Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[C:25]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3ccccc23)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
A microwave vessel was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.008 mmol), 2-naphthylboronic acid (225 mg, 1.310 mmol), tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.076 mmol), sodium carbonate (534 mg, 5.04 mmol), toluene (8.06 mL), and water (2.02 mL). The mixture was heated at 100° C. for 2 h, then cooled to rt and partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), and concentrated. The resulting crude material was purified by flash chromatography, eluting with a gradient of 0-6% EtOAc in hexane to give 4-chloro-5,7-difluoro-3-methyl-2-(naphthalen-1-yl)quinoline. Mass Spectrum (ESI) m/e=340.0 (M+1).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:1][CH:2]([CH2:18][NH:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Product: O=C1CCC(c2cccc(OCC(O)CNCCc3ccccc3)c2)=NN1

Procedure:
6-[3-(2,3-Epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone was reacted with phenylethylamine in a similar manner to that described in Example 1(ii) to give 6-[3-(2-hydroxy-3-phenethylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:25])=[C:17](F)[C:18]=3[O:20][CH:21]([F:23])[F:22])[C:13](=[O:26])[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]2[S:32]([CH3:35])(=[O:34])=[O:33])[CH2:9][CH2:8]1.NC([C@@H]1CCN(C2C(OC)=C3C(C(=O)C(C(OCC)=O)=C(S(C)(=O)=O)N3C3CC3)=CC=2F)C1)(C)C>>[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:25])=[C:17]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)[C:18]=3[O:20][CH:21]([F:23])[F:22])[C:13](=[O:26])[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]2[S:32]([CH3:35])(=[O:33])=[O:34])[CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O
Product: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC(F)F)c(N3CCNCC3)c(F)cc2c1=O

Procedure:
The title compound is prepared from piperazine and ethyl 1-cyclopropyl-8-(difluoromethoxy)-6,7-difluoro-2-(methylsulfonyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate using a procedure analogous to that describing the preparation of (R)-ethyl 7-(3-(2-aminopropan-2-yl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-2-(methylsulfonyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate. (See US 2008071086, and Hashimoto, et al., 2007) 1H NMR (CDCl3): δ 0.30-0.33 (m, 1H), 0.84-0.88 (m, 1H), 0.99-1.04 (m, 1H), 1.20-1.25 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 2.95-3.21 (m, 6H), 3.44 (s, 3H), 3.51-3.58 (m, 2H), 4.13-4.18 (m, 1H), 4.36-4.48 (m, 2H), 6.54 (dd, J=76.0 Hz, 73.0 Hz, 1H), 7.72 (d, J=12.0 Hz, 1H). 19F NMR (CDCl3): δ −120.4 (s, 1F), −82.1 (s, 2F). LCMS: m/z calcd for C21H24F3N3O6S ([M]+) 503. found ([M+H]+) 504.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (3.5 g, 10 mmols), ethyl 6-bromohexanoate (3.6 ml, 21 mmols), potassium carbonate (4.2 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 6-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminohexanoate (2.29 g, 46.6%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([OH:21])[C:17]1=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl[CH2:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([O:21][CH2:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:17]1=[O:22])=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)OC(=O)CCl
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)CON1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
11.3 g of Triethylamine was dropped into a solution of 19.5 g of (3S-trans)-3-(t-butyloxycarbonylamino)-1-hydroxy -4-methyl-2-azetidinone and 14.8 g of chloroacetic acid, 1-methylethyl ester in 400 ml of dry dimethylformamide. The whole was stirred at room temperature for 3 days. Triethylamine hydrochloride was filtered off and the solvent was stripped at 35° C. in vacuo. The residual oil was taken up in ether, the extract was allowed to stand in the refrigerator for about two hours, filtered and the ether again evaporated in vacuo. The resulting oily title compound (30 g) containing about 2 g of impurities was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[Br:11][C:12]1[S:16][C:15](C=O)=[CH:14][CH:13]=1>>[Br:11][C:12]1[S:16][C:15](=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:14][CH:13]=1
Reactant: CCOP(=O)(CN)OCC
Reactant: O=Cc1ccc(Br)s1
Product: CCOP(=O)(CN=C1CC=C(Br)S1)OCC
Yield: 100 %

Procedure:
Starting from 16.7 g. (0.1 mol) diethyl aminomethylphosphonate and 19.1 g. (0.1 mol) 5-bromothien-2-aldehyde and following a procedure identical to that described in Example 1, 34 g. (yield: 100%) of the desired product are obtained in the form of a yellow oil.
Reaction SMILES: CN(CC[C:6]1[C:10]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][CH:7]=1)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:28]([N:32]([CH:37](O)[CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH2:37][CH2:38][C:9]1[C:10]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[CH:6]=[CH:7][CH:8]=1)[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(CCCC)C(C)O
Reactant: CC(C)C1(C(C)C)C=CC=C1CCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCCCN(CCCC)CCC1=CC=CC1(C(C)C)C(C)C
Yield: 53 %

Procedure:
The reaction was carried out in a manner identical to that for (dimethylaminoethyl)di(2-propyl)cyclopentadiene, the tosylate of N,N-di-n-butylaminoethanol being prepared in situ. The conversion was 94%. The non-geminal di-n-butylaminoethyldi(2-propyl)cyclopentadiene was obtained by distillation with a yield of 53%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (28.2 g, 231 mmol), potassium carbonate (47.9 g, 347 mmol), potassium iodide (3.84 g, 23.1 mmol) and N,N-dimethylformamide (280 mL) was added benzyl bromide (27.5 mL, 231 mmol) with stirring at room temperature, and the mixture was stirred at the same temperature for 24 hrs. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid and saturated brine, dried, and concentrated under reduced pressure to give the title compound (48 g, yield 98%) as beige crystals.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.C(N(CC)CC)C.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2([NH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:29](=[O:46])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2([NH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:36][N:37]([C:3]3[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=3)[CH2:38][CH2:39]2)[C:29](=[O:46])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Yield: 53.8 %

Procedure:
4-Chloro-2-methylpyridine hydrochloride (941 mg), triethylamine (1.93 g) and ethanol (50 ml) were added to 4-benzyloxycarbonyl-1-[(4-ethoxycarbonylamino-4-piperidinyl)methyl]-2-piperazinone (2.0 g), and the mixture was reacted at 150° C. for 10 hours in a sealed tube. The reaction mixture was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, and the mixture was extracted with dichloromethane, dried, and concentrated. The resulting residue was purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the colorless amorphous title compound (1.31 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[C:11](=[O:20])[C:10]=2[CH:21]=1)(=[O:5])=[O:4].CO.[BH4-].[K+].[OH-].[K+]>O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([OH:20])[C:10]=2[CH:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2ccc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2

Procedure:
3-Dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-one (6.9 g., 0.022 mole) and 100 ml. of absolute methanol are stirred and heated to refluxing. A solution of 1.6 g. (0.0296 mole) of potassium borohydride in 12 ml. of water containing 1 pellet of potassium hydroxide is added dropwise at a rate such that reflux is maintained without external heating. After another 11/2 hours at reflux, the solution is evaporated to dryness under reduced pressure. The residual white solid is suspended in water, collected, and crystallized from 95% ethanol. The yield of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol is 6.05 g. (87%), m.p. 150°-152°C. The melting point is unchanged by further recrystallization.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@H:7]([C:12]([O:14]C)=O)[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:5])=[O:4])[CH3:2].[NH:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19]>>[CH2:1]([S:3]([NH:6][C@H:7]([C:12]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:10])[CH3:11])(=[O:4])=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCS(=O)(=O)N[C@@H](CC(C)C)C(=O)OC
Product: CCS(=O)(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
EtSO2-Leu-OMe (3.3 g) was saponified (procedure example 1), coupled with H-Pro-OBzl (procedure example 23) and the resulting dipetide was hydrogenated (procedure example 23) using the indicated procedures to give 3.4 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([CH3:17])=[N:10]2)=[CH:5][CH:4]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.CS(C)=O>[CH:18]1([NH:24][C:14]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=[C:11]([CH3:17])[CH:12]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(-n2nc(C)cc2C(=O)O)cc1
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(-n2nc(C)cc2C(=O)NC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2-(4-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (752 mg, 3.24 mmol) was suspended in methylene chloride (25 mL) and DMSO (3 drops) was added. After the reaction was stirred at room temperature for 1 hour, it was concentrated in vacuo. The residue was diluted twice with methylene chloride (60 mL) and concentrated to dryness. The residue was diluted again with methylene chloride (45 mL), cyclohexylamine (650 μL, 5.68 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted further with methylene chloride, washed with NaOH (10%) and 1 N HCl, then dried over Na2SO4. Concentration gave 630 mg of the title compound, which was used in the next reaction without further purification. LC-MS (C18H23N3O2 calculated 313) m/z 314 (M+H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([NH2:18])([CH3:17])[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:15]([NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To the solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.09 mmol) in methanol (35 mL) was added isopropylamine (1.07 mL, 12.54 mmol), acetic acid (0.94 mL, 16.30 mmol) and sodium cyanoborohydride (1.0 g, 16.30 mmol). The resulting solution was stirred at room temperature for 1 hour, then quenched with water. The solution was concentrated in vacuo and redissolved in ethyl ether. The organics were extracted with 0.1 N HCl. The aqueous extracts were basified with 1 N NaOH (pH>8) and extracted with ethyl ether. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford tert-butyl 4-(isopropylamino)piperidine-1-carboxylate (1.2 g, 41%) as a clear liquid.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:20]>>[C:1]1([CH:7]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)COC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)COCC2c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate 43)) (2.58 g, 10.52 mmol) in ammonium hydroxide (28.7 mL, 736 mmol) was heated to 80° C. in a sealed tube and stirred overnight. The reaction mixture was then concentrated to dryness giving 8-phenyl-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione. The crude material was carried on as-is. LC-MS (M+H)+=245.2.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:36][C:32]1[CH:31]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:35]=[CH:34][CH:33]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-tert-butylphenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α,-trifluoro-m-cresol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a pale yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25](Cl)=[N:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1.[Na].CCO[C:33]([CH3:35])=[O:34]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:34][CH2:33][CH2:35][N:26]3[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(Cl)nc2)cc1
Reactant: CCOC(C)=O
Agent: [Na]
Solvent: c1ccccc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)nc2)cc1
Temperature: 70 °C

Procedure:
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][2-chloropyridin-5-yl]methanone (1 g, 2.44 mmol) was dissolved in 10 mL of benzene and 950 mg (7.32 mmol) of 2-hydroxyethyl-1-piperidine was added. To the reaction mixture was added 85 mg (3.7 mmol) of sodium and the reaction was stirred at ambient temperature under a nitrogen atmosphere until all the sodium dissolved. The reaction was heated to 70° C. for two and half hours, then allowed to cool. To the reaction solution was added 150 mL of EtOAc and the solution was washed three times with saturated aqueous Na2CO3. The organic layer was separated and evaporated to dryness. The crude product was chromatographed on a silica gel column eluted with a linear gradient beginning with CHCl3 and ending with CHCl3 -MeOH (19:1). The desired fraction were determined by tlc, combined, and evaporated to dryness. This yielded the title compound as a yellow, amorphous solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][CH2:14][N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C1C=CN=CC=1.F>C(#N)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:16]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCn2nc(-c3ccccc3)ccc2=O)cc1
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1ccc(-c2ccccc2)nn1CCc1ccc(O)cc1
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-(tert-butyldimethylsilyloxy)phenethyl)-6-phenylpyridazin-3(2H)-one (180 mg, 443 μmol) in ACN (3 mL) was added 70% HF-pyridine (0.25 mL) at 23° and stirred for 18 h. Solvents removed under reduced pressure and residue partioned between 9:1 CHCl3/iPrOH (30 mL) and 5% NaHCO3 (15 mL). The aqueous was further extracted with 9:1 CH3Cl/iPrOH (3×20 mL). Combined organics dried over MgSO4 then concentrated to a solid under reduced pressure from toluene. The residue was purified on 40 grams of silica eluting with 0-% EtOAc/CH2Cl2. The isolated solid was recrystallized from ACN (1 mL). MS (ESI pos. ion) m/z (MH+): 293. Calc'd exact mass for C18H16N2O2: 292. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.97 (t, J=7.28 Hz, 2 H) 3.17 (s, 1 H) 4.31 (t, J=7.53 Hz, 2 H) 6.66 (d, J=8.53 Hz, 2 H) 7.02 (t, J=8.28 Hz, 3 H) 7.39-7.54 (m, 3 H) 7.82 (d, J=8.03 Hz, 2 H) 8.01 (d, J=9.54 Hz, 1 H) 9.20 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(NCC)C>CN(C)C=O>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(CCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminophenethyl alcohol (25 g) in N,N-dimethylformamide (500 ml) were added potassium carbonate (30 g) and ethyl bromoacetate (24 ml), and the mixture was stirred for 16 hours at room temperature. Diethylamine (38 ml) was added to the reaction mixture, and the resulting mixture was stirred for 1 hour. The insoluble material was filtered off and the filtrate was concentrated in vacuo. To the residue was added diethyl ether, and the resulting insoluble material was filtered off. The filtrate was washed with 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and brine subsequently, and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave ethyl N-[4-(2-hydroxyethyl)phenyl]aminoacetate (35.5 g).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].C(N(CC)CC)C.[CH3:13][Si:14](OS(C(F)(F)F)(=O)=O)([CH3:16])[CH3:15]>C(Cl)Cl>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:5][C:2]([CH:3]=[CH2:4])=[CH2:1]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=C)O[Si](C)(C)C

Procedure:
70 μl (0.86 mmoles) of 3-buten-2-one [compound of formula 5 wherein R1=R2=R6=H] and 2 ml of anhydrous CH2Cl2 are charged, at 0° C. under argon in a two-necked round bottom flask equipped with magnetic stirrer and dropping funnel. 170 μl (1.22 mmoles) of triethylamine (distilled on KOH) and 209 μl (1.08 mmoles) of trimethylsilyltrifluorometansulphonate (TMDOTf) (drop by drop) are added to the mixture. In this conditions 2-(trimethylsilyloxy)-1,3-butadiene [compound 6 wherein R1=R2=R6=H] is formed “in situ”. The mixture is stirred for 45 minutes and thereafter a solution of 100 mg (0.36 mmoles) of the product from Example 2 in 2 ml of anhydrous CH2Cl2 is added therein, drop by drop, together with 69 μl (0.36 mmoles) of TMSOTf. The mixture is brought to room temperature and after 30 minutes 4 ml of a saturated solution of NaHCO3 are added and the mixture is stirred vigorously for 36 h. 4 ml of water are added to the mixture and the aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated solution of NaHCO3, water, a saturated solution of NaCl and is dried on Na2SO4. After filtration the solvent is removed and 59 mg of crude product are obtained. The product is purified by flash chromatography on silica gel column (FCC) eluting with methylene chloride and triethylamine 1%. 18 mg of the wanted product are obtained (crystals). M.p.: 53-54° C. Yield 25%.