Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-methylpiperidine according to conditions described in general procedure C. Mp: 145-146° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.86 (d, J=6.0 Hz, 3 H), 1.50-1.62 (m, 1 H), 3.30 (m, 8 H), 6.19-6.21 (m, 1 H), 6.99 (d, J=11.0 Hz, 1 H), 7.19 (d, J=9.0 Hz, 1 H), 7.41-7.43 (m, 1 H), 7.49 (s, 1N), 7.57-7.62 (m, 3 H), 7.85 (d, J=8.2 Hz, 1 H), 7.99 (d, J=8.5 Hz, 1 H), 8.25-8.27 (m, 1 H), 10.46 (s, 1 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: Cc1cc(O)ccc1C(C)C
Product: Cc1cc(OCC2CO2)ccc1C(C)C

Procedure:
The title compound was prepared from 4-isopropyl-3-methyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[N:24][OH:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)COc1ccc(C(=NO)c2ccccc2F)c(Cl)c1Cl
Reaction time: 16 h

Procedure:
A mixture of 1.0 g of 2.3-dichloro-4-(2-fluorobenzoyl)phenoxyacetic acid and 1 g of hydroxylamine hydrochloride in 10 ml of pyridine is refluxed for 2 hours. Thereafter, the solvent is evaporated in vacuo and the residue is stirred for 16 hours with 5% hydrochloric acid. The product is filtered off and the collected solid is recrystallized from aqueous ethyl alcohol to give the product 2,3-dichloro-4-(2-fluorobenzohydroximoyl)phenoxyacetic acid having a melting point of 91° to 96° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]([O:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][C:18]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: BrCc1cccc(I)c1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(I)c1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
25 g (84.2 mmol) of 3-iodobenzyl bromide are added to a solution of 24.3 g (88.4 mmol) of diethyl [(tert-butoxycarbonyl)amino]malonate and 3.7 g (92.6 mmol) of sodium hydride in 300 ml of DMF while cooling in ice. After stirring the mixture at RT for 4 h, 5 ml of water are added cautiously while cooling in ice. The mixture is extracted several times with ethyl acetate, and the combined organic phases are washed with a saturated sodium chloride solution and water, dried over magnesium sulfate and concentrated in vacuo. The crude product is dried under high vacuum.
Reaction SMILES: C(Cl)(=O)C.[C:5]([C:7]1[CH:15]=[C:11]([C:12](O)=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)#[N:6].C([N:19](CC)CC)C.S(Cl)(Cl)=O>ClCCl.ClCCCl.CN(C)C=O>[C:5]([C:7]1[CH:15]=[C:11]([C:12]([NH2:19])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)#[N:6]
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(O)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(O)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (43.3 g) was added dropwise with ice-cooling to a solution of 5-cyano-salicylic acid (29.0 g) and triethylamine (54.0 g) in dichloromethane (300 ml). After the addition was complete, the reaction mixture was stirred for 2 hours at ice-cooling temperature to room temperature. The solvent was distilled off under reduced pressure and the residue was extracted by addition of ethyl acetate and an aqueous potassium bisulfate solution. The ethyl acetate layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain oil. This oil was dissolved in 1,2-dichloroethane (100 ml), and thionyl chloride (42.4 g) and dimethylformamide (0.5 ml) were added to the mixture, and the resulting mixture was heated under reflux for 1 hour. After air cooling, the solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (100 ml). This solution was added with ice cooling to a mixed solution of aqueous ammonia (100 ml) and tetrahydrofuran (100 ml), and the mixture was stirred for 1 hour. An aqueous potassium bisulfate solution was added to the mixture to adjust to pH 2 to 3, and the mixture was extracted with ethyl acetate-tetrahydrofuran three times. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude 5-cyano-salicylamide.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (50 mg, 0.112 mmol) in dichloromethane (2 mL). After 1 h, saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. MS 346.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[CH3:17][O:15][C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (supplied by NeoMPS, Inc.), (5.78 g, 25.0 mmol) in N,N-dimethylformamide (30 mL) was subsequently treated with potassium carbonate (4.14 g, 30.0 mmol) and iodomethane (7.10 g, 3.1 mL, 50.0 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with water (4×) and brine then filtered through a hydrophobic frit and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:3 to afford the title compound (4.83 g, 79%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 3.06-3.15 (m, 2H), 3.56-3.64 (m, 1H), 3.75-3.79 (m, 1H), 3.81 (s, 3H), 4.00-4.14 (m, 3H). LCMS (m/z) 268.1 [M+Na], Tr=1.94 min.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH3:5].[CH3:6][O:7][C:8]([CH:10]1[CH:15]([CH3:16])[O:14][CH:13]([CH3:17])[CH2:12][N:11]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9]>>[CH3:6][O:7][C:8]([C@H:10]1[C@H:15]([CH3:16])[O:14][C@@H:13]([CH3:17])[CH2:12][N:11]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:2][C:3]#[C:4][CH3:5])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:9]
Reactant: COC(=O)C1C(C)OC(C)CN1S(=O)(=O)c1ccc(O)cc1
Reactant: CC#CCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2C[C@H](C)O[C@@H](C)[C@@H]2C(=O)OC)cc1

Procedure:
The title compound was prepared in a manner similar to Preparation 3 from 1-chloro-but-2-yne and 4-(4-Hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester. 1HNMR (400 MHz, CDCl3): δ=7.66 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 4.65 (bs, 2H), 4.47 (q, J=6.4 Hz, 1H), 4.23 (s, 1H), 3.92 (m, 1H), 3.50 (s, 3H), 2.93 (dd, J=12.2 and 11.0 Hz, 1H), 1.79(t, J=2.3 Hz, 3H), 1.40 (d, J=6.6 Hz, 3H), 1.01(d, J=6.0, 3H). MS: Calculated for C18H23NO6S (M+H): 382.13. Found: 382.0.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:44][O:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])[C:11]([NH:13][CH:14]2[C:42](=[O:43])[N:16]3[C:17]([C:39]([OH:41])=[O:40])=[C:18]([CH:21]([S:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)[CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:44][O:45][CH2:46][C:47]([OH:49])=[O:48])[C:11]([NH:13][CH:14]2[C:42](=[O:43])[N:16]3[C:17]([C:39]([OH:41])=[O:40])=[C:18]([CH:21]([S:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)[CH2:22][CH2:23][CH2:24][NH2:25])[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCCNC(=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Conc. hydrochloric acid (20.8 g.) was added to a mixture of 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(3-tert-butoxycarbonylaminopropyl)-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 39.1 g.) in methanol (400 ml.), and stirred at room temperature for 4 hours. After removing the solvent in vacuo, tetrahydrofuran (40 ml.) and anisole (40 ml.) were added to the residue and stirred at room temperature for 4 hours. The reaction mixture was added to ethyl acetate at room temperature. The precipitates were collected by filtration and washed with ethyl acetate to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers). The product was subjected to column chromatography on macroporous nonionic adsorption resin "HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Co.) to give the syn isomer of the objective compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1.Cl[CH2:26][CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C.Cl>C(#N)C.C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][C:29]([N:31]4[CH2:32][CH2:33][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]4)=[O:30])[CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1
Reactant: CN(C)C1CCN(C(=O)CCCCl)CC1
Reactant: O=c1oc(-c2cc(Cl)cc3c2OCCC3)nn1C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C1CCN(C(=O)CCCN2CCC(n3nc(-c4cc(Cl)cc5c4OCCC5)oc3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.68 mmol) of 5-(6-chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one hydrochloride, in solution in 50 ml of acetonitrile, is introduced into a 250 ml three-necked round-bottomed flask, 1.24 ml (5.36 mmol) of 1-(4-chloro-1-oxobutyl)-N,N-dimethylpiperidin-4-amine and 1.12 ml (8 mmol) of triethylamine are added and the mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure and the residue is taken up in water and extracted three times with chloroform. The organic phase is dried over magnesium sulphate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with 98/2, 95/5 and then 90/10 mixtures of dichloromethane and methanol. A white solid is obtained which is treated in a solution of gaseous hydrochloric acid in ethanol and, after recrystallizing from ethanol, 0.22 g of hydrochloride is finally isolated. Melting point: 193° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[F:28][C:29]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:31]3[CH2:32][CH2:33][C:29]([F:34])([F:28])[CH2:30]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: FC1(F)CCNC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 3,3-difluoropyrrolidine hydrochloride (43 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (150 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 2 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography purification (silica gel, gradient 10-20% ethyl acetate/isohexane) yielding Compound 62 as a solid (18 mg).
Reaction SMILES: CC1(C)CC(C)C[C:4]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)C1.CC1(C)CC(C)CC(C2C=C(C)C(O)=C(C)C=2)(C2C=C(C)C([OH:39])=C(C)C=2)C1.CC1(C)CC(C)(C)CC(C2C=CC(O)=CC=2)(C2C=CC(O)=CC=2)C1.CC1(C)CC(C)(C)CC(C2C=C(C)C(O)=CC=2C)(C2C=C(C)C(O)=CC=2C)C1.CC1(C)CC(C)C(C2C=CC(O)=CC=2)(C2C=CC(O)=CC=2)C1.CC1(C)CC(C)C(C2C=C(C)C(O)=C(C)C=2)(C2C=C(C)C(O)=C(C)C=2)C1>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:39])=[CH:10][CH:11]=1
Reactant: Cc1cc(C2(c3cc(C)c(O)c(C)c3)CC(C)CC(C)(C)C2)cc(C)c1O
Reactant: CC1CC(C)(C)CC(c2ccc(O)cc2)(c2ccc(O)cc2)C1
Agent: CC1(C)CC(C)(C)CC(c2ccc(O)cc2)(c2ccc(O)cc2)C1
Agent: CC1CC(C)(C)CC1(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cc1cc(C2(c3cc(C)c(O)c(C)c3)CC(C)(C)CC2C)cc(C)c1O
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
The following are further bisphenol components suitable for the preparation of the aromatic polyethers containing ester groups: 3,3,5-Trimethyl-1,1-bis-(4-hydroxyphenyl)-cyclohexane, 3,3,5-trimethyl-1,1-bis-(4-hydroxy-3,5-dimethylphenyl)-cyclohexane, 3,3,5,5-tetramethyl-1,1-bis-(4-hydroxyphenyl)-cyclohexane, 3,3,5,5-tetramethyl-1,1-bis-(4-hydroxy-2,5-dimethylphenyl)cyclohexane, 3,3,5-trimethyl-1,1-bis-(4-hydroxyphenyl)cyclopentane and 3,3,5-trimethyl-1,1-bis-(4-hydroxy-3,5-dimethylphenyl)-cyclopentane.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:14][O:13][C:10]1[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([CH:2]=[O:1])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)c2cccnc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C=O)c2cccnc12
Reaction time: 24 h
Yield: 94.3 %

Procedure:
5-Hydroxymethyl-8-methoxyquinoline (6.5 g, 34 mmol) from Step 1 was dissolved in 250 mL of DCM and treated with 24 g of manganese dioxide. After stirring for 24 h, the mixture was treated with an additional 6 g of manganese dioxide and stirred for 24 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under vacuum to afford 6 g of the title compound as a brown solid. 1H NMR (CDCl3) δ 10.2 (s, 1 H), 9.69 (d, 1 H), 9.01 (d, 1 H), 8.01 (d, 1H), 7.61 (dd, 1H), 7.16 (d, 1H), 4.19 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)#[CH:12].N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)=[CH:14][CH:15]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cnccn3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 5.70-5.81 (m, 2H), 5.85 (s, 1 H), 6.35-6.55 (m, 2H), 7.15 (d, J=2.4 Hz, 1H), 7.19-7.26 (m, 1H), 7.75 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC)cc2)ccc1O
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC)cc2)ccc1OCCCCCBr
Yield: 72.6 %

Procedure:
Starting with 0.484 g (1.31 mmol) of 5-[[4-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 2.4 g (10.44 mmol) of 1,5-dibromopentane, the title compound was obtained in 72.6% yield as a white solid, mp 76.5°-78° C., using the procedure of example 21.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:44]1[CH:45]=[C:46]([C:51]2[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[CH:53][C:52]=2[CH3:64])[CH:47]=[N:48][C:49]=1[CH3:50].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:44]4[CH:45]=[C:46]([C:51]5[CH:63]=[CH:62][C:54]([C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])=[CH:53][C:52]=5[CH3:64])[CH:47]=[N:48][C:49]=4[CH3:50])=[CH:24][N:23]=[C:22]([N:35]4[CH2:36][CH:37]([F:39])[CH2:38]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:4]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:8]=1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(Cl)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
To a 10 mL microwave tube was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2-(3-fluoroazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 22, 86 mg, 0.142 mmol), tert-butyl 4-(5-chloro-6-methylpyridin-3-yl)-3-methylbenzoate (INTERMEDIATE 39, 41 mg, 0.129 mmol), potassium phosphate (41 mg, 0.194 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (20.3 mg, 0.026 mmol), followed by dioxane (2 mL) and water (0.1 mL). The tube was sealed and stirred at 180° C. in the microwave reactor for 10 minutes. After cooling down, the solvent was evaporated. The residue was purified by silica gel chromatography (0 to 100% Ethyl acetate/hexane) and afforded the title compound as a white solid in 46% yield. LCMS (M+H)+: 760.2.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl.[CH3:16]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Commercially available 4-methyl-1-naphthalenecarboxylic acid (250.6 mg) was dissolved in methanol (7.5 ml). Hydrogen chloride gas was blown into the solution for five minutes while cooling with ice. Then, the mixture was stirred for 19 hours at room temperature and the solvent was removed by distillation. The residue was dissolved in chloroform, washed with 1 mol/l aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was dried under reduced pressure to obtain the target compound (269.9 mg) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:10]
Reactant: CCOC(CBr)OCC
Reactant: Fc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(CSc1ccccc1F)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 2-fluorothiophenol (1.00 g, 7.80 mmol), bromoacetaldehyde diethyl acetal (1.41 mL, 9.36 mmol), and Cs2CO3 (3.05 g, 9.36 mmol) in anhydrous DMF (20 mL) was stirred under N2 at room temperature overnight. The reaction mixture was filtered through a sintered funnel, and the filtrate was diluted with water (20 mL). The aqueous mixture was extracted with Et2O (3×100 mL), and the organic phase was dried over anhydrous MgSO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give (2,2-diethoxyethyl)(2-fluorophenyl)sulfane (1.81 g, 95%) as a viscous liquid. 1H NMR (400 MHz, CDCl3): δ 7.46-7.41 (m, 1H), 7.24-7.18 (m, 1H), 7.09-7.02 (m, 1H), 4.64 (t, 1H, J=5.6 Hz), 3.69-3.61 (m, 2H), 3.56-3.49 (m, 2H), 3.10 (d, 2 H, J=5.6 Hz), 1.17 (t, 6H, J=7.2 Hz).