Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (2.48 mL, 32.1 mmol) was added slowly to a solution of 4-benzyloxy-butan-1-ol (5.26 g, 29.2 mmol) and Et3N (6.1 mL, 43 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2, dried (MgSO4), and concentrated in vacuo to give the title compound as a colorless liquid: yield 7.5 g (99%).
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=c1c(Br)coc2ccccc12
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)coc2ccccc12
Yield: 22.5 %

Procedure:
Prepared according to general procedure using 3-bromochromone (338 mg, 1.5 mmol), 4-fluorophenylboronic acid (231 mg, 1.65 mmol), K2CO3 (622 mg, 4.5 mmol), PdCl2(PPh3)2 (45 mg, 0.045 mmol), THF (3 mL) and water (1.5 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford afford 37 (81 mg, 23%) as a white solid. Analytical data for isoflavone 37: 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=9 Hz, 1H), 8.04 (s, 1H), 7.72 (app t, J=9 Hz, 1H), 7.58-7.56 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.47 (app t, J=8 Hz, 1H), 7.16 (app t, J=9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.5, 164.0, 162.0, 156.5, 153.2, 134.0, 131.0, 128.0, 126.7, 125.6, 124.8, 118.3, 115.8; LCMS: Mass calculated for C15H9FO2, [M+H]+, 241. Found 241.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:15])[C:8]([NH2:13])=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1cc2ccnc(Cl)c2cc1Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc2c(Cl)nccc2c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.2 %

Procedure:
To a solution of 2.62 g (12.3 mmol) of 1,7-dichloro-isoquinolin-6-ylamine in DMF (130 mL) was added 5.5 g (15.5 mmol) of Selectfluor® as a solid in one portion. The mixture was stirred at room temperature for 15 h. The mixture was poured over ice and stirred until all of the ice had melted during which time a solid precipitated from solution. The brown solid was collected by filtration, washed with water and dried on the filter pad to provide 1.0 g (60% by 1H-NMR, 21%) of 1,7-dichloro-5-fluoro-isoquinolin-6-ylamine. MS calc. for C9H5Cl2FN2 [M]+: 231.05. Found: 231.68.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>O1CCCC1.C1(C)C=CC=CC=1>[F:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[C:8]([I:12])[CH:9]=1
Reactant: Nc1c(F)cc(I)cc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cc(I)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg (1.78 mmol) of 2-amino-3-fluoro-5-iodo-benzoic acid in 5.0 mL tetrahydrofuran was added 1.4 mL (2.67 mmol) of 20% w/v solution of phosgene in toluene. The reaction was stirred for 16 hours at room temperature. The solution was concentrated to dryness to afford 550 mg (1.79 mmol, quantitative yield) of 8-fluoro-6-iodo-1H-benzo[d][1,3]oxazine-2,4-dione as a brown powder. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.09 (dd, 1H), 7.98 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(C(C)C)C(C)C)C.O>CC(C)=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:20])=[C:15]([O:18][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: -20 °C
Yield: 90 %

Procedure:
Benzhydryl 7β-[(phenylacetyl)amino]-3-hydroxy-3-cephem-4-carboxylate (500 g, 1 mol) was dissolved in acetone (2 L) and methanesulfonyl chloride (86 mL, 1.1 mol) was added dropwise over 10 min with stirring at −20° C. Then, ethyldiisopropylamine (183 mL, 1.05 mol) was added dropwise over 30 min and the mixture was stirred at −20° C. for 40 min. The reaction mixture was poured into iced water (8 L) and the precipitate was collected by filtration. The precipitate was then washed with water (2 L) and ethyl acetate (300 mL), and dried under reduced pressure to give the title compound (523 g, 0.90 mol). yield: 90%.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C@H:16]([NH:29]C(=O)OC(C)(C)C)[CH2:17][N:18]([CH3:28])[C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOCC.CC1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CCO>[NH2:29][C@@H:16]([CH2:15][CH:12]1[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:14][CH2:13]1)[CH2:17][N:18]([CH3:28])[C:19](=[O:20])[O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C[C@@H](N)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
(S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (1.9 g, 3.49 mmol) was dissolved into a minimal volume of Et2O (23.4 mL) and added to a solution of TsOH (0.66 g, 3.49 mmol) in absolute EtOH (5 mL). This solution was placed on a rotary evaporator and the Et2O was removed at ambient temperature. The flask was then lowed into the water bath (temperature: 60° C.) and the selective deprotection of the Boc group proceeded concurrent with removal of the remainder of solvent. The reaction was complete after 2 h and gave a pale yellow oil. The residue was dissolved into EtOAc (30 mL) and washed with 1 M aq NaOH (3×5 mL), brine (4×5 mL). The combined organic layers were dried and concentrated to provide (S)-2-(trimethylsilyl)ethyl 2-amino-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)propyl(methyl)carbamate (1.15 g, 74%). MS (E/Z): 445 (M+H+).
Reaction SMILES: [CH3:1][S:2](=[N:10][C:11]([C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[S:25][C:24]([NH:26]C(=O)OC(C)(C)C)=[N:23][CH:22]=2)[CH:16]=[N:17][CH:18]=1)=[O:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:24]1[S:25][C:21]([C:20]#[C:19][C:15]2[CH:16]=[N:17][CH:18]=[C:13]([CH:14]=2)[C:11]([N:10]=[S@@:2]([CH3:1])(=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])=[CH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccccc3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cnc(N)s2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.5 %

Procedure:
To a solution containing tert-butyl (5-{[5-({[methyl(oxo)phenyl-λ6-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}-1,3-thiazol-2-yl)carbamate (16 mg, 0.032 mmol) in 2.0 mL dichloromethane at room temperature was added trifluoroacetic acid (0.099 mL, 1.3 mmol). The reaction was stirred at room temperature for 17 hours, then partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc layer was washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid film was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a tan solid (9 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1C(O)=O.[CH2:21]([O:23][C:24]([N:26]=[C:27]=NC(C)(C)C)=[O:25])[CH3:22].[O:33]1CCCC1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:13])[F:14])[C:3]=1[C:27]([NH:26][C:24](=[O:25])[O:23][CH2:21][CH3:22])=[O:33]
Reactant: CCOC(=O)N=C=NC(C)(C)C
Reactant: COc1ccc2c(C(=O)O)c(Cl)ccc2c1C(F)(F)F
Reactant: C1CCOC1
Product: CCOC(=O)NC(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12

Procedure:
A solution of 2-chloro-6-methoxy-5-(trifluoromethyl)naphthoic acid (3.50 g, 11.5 mmol, prepared by the process of Example 14), and ethoxycarbonyl-t-butylcarbodiimide (2.2 g, 1.1 eq) in dry tetrahydrofuran (58 mL) was heated to reflux under a dry nitrogen atmosphere for 51/2 hours. The tetrahydrofuran was removed and the resultant solid was triturated with ether (2×15 mL) and dried in vacuo. A second crop was recovered from the ether and combined with the product (3.36 g, 78%). The small sample was further purified by flash chromatography (70/30 petroleum ether/ethyl acetate) to provide the analytically pure product as a white solid, m.p. 169°-171° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:7])[C:3]#[C:4][CH2:5][OH:6].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[CH:24]([SiH:27]([CH:29]([CH3:31])[CH3:30])Cl)([CH3:26])[CH3:25]>>[CH3:7][C:2](=[CH2:1])[C:3]#[C:4][CH2:5][O:6][SiH:27]([CH:29]([CH3:31])[CH3:30])[CH:24]([CH3:26])[CH3:25]
Reactant: C=C(C)C#CCO
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: C=C(C)C#CCO[SiH](C(C)C)C(C)C
Yield: 89.5 %

Procedure:
4-Methylpent-4-en-2-yn-1-ol (2.0 g, 20.80 mmol), dimethylaminopyridine (0.252 g, 2.1 mmol), triethylamine (2.126 g, 21.01 mmol) and diisopropylchlorosilane (3.135 g, 20.80 mmol) were used according to the general procedure described above. The resulting clear, light yellow colored crude compound was purified by flash chromatography to yield pure product (3.914 g, 18.62 mmol, 89.5%) as clear colorless solution: Rf 0.82 (hexanes/Et2O, 9:1); 1H NMR (500 MHz, CDCl3) δ 5.28 (bs, 1H, H-5), 5.22 (bs, 1H, H-5), 4.49 (s, 1H, H-1), 4.21 (s, 1H, H-7), 1.88 (s, 3H, H-6), 0.74-1.37 (m, 14H, H-8, 9); 13C NMR (300 MHz, CDCl3) δ 126.5 (C-4), 121.8 (C-5), 86.5 (C-3), 86.3 (C-2), 54.3 (C-1), 23.2 (C-6), 17.3 (C-9), 17.2 (C-9), 12.3 (C-8); Anal. calcd for C12H22OSi: C, 68.51; H, 10.54. Found: C, 68.32; H, 10.73.
Reaction SMILES: [Na].N.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:20])=[C:8]([C:10]([CH2:18][CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:9]=1.Cl[CH:22](Cl)[C:23]([O-:25])=[O:24].[K+]>C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:20][CH:22]([C:23]([OH:25])=[O:24])[O:11][C:10]([CH2:18][CH3:19])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=1
Reactant: CCC(O)(c1ccccc1)c1cc(Cl)ccc1O
Reactant: O=C([O-])C(Cl)Cl
Agent: N
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
4.8 g of sodium were added in small amounts to a stirred mixture of 250 ml of condensed liquid ammonia and 100 mg of ferric nitrate and then a solution of 26.2 g of 5-chloro-α-ethyl-2-hydroxy-α-phenyl-benzene-methanol [prepared by Step A of Example 23 using ethyl bromide] with a melting point of 85° C. in 200 ml of anhydrous toluene was added thereto at 28°-30° C. over 90 minutes. The temperature was raised to disengage the ammonia and the mixture was then refluxed for 3 hours. 100 ml of toluene was added thereto followed by addition of 18 g of potassium dichloroacetate at 50° C. The mixture was refluxed overnight and 9 g of potassium dichloroacetate were added thereto. The mixture was refluxed for 2 more hours and was cooled and poured into water. The organic phase was decanted and the aqueous phase was acidified and extracted with ether. The ether extracts were washed 3 times with 500 ml of water and was extracted 3 times with 300 ml of sodium bicarbonate solution. The combined aqueous phases were washed twice with 500 ml of ether, were acidified with concentrated hydrochloric acid and extracted 3 times with 500 ml of ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 27 g of raw 6-chloro-4-ethyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid. (mixture of two racemates diastereoisomers).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.[Si:10](OS(C(F)(F)F)(=O)=O)([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12].N1C(C)=CC(C)=CC=1C.[Si](O[C@H](CCC)[C@@H](C)C=O)(C(C)(C)C)(C)C>>[CH2:11]([Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:3][C@@H:4]([CH2:5][CH2:6][CH3:7])[C@H:2]([CH3:1])[CH:8]=[O:9])[CH3:12]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CCC[C@@H]1O[C@]1(C)CO
Agent: CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CCC[C@H](O[Si](CC)(CC)CC)[C@H](C)C=O

Procedure:
Epoxy alcohol 13, 1.4 eq TESOTf, and 1.5 eq of collidine were reacted as in the preparation of 16 to give 95%+yield (<20:1 de) of crude aldehyde 22 which was chromatographed (SiO2, 3% EtOAc/96% Hex/1% TEA) to give 85% of 22. 1H NMR (CDCl3, 500.135 MHz) δ:9.68 (1H, d, J=2.37 Hz), 3.89 (1H, q, J=5.03 Hz), 2.43 (1H, qdd, J=6.95, 5.03, 2.30 Hz), 1.5-1.2 (4H, m), 1.02 (3H, d, J=6.95 Hz), 0.89 (6H, t J=8.0 Hz), 0.85 (3H, t, J=7.14 Hz), and 0.54 (9H, q, J=7.80 Hz). 13C NMR (CDCl3, 90.55 MHz) δ:205.1, 73.3, 51.3, 37.2, 18.1, 14.1, 10.3, 6.4, and 5.1. IR (thin film): 2957 (s), 2938 (s), 2912 (s), 2877 (s), 1726 (s), 1459 (s), 1415 (w), 1379 (w), 1239 (m), 1155 (w), 1074 (s), 1038 (m), 1005 (w), and 741 (s) cm-1. high resolution MS (m/z): 215. 1467, calcd for C11H23O2Si 215.1467 (M-C2H5). [α]D =+14.7° (c=1.89, CH2Cl2). 1H NMR integration of δ 9.69 to δ 9.72 indicated a 90.3:9.7 ratio.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[CH3:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35]>CC(O)C>[Br:1][C:2]1[C:3]([N:27]2[CH2:28][CH2:29][CH2:30][N:24]([CH3:23])[CH2:25][CH2:26]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35].[ClH:22]
Reactant: CN1CCCNCC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)CC1
Product: Cl

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 198 mg, 0.50 mmol), 1-methyl-1,4-diazepane (68.6 mg, 0.60 mmol), iPrOH (2 mL) and DIPEA (0.171 mL, 0.129 g, 2.0 mmol) were subjected to MW irradiation at 140° C. for 95 min. The RM was concentrated under reduced pressure to afford the title compound in an equimolar mixture with DIPEA hydrochloride. UPLC-MS (Condition 8) tR=1.2 min, m/z=473.1 [M+H]+, m/z=471.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH:14]([CH3:17])[CH2:15][OH:16].O.ClCCl>C(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH:14]([CH3:17])[CH2:15][OH:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(N)CO
Solvent: O
Solvent: CCCCO
Solvent: ClCCl
Product: CC(CO)Nc1ccnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.1 %

Procedure:
A mixture of 20 g of 4,7-dichloroquinoline and 16 g of 2-amino-1-propanol in 60 ml of butanol was stirred at reflux. The reaction was complete after three days of stirring and the vessel was allowed to cool to room temperature. Water was added to the mixture and extraction was conducted with dichloromethane. Drying over anhydrous magnesium sulfate and evaportion of solvents resulted in 17 g of solid which was triturated with ether. Recrystallization from ethanol/acetone gave 16 g of crystalline solid with a melting point of 210°-212° C.
Reaction SMILES: C(#N)C1C=CC=CC=1.OO.[C:11](=[O:14])(O)[O-].[K+].[CH2:16]([O:19][C:20]1[C:29]2[O:28][NH:27][C:26](=[O:30])[CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)[CH:17]=C>CO>[O:14]1[CH2:11][CH:17]1[CH2:16][O:19][C:20]1[C:29]2[O:28][NH:27][C:26](=[O:30])[CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: C=CCOc1cccc2c1ONC(=O)C2
Reactant: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: N#Cc1ccccc1
Solvent: CO
Product: O=C1Cc2cccc(OCC3CO3)c2ON1
Reaction time: 72 h

Procedure:
5.2 g of benzonitrile, 18 ml of a 30 percent strength aqueous solution of hydrogen peroxide and 1.0 g of potassium bicarbonate are added to a suspension of 10.1 g of 8-allyloxy2,3-dihydro-(4H)-benz[5.6]oxazin-3-one in 400 ml of methanol and the mixture is then stirred for 3 days at 20°. The reaction mixture is then concentrated to a volume of 40 ml under reduced pressure. After leaving to stand at 0°, 8-(2,3-epoxy-propoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one is obtained in the form of colourless crystals, which are filtered off and washed with a little cold methanol; melting point 158°-160°.
Reaction SMILES: C([O-])C.[Na+].[Cl-].[F:6][C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1.[C:33]([O:40][CH2:41][CH3:42])(=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])=O.C(OCC)(=O)C.CCCCCC>C(O)C>[CH2:41]([O:40][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])=[CH:11][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:32][CH:31]=1)[CH3:42]
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CCC(C)=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CCC(C)=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium ethanolate (0.836 g, 12 mmol) was added under cooling (0° C.) to a solution of 4-fluorobenzyl triphenylphosphonium chloride ([3462-95-1], 5.00 g, 12 mmol) in ethanol, and the mixture was stirred for 45min at r.t. Ethyl levulinate ([539-88-8], 1.77 g, 12 mmol) was added, and the light-orange mixture was refluxed (36 h). After the usual workup, 5-(4-fluoro-phenyl)-4-methyl-pent-4-enoic acid ethyl ester was obtained by column chromatography (silica gel, ethyl acetate/hexane) from the reaction mixture. MS: m/e=237.1 [M+H+].
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)=[O:34]>C(#N)C>[C:38]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:37]=[CH:36][C:35]([C:33](=[O:34])[CH2:32][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:40][CH:39]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1
Yield: 99.6 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (300 mg, 0.95 mmol), with sodium carbonate (200 mg, 1.89 mmol), and 2-bromo-4'-phenylacetophenone (520 mg, 1.89 mmol, 2.0 eq) in acetonitrile (10 mL), provided 484 mg (87%) of L-isoleucine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] benzylamide as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:20])=[O:19].[OH-:21].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:16][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:15]=[CH:20][C:18]([O:19][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:13]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)=O
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(OCc2ccccc2)cc1)C=Cc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 1 using 42.4 g (0.2 mol) 4-benzyloxybenzaldehyde, 700 mL absolute ethanol (EtOH), 5.8 g (0.1 mol) acetone and 10 mL 10% NaOH. The reaction was refluxed for 2 hours. After cooling the reaction was filtered, and the resultant solid dried. It was used without further purification in the next reaction. 1H NMR (CDCl3) δ 5.11 (s, 4 H), 6.91-7.01 (m, 6 H), 7.34-7.45 (m, 10 H), 7.57 (m, 4 H), 7.69 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([OH:35])=[O:34])[CH:28]=[CH:29][C:30]=1[OH:31]>>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([OH:35])=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCOC1CCCCO1
Product: COc1cc2c(Oc3ccc(CC(=O)O)cc3F)ncnc2cc1OCCOC1CCCCO1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in the portion of Note [1] below Example 8 that is concerned with the preparation of starting materials, 4-chloro-6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy) quinazoline was reacted with 2-(3-fluoro-4-hydroxyphenyl) acetic acid to give 2-{3-fluoro-4-[6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy) quinazolin-4-yloxy]phenyl}acetic acid in 52% yield; Mass Spectrum: M+H+ 473.
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=C1CC(=O)CN(C(OCC2C=CC=CC=2)=O)C1.[NH2:32][C:33]([CH3:54])([CH3:53])[C:34]([N:36]1[CH2:48][C:47]2NC3C=CC=C4C(=O)[NH:50][N:51]=[C:38]([C:39]=2C=34)[CH2:37]1)=[O:35]>>[NH2:32][C:33]([CH3:54])([CH3:53])[C:34]([N:36]1[CH2:48][C:47]2[NH:12][C:11]3[CH:10]=[C:9]([F:13])[CH:8]=[C:3]4[C:4](=[O:6])[NH:50][N:51]=[C:38]([C:39]=2[C:2]=34)[CH2:37]1)=[O:35]
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Reactant: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 65 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the same procedures similar to those for Compound 62. 1H NMR (DMSO-d6) δ 12.1 (s, 1H), 10.2 (s, 1H), 7.40 (dd, 1H, J=1.8, 10.2 Hz), 7.20 (dd, 1H, J=1.8, 10.2 Hz), 5.25 (s, 2H), 4.75 (s, 1H), and 1.32 (s, 6H). MS (ESI) m/e [M+1]+330.