Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]([Cl:32])([Cl:31])[CH2:9][O:10][C:11]([NH:13][C@H:14]([C:28]([OH:30])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])=[O:12].O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40].[K+].[Br-]>CCO>[Cl:7][C:8]([Cl:31])([Cl:32])[CH2:9][O:10][C:11]([NH:13][C@H:14]([C:28]([O:30][CH:36]1[CH2:37][C:38](=[O:39])[NH:34][C:35]1=[O:40])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])=[O:12]
Reactant: O=C(NCCCC[C@H](NC(=O)OCC(Cl)(Cl)Cl)C(=O)O)OCC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1O
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC(OC(=O)[C@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)NC(=O)OCC(Cl)(Cl)Cl)C(=O)N1

Procedure:
In a manner similar to Example 2A, utilizing anhydrous ethyl acetate as the solvent, N,N'-bis-trichloroethoxycarbonyl-L-lysine is reacted with N-hydroxy succinimide to obtain the above named compound; [α]D26 -19.6° (EtOH); νmax (KBr) 1820, 1785, 1715 cm-1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[O:32]([C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)=[O:38])[C:33]([CH3:36])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:33]([O:32][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxylcarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b), and triphenylphosphine (525 mg, 2.0 mmol) intetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and was extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate/hexane) to give the title compound as a colorless syrup (895 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2H), 1.47 (s, 9H), 1.76 (d, 2H, J=6.6 Hz), 1.89 (m, 1H), 2.24 (s, 3H), 2.72 (t, 2H, J=2.4 Hz), 3.68 (d, 2H, J=3.2 Hz), 4.13 (m, 2H), 6.47 (t, 1H, J=2.2 Hz), 6.52 (d, 1H, J=0.7 Hz), 6.58 (d, 1 H, J=0.8 Hz), 7.38 (dd, 1H, J=0.6, 0.8 Hz), 7.61 (m, 2H), and 7.97 (dd, 1H, J=0.8, 4.0 Hz).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][O:5][CH:4]=[CH:3]1.[F:8][C:9]([F:20])([F:19])[O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:8][C:9]([F:19])([F:20])[O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=c1ccocc1
Reactant: NCc1cccc(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of 4-oxo-1H-pyran (200 mg) in chloroform (2 mL), 3-trifluoromethoxybenzylamine (380 mg) was added and the resulting mixture was stirred at room temperature for 30 minutes. Sodium (triacetoxy)borohydride (850 mg) was added and the resulting mixture was stirred for an hour. To the reaction mixture, an aqueous solution of 6 M sodium hydroxide was added and extraction was conducted with ethyl acetate. The solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=9:1 to 1:9) to give the titled compound (450 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([O-])(=O)C.[Na+].[Br:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[Br:18][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2]2([CH3:12])[CH3:1]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)Nc2ccc(Br)cc21
Reaction time: 0.83 h
Yield: 92 %

Procedure:
3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmol) and sodium acetate (0.33 g, 4.07 mmol) were stirred in acetic acid (5 cm3) then bromine (0.66 g, 4.13 mmol) in acetic acid (5 cm3) was added drop-wise to the reaction mixture. The reaction was stirred for 50 min., then poured into water. The mixture was basified with sodium carbonate, extracted with ethyl acetate (×3), dried (MgSO4), filtered, and evaporated to give the subtitled compound (0.89 g, 92%) 1H NMR (DMSO-d6) δ 1.21 (s, 6H), 6.76 (d, 1H, J=8.22 Hz), 7.29 (dd, 1H, J=2.12 Hz, 8.23 Hz), 7.49 (d, 1H, J=2.03 Hz), 10.4 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]([F:21])=[C:10](Cl)[N:9]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]([F:21])=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: Cc1cc(Nc2nc(Cl)nc(Cl)c2F)n[nH]1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)nc(N3CCOCC3)c2F)n[nH]1
Temperature: 80 °C

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (4.03 g) in absolute ethanol (100 mL) was added DIEPA (5.3 mL) and 5-methyl-1H-pyrazol-3-amine (2.03 g). The resulting solution was stirred at room temperature for 6 hours. The precipitation was filtered and washed with cold ethanol. The compound was dried by vacuum oven give 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine as solid (3.7 g). m/z 262. A mixture of morpholine (0.181 mL), 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (500 mg) and DIPEA (0.505 ml) in absolute ethanol (10.0 ml) was heated at 80° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (236 mg). 1H NMR δ 12.05 (bs, 1H) 9.57 (s, 1H) 6.21 (s, 1H) 3.67 (t, 4H) 3.57 (t, 4H) 2.22 (s, 3H); m/z 313.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C[C@H]1C(=O)OCN1C(=O)OC(C)(C)C

Procedure:
(4S)-N-tert-Butyloxycarbonyl 4-isobutyl-1,3-oxazolidin-5-one (4) was prepared from N-tert-butyloxycarbonyl-(L)-leucine (2.31 g, 10.0 mM) and para-toluenesulfonic acid (30 mg) following general procedure A and obtained as a colourless, slowly solidifying oil after purification by flash column chromatography, using 30% chloroform/petroleum ether as eluant (1.91 g, 79%): [α] D20 +88.5 (c 0.9, CHCl3); IR (CHCl3): 1790, 1720 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 5.48 (d, J=5 Hz, 1H), 5.09 (d, J=5 Hz, 1H), 4.22 (t, J=6 Hz, 1H), 1.43 (s, 9H), 1.23-1.16 (m, 3H), 0.92 (d, J=5 Hz, 3H), 0.90 (d, J=5 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): δ 172.9, 152.2, 81.5, 77.8, 53.2, 39.4, 27.9, 24.2, 22.4,22.2; LRMS (NH3): 244 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[N:27][CH:28]=1)#[N:33]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Reactant: N#Cc1ccc(N)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCC2
Temperature: -15 °C
Reaction time: 0.42 h

Procedure:
A solution of phenyl 7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 3, 262 mg, 0.798 mmol) and 2-amino-5-cyanopyridine (190 mg, 1.60 mmol) in THF (7.5 ml) at −15° C. under argon was treated drop wise with LHMDS (1M in THF, 1.60 ml, 1.60 mmol). The reaction mixture was stirred at −15° C. for 25 min and then quenched by addition of sat. aq. NH4Cl and extracted with EtOAc (2×). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 1) tR 1.09 min; ESI-MS 354.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[C:22]([Cl:25])(=O)C.[ClH:26].[OH-].[Na+]>C(O)(C)C.CC(C)=O>[ClH:25].[ClH:26].[CH3:1][NH:2][CH2:3][CH2:4][C@:5]([CH3:22])([O:11][C:12]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CNCC[C@](C)(Oc1cccc2ccccc12)c1cccs1
Temperature: 50 °C

Procedure:
The crude wet duloxetine free base (205.0 g) and an acetone (anti-solvent)(600.0 g) were charged in a 4-neck round flask and heated to a temperature of 50° C. while stirring. To another 4-neck round flask, isopropyl alcohol (IPA) (200.0 g) was charged, and the temperature was set to about 0 to about 5° C. while stirring. Fresh hydrochloride was prepared by dropping acetyl chloride (48.0 g) slowly to the isopropyl alcohol solution and stirring the reaction for one hour at a temperature of about 15° C. to 20° C. Then, the fresh hydrochloric acid in isopropyl alcohol was added to the duloxetine free base solution slowly, and the pH value was controlled in a range from 5.5 to 7.5 with NaOH(aq). The temperature was set at 50° C., and the reaction was gradually cooled to 0° C.˜5° C. The reaction was stirred for another one hour at about 0° C.˜5° C., and after filtration, the purified duloxetine hydrochloride was produced. (190 g, 99% ee; purity; 98% by HPLC assay).
Reaction SMILES: [CH3:1][C:2]([CH:6]([F:8])[F:7])=[C:3]([F:5])[F:4].S(=O)(=O)(O)[OH:10]>O>[CH3:1][C:2]([OH:10])([CH:6]([F:8])[F:7])[CH:3]([F:5])[F:4]
Reactant: CC(=C(F)F)C(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(O)(C(F)F)C(F)F

Procedure:
As another example, 2-methyl-1,1,3,3-tetrafluoro-2-propanol may be prepared by fluorinating commercially available 1,1-dichloro-2-propanone to form 1,1-difluoro-2-propanone which may then be reacted with CF2 carbene to form 2-methyl-1,1,3,3-tetrafluoro-1-propene. The 2-methyl-1,1,3,3-tetrafluoro-1-propene may then be reacted with sulfuric acid and then water to form 2-methyl-1,1,3,3-tetrafluoro-2-propanol.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=[CH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[CH2:24][CH2:23]3)[C:12]3[C:13]([O:18][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[N:14][CH:15]=[CH:16][CH:17]=3)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH2:43][CH3:44]>CN(C=O)C.C(OCC)(=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH:19]=[C:11]3[C:12]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[O:18][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([O:3][CH2:42][CH2:43][CH3:44])=[O:2])[C:9]=4[CH2:10]3)[CH2:23][CH2:24]2)=[CH:34][CH:33]=1
Reactant: CCCI
Reactant: O=C(O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 55 °C
Yield: 87.8 %

Procedure:
To a solution of the compound of Example 118 (109 mg, 0.22 mmol) in dry DMF (5 ml) was added potassium carbonate (91 mg) followed by propyl iodide (24 μL, 0.66 mmol). The mixture was heated to 55° C. for 14 hours. The mixture was diluted with ethyl acetate (200 ml), washed twice with water (200 ml) and then with brine (100 ml), and dried with sodium sulfate. The organic solvent was removed under reduced pressure and the residue subjected to silica gel chromatography using a dichloromethane:methanol gradient (0 to 5% MeOH over 1 hour) to give the title compound (103 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.Br[CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][C:15]([CH3:17])=[CH2:16])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: C=C(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CCOc1ccc(Br)cc1C(C)C
Temperature: 60 °C

Procedure:
4-Bromo-2-isopropylphenol (897 mg, 4.17 mmol) was dissolved in DMF (4.17 mL) and 4-bromo-2-methylbut-1-ene (1.24 g, 8.34 mmol) was added followed by K2CO3 (1.15 g, 8.34 mmol). The reaction mixture was heated to 60° C. overnight, cooled to room temperature, and diluted with Hexanes:EtOAc (1:1). Water was added and the organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography, eluting with 0-15% EtOAc/Hexanes to give the title compound as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:12][CH2:13]1
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (1.23 g) in ethyl acetate (12 ml) was added 4N HCl in ethyl acetate (6.66 ml) at room temperature, and the reaction mixture was stirred for 2 hours. The precipitates were filtered, washed with diethyl ether and purified by preparative HPLC eluting with 0.1% trifluoroacetic acid-CH3CN (9:1), then the fractions containing the object compound were concentrated in vacuo. The residue was resolved in water, neutralized with 1N aq. NaOH, desalted by using the resin of HP-20 eluting with isopropanol-H2O (1:1), freeze-dried to give N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine as a white powder (0.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CS(O[CH2:23][CH2:24][O:25][CH2:26][CH3:27])(=O)=O>CN(C)C=O>[CH2:24]([O:25][CH2:26][CH2:27][O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: CCOCCOS(C)(=O)=O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
3.06 g of a 55% sodium hydride dispersion in oil were washed with hexane and covered with 85 ml of dimethylformamide. 17.0 g (71.6 mmol) of t-butyl [4-hydroxyphenethyl]carbamate [see F. Rocchiccioli et al., Tetrahedron, 34, 2917 (1978)] were then added while cooling with ice and the reaction mixture was stirred at room temperature for 15 minutes. After cooling to 0° a solution of 12.04 g (71.6 mmol) of 2-ethoxyethyl methanesulfonate in 85 ml of dimethylformamide was added dropwise within 10 minutes and the reaction mixture was subsequently stirred at room temperature for 24 hours. Thereafter, the reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed on 240 g of silica gel with a mixture of hexane and ethyl acetate as the eluting agent and subsequently recrystallized from ether/hexane, whereby there were obtained 19.1 g of t-butyl [ 4-(2-ethoxyethoxy)phenethyl]carbamate, melting point 56°-57°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH2:39][CH2:40][O:41][CH3:42])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>Cl.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH2:39][CH2:40][O:41][CH3:42])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCCN(C(=O)c1ccc(Oc2ccc(F)cc2)nc1)c1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COCCN(C(=O)c1ccc(Oc2ccc(F)cc2)nc1)c1ccc(CN2CCN[C@@H](C)C2)cc1
Reaction time: 2 h
Yield: 107.2 %

Procedure:
1,1-Dimethylethyl (2S)-4-[(4-{({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)[2-(methyloxy)ethyl]amino}phenyl)methyl]-2-methyl-1-piperazine carboxylate (D119) (0.077 g, 0.13 mmol) was dissolved in 4M HCl in dioxane (5 mL). A few drops of water were added and the reaction was stirred for 2 h. The solvent was removed in vacuo and the resulting yellow oil was dissolved in MeOH and loaded onto an SCX cartridge which was eluted with DCM, MeOH and 2M NH3 in MeOH. The ammoniacal fractions were combined and concentrated to give the title compound as a yellow oil (0.0667 g). MS (ES): MH+ 479.4.
Reaction SMILES: C(=O)([O-])O.[Na+:5].[CH2:6]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]([CH3:27])[C:24]([OH:26])=[O:25])=[CH:15][C:14]1=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH2:6]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]([CH3:27])[C:24]([O-:26])=[O:25])=[CH:15][C:14]1=[O:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[Na+:5]
Reactant: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C(=O)[O-])c1cc(=O)n(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution (1.63 ml.) of 1M-sodium hydrogen carbonate was added to a stirred suspension of powdered α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid (0.50 g.) in distilled water (3.37 ml.), and the mixture was stirred overnight, at ambient temperature. The solid which had formed was separated and dried in vacuo over phosphorus pentoxide to give sodium α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionate (0.52 g.) as its monohydrate (m.p., indefinite; C19H16NO3.H2O requires: C, 65.5; H, 4.9; N, 3.8; found: C, 65.7; H, 5.2; N, 4.0).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][Cl:32].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:29][CH2:30][CH2:31][Cl:32])(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
1.02 g (2.92 mmol) of Compound 27 obtained in Example 27 was dissolved in 25 ml of dimethylformamide under argon atmosphere, 129 mg of sodium hydride (60% oil dispersion) and 2.9 ml of 1-bromo-3-chloropropane were added under ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Recrystallization from ethyl acetate/acetonitrile afforded 434 mg (35%) of 2-[4-[N-acetyl-N-(3-chloropropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>C(Cl)Cl>[CH2:18]([S:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)(=[O:22])=[O:21])[CH3:19]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc2[nH]ccc2c1
Temperature: 23 °C
Yield: 99.1 %

Procedure:
To a solution of 5-amino-1H-indole (10.0 g, 76 mmol) and triethylamine (15.8 mL, 114 mmol) in 100 mL CH2Cl2 at 0° C. was added dropwise a solution of ethanesulfonyl chloride (7.9 mL, 83 mmol) in 25 mL of CH2Cl2. The solution was allowed to slowly warm to 23° C. over 20 h. The reaction mixture was concentrated in vacuo and the residue dissolved in 400 mL of ethyl acetate. The organic layer was washed with 100 mL of water, 50 mL of 0.1M HCl, 50 mL of saturated NaHCO3 solution, and 50 mL of saturated NaCl solution. The organic layer was dried over anhydrous K2CO3, filtered, and concentrated in vacuo to obtain 5-ethanesulfonylamino-1H-indole (16.9 g, >99%) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[CH2:12]([N:26]=[C:27]=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:12]([NH:26][C:27]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][C:27]([NH:26][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCNC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)NCCCCCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with tetradecyl isocyanate gave 3,4-bis [[(tetradecylamino)carbonyl]oxy]nitrobenzene (mp 100°-104°). The structure was confirmed by the nmr spectrum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2.[OH:29]O>C(Cl)CCl.CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[S:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2)=[O:29]
Reactant: OO
Reactant: Cc1cc(C(C)(C)C)ccc1SCCCCOc1ccc2c(c1)CCC(=O)N2
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc(C(C)(C)C)ccc1S(=O)CCCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
Prepared analogous to Example 123 from 6-[4-(2-methyl-4-tert. butylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide. Resinous substance. Rf -value: 0.54 (silica gel fluorescent plate; eluant: ethylene chloride/methanol=95/5).