Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](N(OC)C)=[O:13])[CH:6]=[CH:5]2.[CH3:18][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](=[O:13])[CH3:18])[CH:6]=[CH:5]2
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2cc(Br)ccc2n1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 6-bromo-N-methoxy-N-methylquinoline-2-carboxamide (4.29 g, 14.5 mmol) in THF (100 ml) was added methyl magnesiumbromide (18.2 ml, 17.4 mmol, 0.96M in THF solution) at 0° C. dropwise and the mixture was stirred at 0° C. for 1 hour. Then, the mixture was quenched with saturated ammonium chloride aqueous solution (50 ml) and water (200 ml). After stirring for 30 min, the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation and purification through silica gel column chromatography, eluting with hexane/ethyl acetate (4:1), furnished the title compound (3.47 g, 96% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.66 (3H, s), 7.83-7.88 (1H, m), 8.02-8.20 (4H, m). MS (ESI): m/z 250, 252 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-]#N.[Na+].[I-].[Na+].CS(C)=O.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>O>[F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:20]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cc1cccc(CBr)c1F
Reactant: CCOC(C)=O
Agent: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cccc(C)c1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-3-methylbenzyl bromide (2.0 g), sodium cyanide (2.41 g), sodium iodide (148 mg) and DMSO (10 ml) was stirred at 60° C. for two hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. 5 N hydrochloric acid (15 ml) was added to the residue, and the reaction solution was heated at 110° C. for 22 hours. The reaction solution was brought to room temperature. Chloroform was added and the organic layer was separated. The organic layer was concentrated under reduced pressure. Saturated hydrogen chloride-ethanol (15 ml) was added to the residue, and the reaction solution was stirred at 85° C. for four hours. The reaction solution was concentrated under reduced pressure, and then diluted with ethyl acetate and washed with saturated sodium bicarbonate water and then with brine. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.1 g). The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[C:31]([F:33])([F:34])[F:32])=[CH:24][CH:23]=2)[C:29]1=[O:30])[CH3:13]
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 53.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.98 g of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.04 g of 2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.882 g of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]>CN(C)C=O>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
19.9 g (92 mmols) of BOC-Val-OH are dissolved in 200 ml of freshly distilled dimethylformamide, while heating. After cooling to 0°C, 25.9 ml of absolute triethylamine are added and the solution cooled to -10°C before 8.64 ml of chlorocarbonic acid ethyl ester are added. After 10 minutes, a solution of 23.2 g (90 mmols) of H-Leu-OBzl, HCL in 90 ml of dimethylformamide is added at -10°C. The mixture is allowed to stand at -10°C for 30 minutes, at 0°C for 3 hours, and at 20°C for 16 hours. Undissolved matter is then filtered off and the filtrate concentrated to dryness under a high vacuum. The residue is dissolved in ethyl acetate and the solution washed with dilute citric acid solution, water, sodium bicarbonate solution, and water, dried with sodium sulfate, and evaporated. On addition of petroleum ether the product crystallizes overnight. Melting point 88.5° - 89.5°C; [α]D20 -22° (c = 2 in dimethylformamide); Rf2 = 0.73.
Reaction SMILES: O[CH:2]([CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:3][CH2:4][CH2:5][CH3:6].Cl.[OH-].[Na+]>C(O)CCC>[CH2:2]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(O)C1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCC1=CCCC1=O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
42.6 g of 2-(1-hydroxypentyl)-cyclopentanone were dissolved in 161.9 g of n-butanol and heated to 130° C. Then, 24.5 g (0.24 mol) of a 35% hydrochloric acid were added dropwise thereto for 30 minutes at the same temperature. After the dropping addition was finished, the resultant mixture was stirred for 2 hours under heating at the same temperature. After the reaction was finished, the mixture was cooled to the room temperature and neutralized with an aqueous solution of sodium hydroxide. Then, the resultant organic layer was analyzed in the same manner as in Example 8. As the result, 22.9 g of 2-pentyl-2-cyclopentenone were obtained (yield: 60.0%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>O>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:15])[CH3:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
An amount of 4-hydroxybenzoic acid (92.1 grams (g), 0.67 mole) was dissolved in a solution of sodium hydroxide (NaOH) (53.4 g, 1.33 moles) and 1.33 liters (L) of water in a 4 L beaker. The solution was stirred and cooled to a temperature of 0° C. by adding crushed ice, then acetic anhydride (102.1 g, 1.00 mole) was added. The temperature was maintained at -2° C. for 1 hour by adding one kilogram (Kg) of crushed ice. A solution of concentrated hydrochloric acid (HCl) (144.7 g, 1.42 moles) in 267 milliliters (ml) of water was added. The slurry was stirred briefly and filtered. The product was washed twice by stirring it with 2 L portions of fresh water then filtered and dried in a vacuum oven at 80° C. for 16 hours. After recrystallization from methyl isobutyl ketone, the product consisted of 111 g of white crystals with a melting point (m.p.) of 192.0° C. to 192.5° C.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:36](=[O:37])[N:5]2[C:6]([C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:26])=[C:7]([CH2:10][S:11][C:12]3[N:17]4[N:18]=[C:19]([CH2:21][O:22][CH3:23])[N:20]=[C:16]4[N:15]=[C:14]([CH3:24])[CH:13]=3)[CH2:8][S:9][C@H:4]12.[NH2:38][C:39]1[S:40][CH:41]=[C:42](/[C:44](=[N:58]/[O:59][CH3:60])/[C:45](OSC2SC3C=CC=CC=3N=2)=[O:46])[N:43]=1>C(Cl)Cl.C(O)C>[ClH:1].[NH2:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[N:58][O:59][CH3:60])[C:45]([NH:2][CH:3]2[C:36](=[O:37])[N:5]3[C:6]([C:25]([O:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[O:26])=[C:7]([CH2:10][S:11][C:12]4[N:17]5[N:18]=[C:19]([CH2:21][O:22][CH3:23])[N:20]=[C:16]5[N:15]=[C:14]([CH3:24])[CH:13]=4)[CH2:8][S:9][C@H:4]23)=[O:46])[N:43]=1
Reactant: CO/N=C(\C(=O)OSc1nc2ccccc2s1)c1csc(N)n1
Reactant: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(N)[C@H]4SC3)n2n1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(NC(=O)C(=NOC)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
In 100 ml of methylene chloride was dissolved 11.8 g of pivaloyloxymethyl 7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate.hydrochloride, and 5.82 g of benzthiazolylthio 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyiminoacetate was added to the solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 100 ml of a 5% sodium acetate aqueous solution and further washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. 100 ml of isopropanol containing 1.5 ml of conc. hydrochloric acid was added to the residue, and the mixture was thoroughly stirred and further stirred by adding 150 ml of ether. Then, precipitates were collected by filtration, washed with water and dried to obtain powder. This was dissolved in 50 ml of ethanol and filtered and the filtrate was added dropwise into 300 ml of ether. Precipitates were collected by filtration, washed with ether and dried to obtain 7.91 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][NH:44][CH3:45])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[NH2:56][C:57]1[N:62]=[CH:61][C:60]([C:63]([OH:65])=O)=[CH:59][CH:58]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[NH2:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]([N:44]([CH2:43][CH2:42][CH2:41][N:40]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]2[C:25]3([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]4([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=[C:3]([C:2]([F:54])([F:1])[F:55])[CH:4]=5)[CH2:12]4)[CH2:23][CH2:24]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[CH3:46])[CH3:45])=[O:65])=[CH:61][N:62]=1
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCN(C)C(=O)c1ccc(N)nc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
The compound (200 mg, 0.257 mmol) obtained in Example 1k was dissolved in methylene chloride (3 mL)-N,N-dimethylformamide (2 mL), 6-aminopyridine-3-carboxylic acid (36 mg, 0.257 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74 mg, 0.386 mmol) and 4-dimethylaminopyridine (4 mg, 0.0258 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=40:1, v/v) to give the title compound (196 mg; yield, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:25])[CH:17]=2)=[N:7]1)=[O:5].[CH3:34][C:35](OC(C)=O)=[O:36].[Mg+2].[I-].[I-]>C(OCC)C>[C:35]([O:25][C:18]1[CH:17]=[C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[N:6]([C:4](=[O:5])[C:3]3[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])[N:7]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])(=[O:36])[CH3:34]
Reactant: O=C(O)c1ccc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3cccc(F)c23)cc1O
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3cccc(F)c23)ccc1C(=O)O
Temperature: 40 °C

Procedure:
A suspension of compound 26A (48 mg, 0.1 mmol), Ac2O (0.8 mL) and MgI2 (28 mg, 0.1 mmol) in anhydrous ethyl ether (3 mL) was refluxed at 40° C. for 0.5 h. The reaction was cooled to rt, quenched with H2O, extracted with ether, and concentrated. The crude product was dissolved in THF (10 mL)/H2O (10 mL) and refluxed at 80° C. for 1 h. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc. The combined organic extracts were concentrated and purified by flash chromatography PE/EA (5/1) to give the title compound as a white solid. LCMS (ESI): calc'd for C22H12ClF4N2O4 [M+H]+: 521. found: 521, 1H NMR (400 MHz, MeOD) δ 8.47 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz), 7.90-7.76 (5H, m), 7.53 (1H, t, J=1.6 Hz), 3.34 (1H, q, J=8.0 Hz), 2.31 (3H, s).
Reaction SMILES: O.[CH2:2]([O:4][C:5]([C:7]1[C:16]([Cl:17])=[CH:15][C:14]2[C:9](=[C:10]([C:18]#N)[CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:3].CC(O)=[O:22]>[Ni].N1C=CC=CC=1>[CH2:2]([O:4][C:5]([C:7]1[C:16]([Cl:17])=[CH:15][C:14]2[C:9](=[C:10]([CH:18]=[O:22])[CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(C#N)cccc2cc1Cl
Reactant: CC(=O)O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc2c(C=O)cccc2cc1Cl
Temperature: 125 °C

Procedure:
NaH2PO2×H2O (2.12 g, 20.02 mmol, 8.0 equiv) and Raney nickel (1.50 g) were added at room temperature to a solution of 3-chloro-8-cyano-naphthalene-2-carboxylic acid ethyl ester (0.65 g, 2.50 mmol) in pyridine (16 ml)/AcOH (8 ml)/H2O (8 ml). The heterogeneous mixture was heated to 125° C. for 2 hours. After cooling and filtering off the Raney nickel catalyst, the reaction mixture was diluted with water (100 ml). After extraction with EtOAc (2×400 ml), the combined organic layers were washed with brine (2×50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 90:10) to afford the title compound (350 mg, 53%, inseparable 1:1.5 mixture of regioisomers A:B) as a white solid. 1H NMR (400 MHz, CDCl3): δ=10.35 (s, 1H isomer B), 10.33 (s, 1H isomer A), 9.70 (s, 1H isomer B), 9.41 (s, 1H isomer A), 8.39 (s, 1H isomer A), 8.14 (d, J=8.4 Hz, 1H isomer A). 8.08 (dd, J=7.1/1.2 Hz, 1H isomer B), 8.04-8.01 (m, 1H isomer A+1H isomer B), 7.99 (1H isomer B), 7.77-7.70 (m, 1H isomer A+1H isomer B), 4.48 (q, J=7.1 Hz, 2H isomer B), 4.47 (q, J=7.1 Hz, 2H isomer A), 1.46 (t, J=7.1 Hz, 3H isomer B), 1.45 (t, J=7.1 Hz, 3H isomer A). MS (ES+): 263 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].Cl[C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])[CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:15][CH:16]=1
Reactant: COC(=O)CCc1ccccc1OCCOC1CNCCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccccc1OCCOC1CN(C(=O)OCc2ccccc2)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.15 g of methyl 3-{2-[2-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxy)ethoxy]phenyl}propionate (Example 52) in 3 ml of ethyl acetate is admixed with 3 ml of saturated aqueous sodium bicarbonate solution. The mixture is cooled to 0° C. and admixed with 0.046 ml of benzyl chloroformate. After 1 hour, another 1 ml of saturated aqueous sodium bicarbonate solution and 0.020 ml of benzyl chloroformate are added. The aqueous phase is removed and extracted with ethyl acetate (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.32 (2:5 EtOAc-heptane); Rt=6.07.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][OH:25]>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][C@H:23]([CH2:26][CH3:27])[CH2:24][OH:25])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CC[C@@H](N)CO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Crude 4-chloro-3-nitroquinoline (413.8 g, 1 eq.) was dissolved in dichloromethane (1.65 L). The solution was heated to reflux and then filtered through a layer of Celite® filter agent. The filtrate was cooled to 5° C. with stirring. Triethylamine (305.4 mL, 1.1 eq.) was added in a single portion. The reaction mixture was stirred for 15 minutes. (R)-(−)-2-Amino-1-butanol (205 mL, 1.1 eq.) was added dropwise while maintaining the temperature of the reaction mixture below 40° C. The reaction mixture was allowed to stir at ambient temperature for several days. The reaction mixture was cooled to −30° C. A yellow precipitate was isolated by filtration, washed with very cold dichloromethane and then sucked dry. The solid was slurried for 1 hour with cold 80/20 water/methanol (1 L), isolated by filtration, washed with cool water, washed with very cold methanol (2×300 mL), and then sucked dry on the filter overnight to provide 475 g of (2R)-2-[(3-nitroquinolin-4-yl)amino]butan-1-ol.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[I:1])[CH3:13]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A suspension of 2-iodo-4-nitrophenol (21 g, 79.2 mmol) [ref: Kometani, T.; Watt, D. S.; Ji, T., Tetrahedron Lett. (1985), 26(17), 2043], ethyl iodide (9 mL, 0.48 mol) and potassium carbonate (40.7 g, 0.3 mol) in 100 mL of N,N-dimethylformamide was heated at 70° C. for 3 hours. The reaction was cooled to room temperature and ethyl acetate was added. The inorganic salts were filtered and washed with ethyl acetate. The organic material was washed with water (3×) and brine, dried over magnesium sulfate and filtered. Upon concentration of the filtrate a solid appeared. This solid was filtered and washed with hexanes to give 5.2 g of 1-ethoxy-2-iodo-4-nitrobenzene as white crystals. Concentration of the filtrate provided an additional 11.3 g of the desired product, mp 81-83° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.42 (t, 3H), 4.26 (q, 2H), 7.18 (d, 1H), 8.26 (dd, 1H), 8.55 (d, 1H)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH:43]2[CH2:48][CH2:47][N:46]([C:13](=[O:14])[C@H:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: C1CCN(C2CCNCC2)CC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.01 mmol) [1,4′]bipiperidinyl.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](=[O:30])[NH:18][C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=2[O:28][CH3:29])[C:6]1=[O:31].[OH-].[K+]>CO.O>[Cl:25][C:23]1[C:22]([O:26][CH3:27])=[CH:21][C:20]([O:28][CH3:29])=[C:19]([NH:18][C:17]([CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:15])[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]2=[O:31])=[O:30])[CH:24]=1
Reactant: COC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)c(OC)cc2OC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A white suspension of {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid methyl ester (Intermediate B) (10 mg) in MeOH (300 μL) is treated with 5 M KOH (200 μL). The white suspension is left to stir at RT overnight. The reaction mixture is diluted with water to give a thick white precipitate which is filtered-off, washed with water and vacuum dried. The aqueous phase is acidified to pH 4 with dilute HCl followed by extraction with EtOAc (3×). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as off-white solid. This is taken up in a minimal amount of DMF and purified further by reverse phase column chromatography (Isolute™ C18: 0-100% MeCN in water—0.1% TFA) to afford the title compound, [M+H]+ 448.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][NH:4][C:3]1=[O:7].[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH2:17][N:4]1[C:3](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:6][O:5]1
Reactant: CC1(C)CONC1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC1(C)CON(Cc2ccc(F)cc2Cl)C1=O
Yield: 30.3 %

Procedure:
A solution of 0.52 grams (0.005 mole) of 4,4-dimethyl-3-isoxazolidinone, 1.0 gram (0.005 mole) of (2-chloro-4-fluorophenyl)methyl bromide and 0.62 gram (0.005 mole) of potassium carbonate in 40 ml of dimethylformamide was stirred at ambient temperature for 18 hours. The dimethylformamide was removed under high vacuum with mild heat. The residue was extracted with methylene chloride. The extract was filtered and dried with sodium sulfate. The mixture was refiltered and the filtrate concentrated under reduced pressure to give an oil residue. The residue was slurried in warm hexane and a solid was removed by filtration. The filtrate was concentrated under reduced pressure to give 0.39 gram of 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as an oil.