and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with 1N hydrochloric acid, a 5% aqueous sodium hydrogencarbonate solution, water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=20/1-10/1). The obtained 2-(tetrahydro-2H-pyran-2-yloxy)-3-(trifluoromethyl)benzaldehyde as a pale yellow oil was left to stand at room temperature overnight to give 2-hydroxy-3-(trifluoromethyl)benzaldehyde as a pale yellow solid (31.7 g, yield: 96%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)=[O:12])#[N:2]
Reactant: N#Cc1cccc(OCCCC(=O)O)c1
Reactant: N#Cc1ccc(N)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)CCCOc2cccc(C#N)c2)cc1
Reaction time: 0.03 h

Procedure:
100 mg (0.49 mmol) of 4-(3-cyanophenoxy)butyric acid and 50 mg (0.49 mmol) of triethylamine were stirred in dimethylformamide under cooling with ice. 53 mg (0.49 mmol) of ethyl chloroformate was added to the resultant mixture. After stirring for 2 minutes, 58 mg (0.49 mmol) of p-aminobenzonitrile was added to the reaction mixture. The temperature was elevated to room temperature, and they were stirred overnight. 1 N hydrochloric acid was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[OH:32][C:28]1[CH:27]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2cccc(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (37.24 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. Ethyl acetate and Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 45% (58 mg, 0.140 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2O[C:9](=O)[NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[NH3:14]>C(N)=O>[F:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:14]=[CH:9][NH:8][C:7]2=[O:12]
Reactant: O=c1[nH]c(=O)c2cc(F)ccc2o1
Reactant: N
Solvent: NC=O
Product: O=c1[nH]cnc2ccc(F)cc12
Reaction time: 0.17 h

Procedure:
1. 3.62 g of 6-fluoro-2H-1,3-benzoxazine-2,4(1H)-dione are suspended in 15 ml of formamide. Gaseous ammonia is introduced while stirring during about 10 min. until the suspension is saturated and the mixture is stirred at room temperature for a further 1 h. Subsequently, the mixture is stirred at 125° C. (bath temperature) for 16 h. The solvent is then distilled off in a high vacuum. The residue is triturated in 50 ml of water and then cooled slightly. The resulting crystals are filtered off, washed with ice-cold water and dried over calcium chloride in a vacuum. 2.9 g of crude 6-fluoro-3H-quinazoline-4-one are obtained. The substance melts at 252°-255° C. after recrystallization from ethyl acetate.
Reaction SMILES: C1(O[C:8]([NH:10][C@H:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])C=CC=CC=1.[CH:26]([NH:29]C(C)C)([CH3:28])[CH3:27]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH:29]([CH:26]([CH3:28])[CH3:27])[C@:11]([N:10]=[C:8]=[O:9])([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)Oc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@](N=C=O)(NC(C)C)C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 17 h

Procedure:
To a solution of PhOCO-Leu-OBzl (70 mg, prepared in (1)) in chloroform (2 ml) were added diisopropylamine (575 μl) and TEA (286 μl) at room temperature under argon atmosphere. The mixture was stirred at 55° C. for 17 h and cooled to room temperature. The mixture was diluted with ethyl acetate, washed with N-hydrochloric acid, sat. aq. NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[NH:8][C:9](=O)[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:13][C:11]=2[N:12]=1)[CH:2]([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:38]>C(Cl)(Cl)Cl>[Cl:38][C:9]1[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:13][C:11]=2[N:12]=[C:7]([CH2:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[N:8]=1
Reactant: CC(C)COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CC(C)COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Reflux a mixture of 2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (0.510 g, 1.35 mmol), 2,6-lutidine (0.62 mL), and POCl3 (0.50 mL) in CHCl3 (10 mL) for 16 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine as yellow viscous oil.