Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]=[N+]=[N-])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-(-)-4-[4-[5-(azidomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 7, 12.05 g) in dry tetrahydrofuran (96 mL) under N2 is treated with triphenylphosphine (8.29 g) over five minutes, and the resulting mixture is stirred at ambient temperature for two hours. The mixture is then treated with water (3.1 mL), heated up to 40° C., stirred at 40° C. for five hours and at ambient temperature for 12 hours, and then concentrated under reduced pressure to give a viscous oil which is chromatographed on silica gel (70-230 mesh, 500 g), eluting with a gradient of methanol/methylene chloride (2.5/97.5-15/85). Pooling and concentration of those fractions with an Rf =0.26 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 136-137° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][C:2]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:7][N:6]=1
Reactant: C1COCCN1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(c1cnc(N2CCOCC2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (0.099 mmol) and morpholine (1.5 mL) in NMP (0.5 mL) was stirred at 195° C. for 2 hours in a microwave reactor. After cooling to the ambient temperature, it was poured into water, and extracted with EtOAc. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [K].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH2:11]([OH:15])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:3]1[N:8]=[C:7]([O:15][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([F:10])=[CH:5][N:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCO
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [K]
Product: CCCCOc1ncc(F)c(OCCCC)n1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
A 9.8 g quantity of metal potassium is dissolved in 300 ml of absolute n-butanol, 16.7 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution and the mixture is stirred at 60° to 70° C for 5 hours. After the reaction, the solvent is distilled off, 50 ml of water is added to the residue and the mixture is extracted with 300 ml of toluene. The toluene layer is washed with water, dried and concentrated. The concentrate is distilled at reduced pressure to give 20.6 g of colorless oily 2,4-di(n-butoxy)-5-fluoropyrimidine in a yield of 85.1%, b.p. 125°-126° C/3-4 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][NH:17][CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:17]1[CH2:16][CH2:15][C:14]2[NH:13][CH:12]=[C:11]3[C:20](=[O:21])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[C:10]3[C:19]=2[CH2:18]1)(=[O:24])[CH3:23]
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CNCC3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
2-p-Chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one is treated with an excess of acetic anhydride with heating to obtain 8-acetyl-2-p-chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one, mp above 350°; IR: 1640, 1670 cm-1.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH:12]1([CH2:15][N:16]([C:24]2[C:25]([CH2:33][CH3:34])=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:13]1.[Br:35]C(F)(F)C(F)(F)Br.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:35][C:32]1[N:27]2[N:26]=[C:25]([CH2:33][CH3:34])[C:24]([N:16]([CH2:15][CH:12]3[CH2:13][CH2:14]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:28]2[CH:29]=[CH:30][CH:31]=1
Reactant: CCc1nn2ccccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reactant: FC(F)(Br)C(F)(F)Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Yield: 87.9 %

Procedure:
A solution of n-butyllithium in hexane (1.6M, 3.88 mL, 6.18 mmol) was added dropwise to a solution of tert-butyl N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (1.5 g, 4.76 mmol) in tetrahydrofuran (15 mL) at −70° C. After stirring the reaction mixture for 50 minutes at the same temperature, 1,2-dibromotetrafluoroethane (1.0 mL, 8.33 mmol) was added dropwise to the reaction mixture. The temperature of the reaction mixture was slowly increased and aqueous sodium bicarbonate was added at 0° C. The reaction mixture was extracted with ethyl acetate, and the organic extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to afford 1.65 g of the title compound as a yellow oil (87.8% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[K].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Product: Cc1oc2cc(OCc3ccccc3)ccc2c(=O)c1-c1ccccc1

Procedure:
10 g of 7-hydroxy-2-methyl-isoflavone, 10 g of anhydrous potassium carbonate, 1 g of potassium iddide and 12.5 g of benzyl chloride are boiled in 200 ml of anhydrous acetone for 2 hours with stirring, under a reflux condenser. On subjecting the mixture to steam distillation, the crude product precipitating from a mixture of 100 ml of methanol and 40 ml of acetone, yielding white needle crystalls of 7-benzyloxy-2-methyl-isoflavone, m.p. 139°-141°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCCN1CCCC1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCN2CCCC2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
218 mg (0.817 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 126 mg (0.981 mmol) of 1-(3-aminopropyl)pyrrolidine were dissolved in 10 ml of DMF. 235 mg (1.23 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)[CH:25]=2)=[CH:35][CH:34]=1)=[O:37]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(C=O)cc4)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1oc(-c2cccc(-c3ccc(C=O)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-(4-{2-[2-(4′-formylbiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.711 mmol) in ethanol (8.9 mL) was treated with NaOH(aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield a white, crystalline solid: Rf 0.14 in 6:4 ethyl acetate:hexanes; MS (EI) 486.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[F:11][C:12]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:13]=1[C:14](N(OC)C)=[O:15]>C1COCC1>[F:11][C:12]1[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:21]=[CH:20][C:13]=1[C:14]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:15]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
1 milliliter of a 1M THF solution of 4-methoxyphenylmagnesium bromide (1 mmol) was added to a solution of 126 mg (0.5 mmol) of 2-fluoro-N-methoxy-N-methyl-3-trifluoromethyl-benzamide in 2 ml of THF at 0° C. The reaction mixture was stirred for 2 hrs. at this temperature and then quenched with saturated NH4Cl solution and the phases were separated. The aqueous phase was extracted twice with CH2Cl2 and the combined organic phases were washed with brine and dried over Na2SO4. The resulting ketone (135 mg) was obtained after flash chromatographic purification using 5% EtOAc in heptane as an eluent.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1.NC(N)=S.C[S:15]([C:18]1[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][N:19]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:23][C:21]1([CH3:24])[O:20][N:19]=[C:18]([S:15][CH2:2][C:3]2[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)[CH2:22]1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: COc1cc(CBr)on1
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(CSC2=NOC(C)(C)C2)on1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
5-Bromomethyl-3-methoxy-isoxazole (1.22 g, 6.35 mmol) was dissolved in ethanol (30 ml) and thiourea (484 mg, 6.4 mmol) was added. The mixture was stirred at room temperature until the solids were dissolved. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (1.08 g, 6.4 mmol) and potassium carbonate (880 mg, 6.4 mmol) were added and the mixture was heated under reflux for 1 hour. The solids were removed by filtration and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as colourless oil (0.69 g, 45% yield over 3 steps).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:14]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:24])[CH:11]([CH3:13])[CH3:12])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:14]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:24]
Reactant: CC(C)N(CCNC(=O)OC(C)(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To the solution of rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.2 mmol) in DCM (10 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature for 2 hr, then washed with NaOH solution (5%) and water. The organic layer was dried over Na2SO4, concentrated in vacuo to give 60 mg rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one. MS: [M+H]+=392
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C1COCC1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH3:28])[CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[OH:24])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: COc1cc(Cl)ccc1C=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1C(O)c1cccnc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
Toluene (3.5 mL) was added to a 3-necked flask and cooled to −60° C. n-BuLi (1.3 mL, 2.5M in hexanes) was added. A solution of 3-bromopyridine (0.3 mL, 3 mmol) in toluene (1.2 mL) was added dropwise to maintain internal temperature <−50° C. The resulting slurry was then stirred for 30 minutes at −60° C. THF (1.2 mL) was added dropwise, and the mixture was stirred for an additional 15 minutes. 4-Chloro-2-methoxy-benzaldehyde (561 mg, 3.3 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 201 mg (27%) of the title compound. MS (ESI) m/e 250 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][C:35]#[CH:36])[C:28]=2[CH:37]=1.C(O)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][C:35]#[C:36][C:16]3[S:17][C:13]4[N:12]5[C:19]([CH3:22])=[N:20][N:21]=[C:11]5[CH2:10][N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:14]=4[CH:15]=3)[C:28]=2[CH:37]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCN1C(=O)COc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)COc4ccc(Cl)cc43)cc1C(c1ccccc1Cl)=NC2
Reaction time: 72 h

Procedure:
The titIe compound was prepared by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 6-chloro4-(2-propynyl)-2H-1,4-benzoxazin 3(4H)-one [ref. p. Rao et al. Indian J. Chem. 24 B, 1120 (1985)]as described in Example 37 but the reaction time was extended to 72 hours. The product was isolated by chromatography over the 100 -fold amount of silica gel (Merck 230-400 mesh) using 10% (v/v) of ethanol in methylene chloride. Crystallization of the residue obtained after evaporation of the combined clean fractions from ethyl acetate gave colorless crystals of 6-chloro-4-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3 a][1,4]diazepin-2-yl]-2-propynyl}-2H-1,4-benzoxazin-3(4H)-one with m.p. 202°-205°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][NH:20][C:21]4([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]=O>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:33])[C:21]4([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCOCC1
Reactant: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCOCC1

Procedure:
4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid was coupled with paraformaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.70-1.89 (m, 2H), 2.05-2.19 (m, 2H), 2.20 (s, 3H), 3.10-3.60 (m, 2H+ H2O), 3.70 (s, 2H), 3.88 (m, 2H), 3.93 (s, 3H), 7.18 (s, 1H), 7.28 (m, 1H), 7.40-7.60 (m, 2H), 8.30 (s, 1H), 8.41 (s, 1H), 9.76 (brs, 1H). Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [NH2:1][C:2]1([CH2:6][C:7]([O:9]CC)=O)[CH2:5][O:4][CH2:3]1.[CH3:12][NH:13][CH3:14].O>C1(C)C=CC=CC=1>[NH2:1][C:2]1([CH2:6][C:7]([N:13]([CH3:14])[CH3:12])=[O:9])[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)CC1(N)COC1
Reactant: CNC
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C(=O)CC1(N)COC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 87 %

Procedure:
In a microwave tube was added ethyl 2-(3-aminooxetan-3-yl)acetate (CAN 1207175-54-9, 470 mg, 2.95 mmol). Toluene (7.0 ml) and 40%-dimethylamine solution in water (8.9 g, 10.0 ml, 79.0 mmol) were added. The tube was sealed and the reaction mixture was stirred vigorously at room temperature for 7 days. The reaction mixture was concentrated in vacuo and azeotroped several times with 30 mL toluene. The crude solid was dried under high vacuum at 40° C. for 3 hours to yield the title compound (405 mg, 87%). MS (ESI, m/z): 159.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH2:21])[CH:12]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:21][C:13]2[CH:12]=[N:11][C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A solution of 4-fluorobenzoic acid (2.57 g, 18.3 mmol), quinolin-3-ylamine (2.5 g, 17.4 mmol), O-benzotriazol-1-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (7.3 g, 19.3 mmol) and N,N-diisopropylethylamine (6.4 mL, 36.7 mmol) in acetonitrile (75 mL) was stirred at ambient temperature for ten minutes, then heated at reflux for 20 hours. The solution was cooled to 0° C., and the product crystallized. The product was collected by filtration and washed with acetonitrile, to give a colorless solid, 3.86 g (79%). MS: m/z 267 (MH+). 1H NMR(DMSO-d6): δ 7.39-7.46 (m, 2 H), 7.58-7.71 (m, 2 H), 7.97-8.01 (m, 2 H), 8.11-8.16 (m, 2 H), 8.85 (d, 1 H), 9.15 (d, 1 H) and 10.73 (s, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]4[C:24]([CH:27]=O)=[CH:25][CH:26]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2].Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]4[C:24](/[CH:27]=[N:34]\[OH:35])=[CH:25][CH:26]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C=O)ccc23)cc1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(/C=N\O)ccc23)cc1OC
Temperature: 70 °C
Yield: 86 %

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (950 mg, 2.21 mmol) in ethanol (4.7 mL) was heated at 60° C. A solution of hydroxylamine hydrochloride (693 mg, 9.97 mmol) and sodium acetate (1.38 g, 16.8 mmol) in water (4.7 mL) was added to the carbaldehyde solution. The reaction mixture was heated at 70° C. for 30 minutes before it was cooled to room temperature. Water was added and the product formed a white precipitate which was collected by filtration. The solids were washed with water and toluene, and dried under reduced pressure to give (Z)-1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde oxime (847 mg).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[C:22]2[S:27](Cl)(=[O:29])=[O:28])(=[O:15])[CH3:14].C(N(CC)CC)C.Cl>O1CCCC1>[C:1]1([CH2:11][NH:12][S:27]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[CH:24]=[CH:25][CH:26]=[C:17]3[NH:16][C:13](=[O:15])[CH3:14])(=[O:29])=[O:28])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCc1cccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2c(S(=O)(=O)NCc3cccc4ccccc34)cccc12
Yield: 80.3 %

Procedure:
1-Naphthylmethylamine (174 mg, 1.1 mmol) was dissolved in tetrahydrofuran (10 ml), and 5-(acetylamino)-1-naphthalenesulfonyl chloride (284 mg, 1 mmol) was added under ice cooling and stirring. Then, triethylamine (0.17 mL, 1.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate, water, and saturated brine, and after the layer was dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by a mixed solvent of ethyl acetate/diisopropyl ether to give the title compound as a light brown crystal (325 mg, 80.4%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.Br[CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:15]=1[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>C(O)C(C)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:11][CH2:13][C:14]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:15]=2[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(CBr)c1C(=O)OCC(C)C
Reactant: COc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Product: COc1cccc(SCc2cccc(C)c2C(=O)OCC(C)C)c1
Reaction time: 0.25 h

Procedure:
A 10N solution of sodium hydroxide (0.32 mL, 3.2 mmol) is added slowly to a solution of 3-methoxybenzenethiol (0.42 g, 3.0 mmol) in isobutanol (2 mL) followed by a solution of isobutyl 2-bromomethyl-6-methyl-benzoate (0.96 g, 3.3 mmol, example 2) in isobutanol (2 mL). The reaction is allowed to stir 15 min and is then partitioned between ethyl acetate and dilute aqueous HCl. The organic phase is washed with water, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 40% dichloromethane in hexanes) to provide the title compound. MS (EI) 344 (M)+.