Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][CH:4](OC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:31])[N:20]([CH:22]([C:27]([NH:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])[CH3:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1>CC(C)=O>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:31])[N:20]([CH:22]([C:27]([NH:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])[CH3:21])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(C(OC)OC)cc2)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
Under ice cooling, a 1.0 mol/L hydrochloric acid aqueous solution (4.0 mL) was added to an acetone (50 mL) solution of 1-(dimethoxymethyl)-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (6.5 g) as obtained in Example 10-(4), and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off, and then hexane/AcOEt (20:1 (v/v)) was added to the residue, whereafter the mixture was stirred for a while. Then, the precipitate was filtered off and dried to obtain 1-formyl-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (white solid) (4.6 g, 79%).
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[CH:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]23)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.C(N(CC)CC)C.[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)([O-:34])=[O:33].CN(C)C=O>O>[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39][O:15][C:14]([CH:9]2[N:8]3[C:17](=[O:18])[CH:6]([N:5]4[C:4](=[O:19])[C:3]5=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]5[C:1]4=[O:24])[C@H:7]3[S:11][C:10]2([CH3:12])[CH3:13])=[O:16])=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)S[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
6-Phthalimido-2,2-dimethyl-penam-3-carboxylic acid p-nitrobenzyl ester is prepared by placing a mixture of 1.0 g. of 6-phthalimido-2,2-dimethyl-penam-3-carboxylic acid, 0.4 ml. of triethylamine, 0.75 g. of p-nitrobenzyl bromide and 10 ml. of dimethyl formamide in a refrigerator for 3 hours. Thereafter, 10 ml. of water are added and the resulting precipitate formed is filtered, washed with acetone and recrystallized from methylethyl ketone to yield colorless crystals; mp 233°-34° C.; nmr (CDCl3) 89(S,3H); 111(S,3H); 287(S,1H); 322(S,2); 338.5(d,1H,J=4.5 Hz); 342(d,1H,J=4.5 Hz); 472 cps (m,8 ArH).
Reaction SMILES: [H][H].[OH:3][C:4]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH3:28])[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1>[C].[Pd].C(OCC)(=O)C>[OH:3][C:4]1[C:21]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH3:28])[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COc1ccc(C=CC(=O)c2ccc(OC)c(CC=C(C)C)c2O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2ccc(OC)c(CCC(C)C)c2O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To 20 ml of an ethyl acetate suspension of 0.3 g of 5% palladiumcarbon, in which hydrogen had been adsorbed in advance, was added 1.0 g of the so-obtained 2'-hydroxy-4,4'-dimethoxy-3'-(3-methyl-2-butenyl)chalcone, and the mixture was stirred at room temperature for 5 hours and hydrogen was absorbed. After the reaction, the suspension was filtered to remove the palladiumcarbon, and removal of the solvent by distillation gave 1.0 g (yield=98.7%) of 1-(2-hydroxy-3-isopentyl-4-methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a colorless solid.
Reaction SMILES: Cl.[CH2:2]([N:6]=[C:7]([NH2:19])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][S:15][CH2:16][CH2:17][NH2:18])[N:13]=1)[CH2:3][CH2:4][CH3:5].[CH3:20][N:21]=[C:22]=[S:23].C(N(CC)CC)C.CO>O>[CH2:2]([N:6]=[C:7]([NH2:19])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][S:15][CH2:16][CH2:17][NH:18][C:22]([NH:21][CH3:20])=[S:23])[N:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN=C(N)Nc1nc(CSCCN)cs1
Reactant: CN=C=S
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCN=C(N)Nc1nc(CSCCNC(=S)NC)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(2-n-butylguanidino)-4-(2-aminoethyl)thiomethylthiazole hydrochloride (1.10 g.), methylisothiocyanate (0.70 g.), triethylamine (0.90 g.) and methanol (5 ml.) was stirred at room temperature for four hours. It was then diluted with water (25 ml.), extracted with ethyl acetate (2×25 ml.) and the combined extracts washed with water (50 ml.). The organic layer was then extracted with 1 N hydrochloric acid (2×25 ml.), the combined aqueous layers washed with ethyl acetate (25 ml.) and then basified by addition of aqueous ammonia. The resulting emulsion was extracted with ethyl acetate and the extract was washed with water and dried over magnesium sulphate. It was filtered and evaporated to dryness to give 2-(2-n-butylguanidino)-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole as a brown gum. The n.m.r. spectrum in d6 dimethyl sulphoxide (DMSO) using tetramethylsilane as internal standard had the following resonances (δ): 0.6-1.5 (7H, multiplet); 2.5 (2H, multiplet); 2.75 (3H, triplet); 3-3.5 (4H, multiplet); 3.55 (2H, singlet); 6.45 (1H, singlet); 6.7-7.6 (broad multiplet).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([OH:36])[CH:32]=[C:33]([CH3:35])[CH:34]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:36][C:31]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)=[N:3][CH:4]=1
Reactant: COc1cc(C)cc(O)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: COc1cc(C)cc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3-methoxy-5-methylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.17 (2H, d, J=2.8 Hz), 7.95 (2H, dd, J=6.6, 1.8 Hz), 7.39 (2H, d, J=8.1 Hz), 6.67 (1H, br.s), 6.55–6.51 (2H, m), 5.40–5.30 (1H, m), 3.80 (3H, s), 2.37 (3H, s), 1.58 (9H, s), 1.57 (3H, d, J=6.8 Hz).
Reaction SMILES: [Br-].[C:2]1(/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C2C(=O)C3C(=CC=CC=3)C=2CCC1.II>C1CCCCC1>[C:2]1([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=C\c1ccccc1)\c1ccccc1
Agent: II
Agent: O=C1C2=C(CCCC2)c2ccccc21
Agent: [Br-]
Solvent: C1CCCCC1
Product: C(=Cc1ccccc1)c1ccccc1

Procedure:
3.3 g. (0.01 mole) cis-stilbene bromide are dissolved in 100 ml. anhydrous 1,2,3,4-tetrahydro-9-fluorenone. This solution is diluted with 1200 ml. anhydrous cyclohexane and mixed with 1.7 g. iodine. The solution is illuminated, while passing in nitrogen, with a laboratory immersion lamp with cooling tube of the type TQ 150 (Hanau) for 12 to 14 days. The reaction is monitored by thin layer chromatography (dichloromethane/petroleum ether (b.p. 30° to 50° C.) 1:2 v/v). The organic phase is shaken out three times with 300 ml. amounts of thiosulphate solution in order to remove excess iodine. After drying over anhydrous magnesium sulphate, the organic phase is evaporated on a rotary evaporator and the crude product obtained is recrystallised from petroleum ether (b.p. 60° to 90° C.). Yield 1.55 g. (47% of theory).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=O)C.[OH-].[Na+]>[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.O>[CH2:5]([OH:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCOC(C)=O
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCO
Temperature: 50 °C
Yield: 48.3 %

Procedure:
A mixture of 100 grams (0.35 mole) of n-hexadecyl acetate, 50 grams of 50% aqueous sodium hydroxide solution (25 grams -- 0.62 mole of NaOH) and 1 gram of tricaprylylmethylammonium chloride were stirred in a beaker. After10 minutes, 50 ml of water was added to the reaction mixture, and the temperature rose to 54° C. After stirring for 2 hours, the organic layer solidified. The mixture was then heated to 50° C for 20 minutes. After cooling, the solid which separated was collected on the filter, washed with water and dried to give 41 grams (95%) of 1-hexadecanol having a melting point of 43°-48° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=C(F)[C:16]=1[F:25]>O1CCCC1>[F:25][C:16]1[C:15]([F:14])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[C:5]=1[CH2:4][C:3]([OH:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a suspension of NaH (11.3 g, 60% oil dispersion, 282 mmol) in tetrahydrofuran (THF) (35 mL) in an ice-bath was added a solution of diethyl malonate (45.2 g, 42.9 mL, 282 mmol) in THF (70 mL) over a period of an hour so that the reaction temperature was kept below 20° C. Some white solid precipitated during the addition. To the above reaction mixture was added a solution of 1,2,3-trifluoro-4-nitrobenzene (25.0 g, 141 mmol) in THF (35 mL) over a period of 1 hour so that the reaction temperature was kept below 10° C. The ice-bath was removed and the mixture was stirred at ambient temperature for 2 hours. Acetic acid (18 mL) was added to the reaction solution, and THF was evaporated under reduced pressure. Chloroform (200 mL), H2O (250 mL), and concentrated HCl (18 mL) were added. The organic layer was separated, concentrated, mixed with 4N HCl (45 mL) and acetic acid (35 mL), and refluxed for 14 hours. The reaction mixture was allowed to cool to room temperature. The solid precipitated upon cooling was filtered off, washed with diisopropyl ether, and dissolved in MeOH (70 mL). After treating with active carbon, the solvent was evaporated, and the crystalline residue washed with isopropyl ether, and filtered off to give the title compound (17.6 g, 58% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.05-8.01 (m, 1H), 7.47 (dd, J=17.4, 8.9 Hz, 1H), 4.10 (s, 2H).
Reaction SMILES: [F:1][C:2](F)(F)[C:3]([OH:5])=O.C(C1C=CC(NC(C2C=C(OC)C(OC)=CC=2F)C2NC(=O)N(C3C=CC=CC=3C(O)=O)N=2)=CC=1)(=N)N.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH2:55]O)[CH:50]=[C:51]([CH2:53][OH:54])[CH:52]=1.[H-].[Na+].FCCI>CN(C=O)C.C(OCC)(=O)C.O>[F:1][CH2:2][CH2:3][O:5][CH2:55][C:49]1[CH:50]=[C:51]([CH2:53][OH:54])[CH:52]=[C:47]([O:46][CH3:45])[CH:48]=1
Reactant: COc1cc(CO)cc(CO)c1
Reactant: O=C(O)C(F)(F)F
Agent: COc1cc(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Agent: FCCI
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CO)cc(COCCF)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1g of 5-methoxy-1,3-benzenedimethanol in 10 ml of DMF there was added 238 mg of sodium hydride (60% oily suspension) at 0° C. After stirring at room temperature for 30 minutes, 1.04 g of 1-fluoro-2-iodoethane was added and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (145 mg) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (14.99 g) and 4-chlorobenzonitrile (10.35 g) in DMF (100 mL) was treated with sodium hydride (60%, 3.8 g). The resulting dark mixture was then heated to 65 C for 16 h, and allowed to cool to RT. The mixture was poured into water (1 L) and extracted with ether (3×400 mL). The combined organic phases were evaporated and the brown oil dissolved in methanol (500 mL) and treated with concentrated hydrochloric acid (20 mL). After 24 h the methanol was removed, 5% aqueous sodium hydroxide (300 mL) and water (300 mL) were added, and the mixture was extracted with DCM (3×300 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Bulb to bulb distillation of the residue gave the title compound as an off white waxy solid (12.23 g).
Reaction SMILES: [Cl:1]OC(C)(C)C.[CH:7]([C:10]1([CH3:26])[C:14](=[O:15])[NH:13][C:12]([C:16]2[N:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[N:11]1)([CH3:9])[CH3:8].CO>C(Cl)Cl>[Cl:1][N:13]1[C:14](=[O:15])[C:10]([CH:7]([CH3:9])[CH3:8])([CH3:26])[N:11]=[C:12]1[C:16]1[N:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)(C)OCl
Reactant: COC(=O)c1cccnc1C1=NC(C)(C(C)C)C(=O)N1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccnc1C1=NC(C)(C(C)C)C(=O)N1Cl
Reaction time: 24 h
Yield: 63.7 %

Procedure:
Tert-butyl hypochlorite (5.92 g, 0.0545 mol) is added to a solution of methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (10.0 g, 0.0363 mol) and methanol. The reaction mixture is covered with foil and stirring is continued for 1 day. The reaction mixture is concentrated in vacuo to give a liquid. The liquid is dissolved into methylene chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow syrup. The yellow syrup is chromatographed using silica gel and 5% ethyl acetate in hexanes as eluent to give the title compound as a colorless syrup (7.16 g, 64%), identified by IR and NMR spectral analyses.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(C1C=CC([O:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][NH+:25](C)[CH2:24][CH2:23]2)=CC=1C)=O.O1C2(CCNCC2)OCC1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CC(O)C.CO>[NH:25]1[CH2:26][CH2:27][CH:22]([O:21][CH2:20][CH2:19][OH:18])[CH2:23][CH2:24]1
Reactant: Cc1cc(OCCOC2CC[NH+](C)CC2)ccc1C=O
Agent: C1CC2(CCN1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(C)O
Solvent: CO
Solvent: CCCCCC
Product: OCCOC1CCNCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
4-[2-(4-Formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidinium toluene-4-sulfonate. To a solution of 1,4-dioxa-8-aza-spiro[4.5]decane (1.0 g, 7.0 mmol, 1.0 equiv) in toluene (20 mL) at 0° C. was added 1.0 M diisobutylaluminum hydride in hexane (20 mL, 20 mmol, 2.9 equiv). The solution was warmed to 80° C. and stirred for 12 h. Methanol (20 mL), satd. aq. sodium potassium tartrate (20 mL), and 10% 2-propanol in chloroform (100 mL) were added and the mixture was stirred for 30 min. The chloroform layer was separated and the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide crude 2-(piperidin-4-yloxy)-ethanol as a white solid. The solid was dissolved in dichloroethane (20 mL) and 37% aq. formaldehyde (0.60 mL, 6.9 mmol) was added. After stirring for 30 min, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture was stirred for 1.5 h. The reaction mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted six times with 10% 2-propanol in chloroform (80 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residue was dissolved in dichloromethane, cooled to 0° C., and pyridine (463 μL, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added. The solution was warmed to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partially purified by Method 2. The resulting material, toluene-4-sulfonic acid 2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture of 4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and K2CO3 (699 mg, 5.1 mmol) in DMF. The mixture was heated to 100° C. and stirred for 16 h. After cooling to rt, the mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude product was purified by Method 2 to afford 409 mg of the title compound. 1H NMR (400 MHz, CD3OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07-1.83 (m, 4H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C@@H:20]([OH:29])[CH2:21][C@@H:22]([CH3:28])[C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[CH2:37]([C@H:44]([CH2:48][C:49]([N:51]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:52])=[O:50])[C:45]([OH:47])=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([C@H:44]([CH2:48][C:49]([N:51]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:52])=[O:50])[C:45]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C@@H:20]([OH:29])[CH2:21][C@@H:22]([CH3:28])[C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:47])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Product: CCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Yield: 29 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 325 mg (0.62 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-N-ethyl-4-hydroxy-2-methylhexanamide [prepared as described in Example 19(a)] and 200 mg (0.64 mmole) of 2(R)-benzyl-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 129 mg of the title compound as white crystals, melting at 148°-150° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:31]S(C(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:21]C(C)(C)[N:19]([C:24](=[O:28])[CH:25]([F:27])[F:26])[C@@H:18]3[CH2:29][F:30])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)#[N:2].Cl>C(OCC)(=O)C.O1CCOCC1.N>[NH2:31][CH:4]([C:5]1[N:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([OH:21])[C@H:18]([NH:19][C:24](=[O:28])[CH:25]([F:26])[F:27])[CH2:29][F:30])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)[CH2:3][C:1]#[N:2]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(C(CC#N)NS(=O)C(C)(C)C)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#CCC(N)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.8 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [2-cyano-1-(5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-yl)-ethyl]-amide (0.21 g, 0.392 mmol) in Ethyl acetate (2 mL) is added HCl in dioxane (2.0 mL) at 0° C. The resulting reaction mixture is stirred at room temperature for 3 hours. Solvent is evaporated in vacuo to get the crude residue and diluted with aqueous ammonia solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography using 7-8% methanol in CH2Cl2 to afford the title compound (0.032 g): 1HNMR (400 MHz, DMSO-d6) δ: 2.85-2.99 (m, 2H), 4.24-4.35 (m, 2.5H), 4.40-4.44 (m, 0.5H), 4.54-4.55 (m, 0.5H), 4.64-4.67 (m, 0.5H), 4.87-4.88 (m, 2H), 5.92 (d, J=4.44 Hz, 1H), 6.20 (t, J=53.8 Hz, 1H), 7.46 (d, J=8.16 Hz, 2H), 7.62 (d, J=8.16 Hz, 1H), 7.71 (d, J=8.22 Hz, 2H), 8.09-8.12 (dd, J1=2.32 Hz, J2=8.2 Hz, 1H), 8.84-8.87 (m, 2H). LC-MS (m/z): [M+H]=393.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[NH2:27][NH2:28]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([NH:27][NH2:28])=[O:14])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a 100 mL volume three-necked flask, ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate ((9-a) (10.0 g)) and toluene (35 ml) were added. Hydrazine hydrate (2.13 ml) was added dropwise thereto at 60° C. and the obtained mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, water was added thereto and the organic layer was removed. The aqueous layer was extracted with toluene. The organic layers were combined and concentrated under reduced pressure to give 9.40 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:17]([F:27])[CH:16]=1)[CH2:9][C:8]2([CH3:29])[CH3:28])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:27][C:17]1[CH:16]=[C:15]([CH:10]2[CH2:9][C:8]([CH3:28])([CH3:29])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(F)cc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(c2cc(F)cc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (398.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (345.6 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=385.1.