Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:21][OH:22])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]([CH2:15][CH2:16][OH:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41]>>[OH:17][CH2:16][CH2:15][N:7]([CH2:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]2[N:1]=[C:32]([C:30]3[CH:29]=[CH:28][C:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=3)[O:22][N:21]=2)[CH:4]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cccc(C(N)=NO)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cccc(CN(CCO)C(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 69 (185.62 mg; 0.60 mmol) and Intermediate 28 (161.47 mg; 0.63 mmol), the crude mixture was purified by flash chromatography (cHex/(DCM/EtOAc 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 8.43 (d, J=1.4 Hz, 1H), 8.17 (dd, J=7.9, 1.9 Hz, 1H), 8.13-8.11 (m, 2H), 7.50 (t, J=8.0 Hz, 1H), 7.43-7.41 (m, 1H), 7.36-7.24 (m, 4H), 7.13 (d, J=7.1 Hz, 1H), 4.58 (s, 2H), 4.23 (s, 2H), 3.73 (br s, 2H), 3.46 (br s, 2H), 3.33 (s, 3H), 2.08 (s, 3H), 1.52 (s, 9H). LC/MS (Method B): 530.4 (M+H)+. HPLC (Method A) Rt 5.91 min (Purity: 96.0%).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:11]1[O:12][C:13]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=2[N:15]=1>O1CCCC1>[CH3:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:12][C:13]=2[CH:19]=1
Reactant: CCOC(=O)CO
Reactant: Cc1ccc2nc(Cl)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1nc2ccc(C)cc2o1
Yield: 92.1 %

Procedure:
0.73 g (7 mmol) ethyl hydroxyacetate is dissolved in 20 ml tetrahydrofurane and 0.36 g (9 mmol) 60% sodium hydride is added to it. After 20 minute stirring 1.0 g (6 mmol) 2-chloro-6-methyl-1,3-benzoxazole is added and the mixture is heated under reflux for 3 hours. The solvent is removed, the residue is dissolved in 15 ml water, extracted with 3×20 ml ethyl acetate. The united organic phase is dried over sodium sulfate and evaporated to obtain 1.3 g title compound as an oil. LC-MS[MH+]=236 (C12H13NO4 235.24)
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12].C(N(C(C)C)C(C)C)C.[CH:29]1(/[CH:35]=[CH:36]/[C:37](Cl)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1(/[CH:35]=[CH:36]/[C:37]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]2[CH:8]=[C:7]([F:6])[CH:18]=[C:17]([F:19])[CH:16]=2)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/C1CCCCC1)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are slowly added and then, dropwise, 4.29 g (24.9 mmol) of trans-3-cyclohexyl-2-propenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for two days. For working up, the mixture is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aq. sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with diethyl ether. The combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue (4.63 g) is washed by stirring with diethyl ether and filtered. 3.64 g (43% of th.) of colorless solid are obtained. The residue from the concentrated mother liquor and the residue from the concentrated diethyl ether phase of the alkaline extraction (see above), are taken up together in ethyl acetate and extracted with 1N hydrochloric acid. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is washed by stirring with diethyl ether and filtered off with suction. A further 2.18 g (26%) of product are isolated.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]=[C:9]=[O:10])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:30][C:31]([NH2:35])=[N:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[NH2:35][C:31]1[CH:30]=[C:29]([N:36]2[CH2:37][CH2:38][N:39]([C:9]([NH:8][C:7]3[C:2]([F:1])=[C:3]([F:14])[C:4]([F:13])=[C:5]([F:12])[C:6]=3[F:11])=[O:10])[CH2:40][CH2:41]2)[C:28]2[C:33](=[CH:34][C:25]([Cl:24])=[CH:26][CH:27]=2)[N:32]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C=Nc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)Nc3c(F)c(F)c(F)c(F)c3F)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of pentafluorophenyl isocyanate (0.03 mL, 0.23 mmol) and iPr2NEt (0.05 mL, 0.29 mmol) in DMF (1 mL), a hot solution of 7-chloro-4-(1-piperazinyl)-2-quinolinamine (50 mg, 0.19 mmol) in DMF (2 mL) was added. After stirring at rt overnight, the mixture was poured into ice-water. The solid was collected by filtration and re-dissolved in CH2Cl2-MeOH, then purified by preparative TLC (CH2Cl2-MeOH, 9:1) affording the product as a light yellow solid. LC-MS: 472 (M++1). 1HNMR (DMSO-d6) δ 3.02 (br.s, 4H), 3.70 (br.s, 4H), 6.28 (s, 1H), 6.50 (s, 2H), 7.10 (d, 1H), 7.39 (s, 1H), 7.78 (d, 1H), 8.80 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:21]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[CH:8]=[C:7]([I:21])[CH:6]=[C:5]([F:9])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Nc1c(F)cc(I)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
To a solution of 2,6-difluoroaniline (5.0 g, 38.7 mmol) and p-toluenesulfonic acid (1.45 g, 7.62 mmol) in DMF (70 mL) was added dropwise N-iodosuccinimide (9.6 g, 42.7 mmol) dissolved in DMF (50 mL) at 5° C. The mixture was stirred for 2.5 hours at room temperature. The mixture was concentrated under reduced pressure, and then diluted with EtOAc and water. The organic layer was washed with saturated aqueous sodium thiosulfate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by crystallization from EtOAc and hexane to give 2,6-difluoro-4-iodoaniline (9.12 g, 92.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: COCCCBr
Reactant: CCOC(=O)c1cc(O)c2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCCCOC)c2c(c1)OCCO2
Temperature: 25 °C

Procedure:
The mixture of 8-hydroxy-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (1.65 g, 7.36 mmol), 1-bromo-3-methoxypropane (1.38 g, 8.83 mmol) and anhydrous K2CO3 (1.53 g, 11.0 mmol) in acetone (40 mL) is refluxed overnight. After cooling to room temperature, the mixture is poured into ice water and extracted with AcOEt. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 3:1) yields the title compound as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.32. MS: 297.0 [M+H]+. 1H-NMR (CDCl3): δ 1.41 (t, 3H), 2.16 (m, 2H), 3.40 (s, 3H), 3.61 (m, 2H), 4.20 (m, 2H), 4.31 (m, 2H), 4.35-4.45 (m, 4H), 7.27 (d, 1H), 7.31 (d, 1H) ppm.
Reaction SMILES: C(NC1C=C(C(OCC)=O)C(C2[C:12]([C:17]3[CH:22]=[C:21]([C:23](F)(F)F)[CH:20]=[CH:19][C:18]=3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:13]C=CC=2)=CC=1)(=O)C.C1(COC2C=CC=CC=2C2C=CC=CC=2B(O)O)C=CC=CC=1.Br[C:64]1[CH:69]=CC=C[C:65]=1[C:70]1[C:71]([C:77]([O:79][CH2:80][CH3:81])=[O:78])=[CH:72][C:73]([CH3:76])=[CH:74][CH:75]=1>>[CH3:76][C:73]1[CH:72]=[C:71]([C:77]([O:79][CH2:80][CH3:81])=[O:78])[C:70]([C:65]2[C:22]([C:17]3[CH:12]=[CH:13][CH:20]=[CH:19][C:18]=3[O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:21][CH:23]=[CH:69][CH:64]=2)=[CH:75][CH:74]=1
Reactant: CCOC(=O)c1cc(C)ccc1-c1ccccc1Br
Reactant: CCOC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1-c1cc(C(F)(F)F)ccc1OCc1ccccc1
Agent: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Product: CCOC(=O)c1cc(C)ccc1-c1ccccc1-c1ccccc1OCc1ccccc1

Procedure:
Prepared in a similar way to ethyl 4-(acetylamino)-2″-[(phenylmethyl)oxy]-5″-(trifluoromethyl)-1,1′:2′,1″-terphenyl-2-carboxylate but using {2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid instead of [2-[(phenylmethyl)oxy]-5-(trifluoromethyl)phenyl]boronic acid and ethyl 2′-bromo-4-methyl-2-biphenylcarboxylate instead of ethyl 4-(acetylamino)-2′-bromo-2-biphenylcarboxylate. LC/MS t=4.11, [MH+] 423.1
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13]C(CCC[C@@H](N)C(O)=O)=O)[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=[O:3].[Na].C(N(CC)C1C=CC=CC=1)C.C(Cl)(=O)C>O1CCCC1>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:26]([OH:28])=[O:27])=[C:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[CH2:25][S:24][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -35 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Cephalosporin C, sodium salt, dihydrate, 4.8 gm (10 mmol), was suspended in 80 ml of tetrahydrofuran (dried over 5A molecular sieves). Diethyl aniline (dried over KOH), 7.4 gm (8.0 ml, 50 mmol), and acetyl chloride, 4.7 gm (4.3 ml, 60 mmol), were added. The mixture was stirred in a water bath at about 30° to 40° C. for 1 hour and then at room temperature for about 2.5 hours. Filtration removed 5.7 gm of undissolved material. The reaction solution was cooled in an ice-alcohol bath before addition to a solution of the triphenyl phosphitechlorine complex prepared as in Paragraph A above, but using tetrahydrofuran as a solvent instead methylene chloride. After mixing the two solutions, a solution of diethylaniline, 3.3 gm (22 mmol) in 20 ml of dry tetrahydrofuran, was added dropwise over a period of 10 minutes. The reaction mixture was stirred in the cold for 2 hours, cooled further to about -35° C., and then treated with 16 ml of propylene glycol. A stream of dry hydrogen chloride was passed through the reaction for about 15 seconds. The reaction solution was refrigerated overnight. Workup as described in Paragraph A immediately hereinabove yielded 1.2 gm (45%) of 7-ACA.
Reaction SMILES: Br[CH2:2][C:3]([CH3:20])=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:16])=[C:8]([CH3:17])[C:7]=1[O:18][CH3:19].[CH3:21][O:22][P:23]([O:26]C)[O:24][CH3:25]>>[CH3:21][O:22][P:23]([CH2:2][C:3]([CH3:20])=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:17])[C:7]=1[O:18][CH3:19])[CH2:10][O:11][C:12]2=[O:16])(=[O:26])[O:24][CH3:25]
Reactant: COP(OC)OC
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Product: COc1c(C)c2c(c(O)c1CC=C(C)CP(=O)(OC)OC)C(=O)OC2
Yield: 55.7 %

Procedure:
A solution of 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (33 mg, 0.097 mmol) in trimethylphosphite (1.0 mL, 8.5 mmol) was heated to 100° C. for 1 hour, whereupon complete reaction was indicated by LCMS. The reaction was worked up by removal of the excess reagent under reduced pressure and the residue was purified by silica gel chromatography using EtOAc-hexanes (20-100%) to provide 20 mg (60%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H), 2.09 (s, 3H), 2.48 (d, 2H, J=22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J=11 Hz), 3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H) ppm; MS (m/z) 371 [M+H]+.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=O)[O:3][CH:2]=1.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11].N1CCCCC1.Cl>N1C=CC=CC=1.O>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1/[CH:6]=[CH:9]/[C:10]([OH:12])=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccco1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccco1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a mixture of 2-furfural (500 g, 5.20 mol) and malonic acid (595 g, 5.72 mol) in pyridine (500 mL) was added piperidine (50 mL, 0.505 mol) at room temperature, and the mixture was stirred at 100° C. for 3 hr. The reaction solution was poured into water (1 L) and acidified with 6M hydrochloric acid. The resulting precipitate was collected by filtration to give the title compound (660 g, yield 92%).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:69])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:68])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:69])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:59][CH:58]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:68])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 102 was prepared analogous to compound of example 98 by hydrolysis of compound of example 101.
Reaction SMILES: CN([CH:4]=[O:5])C.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18](O)=[O:19])=[CH:11][CH:10]=1)([O-:8])=[O:7].C([O-])([O-])=O.[K+].[K+].CI>O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([O:5][CH3:4])=[O:19])=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a 500 mL RB flask fitted with magnetic stirrer was charged with 120 mL of DMF. To the stirred solvent was added (1R,2R)-2-(4-nitrophenyl)cyclo propane carboxylic acid (15 g, 72 mmol), K2CO3 (29 g, 217 mmol) and methyl iodide (5.5 mL, 86 mmol), stirred at RT for 8 h. The RM was poured into water (100 mL) and extracted with ethyl acetate (150 mL×2). The organic layer was washed with saturated NaHCO3 solution (50 mL), water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow color liquid (14 g, yield: 87.9%). MS (ESI, 120 eV): m/z=206.1 (M−H)+.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>O>[O:16]=[C:17]1[CH:22]=[CH:21][N:20]([C:2]2[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=2)[CH:19]=[CH:18]1
Reactant: Oc1ccncc1
Reactant: CC(CC(=O)O)C(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)C(=O)c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A solution of 3-(4-fluorobenzoyl)butanoic acid (885 g), 4-hydroxypyridine (663 g) and sodium hydroxide (453 g) in water (2.2 liters) was stirred under reflux for 24 hours. The reaction mixture was cooled, diluted with water (10 liters) and filtered through diatomaceous earth. The filtrate was acidified to pH 3 with concentrated hydrochloric acid to afford as a cream solid 3-[4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl]butanoic acid, 1127 g (94%), m.p. 251°-254° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=O.[CH3:14][C:15]([CH3:17])=[O:16]>O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])[CH:11]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(F)cc1C=CC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In water (200 ml) was dissolved sodium hydroxide (3 g), and to the solution was added acetone (80 ml) and then was added dropwise a solution of 5-fluoro-2-methoxybenzaldehyde (10 g) in acetone (25 ml). The reaction solution was stirred at room temperature for 4 hours, and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure to give 4-(5-fluoro-2-methoxyphenyl)-3-buten-2-one (13 g).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=[O:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:2][C:1]1[O:20][C:11]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc(C)oc1CCc1ccccc1

Procedure:
To the entire oily residue obtained in Step A is added at 0° C., 60 ml. of thionyl chloride and the resulting mixture refluxed for 40 minutes. The reaction mixture is then cooled and evaporated (under vacuum) to obtain a residue. The residue is dissolved in methylene chloride, and the solution washed with 5% aqueous sodium bicarbonate (100 ml.). The organic layer is then dried over anhydrous sodium sulfate and evaporated (under vacuum) to obtain the title compound as a crude residue.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[CH2:4]1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C@@H:4]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CF)CC1=O
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C(=O)N([C@H](C)c2ccccc2)C[C@@H]1CF
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of (4R)-4-fluoromethyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (34.1 g, 154 mmol) and ethyl chloroformate (16.1 mL, 169 mmol) in tetrahydrofuran (500 mL), lithium bistrimethylsilyl amide (323 mL, 323 mmol, 1.0M solution in tetrahydrofuran) was added at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous solution of ammonium chloride (700 mL) was added to reaction mixture at the same temperature, and the mixture was extracted with ethyl acetate (700 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (500 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution with hexane:ethyl acetate, 5:1→2:3) to obtain 35.0 g (77%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[S:7][C:6]=2[CH:25]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:8]1[S:7][C:6]2[CH:25]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(C)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(C)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 6-methyl-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-aminoanilino)-6-methylbenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([OH:35])[CH:29]=2)#[N:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([O:35][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)[CH:29]=2)#[N:24]
Reactant: N#Cc1cnc2cc(O)ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc(C#N)cnc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Yield: 86.4 %

Procedure:
4-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 10), was suspended in DMF (3 ml) under argon. 3-Cyano-7-hydroxyquinoline (116 mg, 0.68 mmol) and potassium carbonate (129 mg, 0.93 mmol) were added and the reaction mixture was heated at 95° C. for 90 minutes. Upon cooling to ambient temperature the mixture was diluted with dichloromethane and poured on the top of an ISOLUTE silica column. Elution was done using successively dichloromethane, dichloromethane/methanol (95/5) and dichloromethane/methanol saturated with ammonia (95/5). Evaporation of the solvent and trituration of the solid in ether gave 4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (244 mg, 86%).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C@H:22]4[CH2:27][CH2:26][C@H:25]([CH2:28]C)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][N:11]=2)=[CH:5][C:4]=1[F:30])#[N:2].C(C1C(F)=CC(C2N=CC(C3C=CC([C@H]4CC[C@H](CCCCCC)CC4)=CC=3)=CN=2)=CC=1F)#N>>[C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[N:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C@H:22]4[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)=[CH:5][C:4]=1[F:30])#[N:2]
Reactant: CC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4cc(F)c(C#N)c(F)c4)nc3)cc2)CC1
Agent: CCCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4cc(F)c(C#N)c(F)c4)nc3)cc2)CC1
Product: C[C@H]1CC[C@H](c2ccc(-c3cnc(-c4cc(F)c(C#N)c(F)c4)nc3)cc2)CC1

Procedure:
2-(4'-cyano-3',5'-difluorophenyl)-5-[4'-(trans-4"-ethylcyclohexyl) phenyl] pyrimidine ##STR37## 2-(4'-cyano-3',5'-difluorophenyl)-5-[4'-(trans-4"-butylcyclohexyl) phenyl] pyrimidine ##STR38## 2-(4'-cyano-3',5'-difluorophenyl)-5-[4'-(trans-4"-pentylcyclohexyl) phenyl] pyrimidine ##STR39## 2-(4'-cyano-3',5'-difluorophenyl)-5-[4'-(trans-4"-hexylcyclohexyl) phenyl] pyrimidine