Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:10]2[C:5](=[CH:6][C:7]([N+:23]([O-])=O)=[C:8]([N:11]([CH3:22])[C:12](=O)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]1=[O:31]>C(Cl)Cl.CO>[CH3:22][N:11]1[C:8]2=[CH:9][C:10]3[C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:5]=3[CH:6]=[C:7]2[N:23]=[C:12]1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N(C)C(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Solvent: ClCCl
Solvent: CO
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(CCc1ccccc1)n3C

Procedure:
1,7,7-Trimethyl-5-pentyl-2-phenethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one is prepared from crude N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-N-methyl-3-phenyl-propionamide as described in Example 3b. The desired compound (78 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (98:2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[ClH:11].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.CO>C(O)(=O)C>[ClH:11].[ClH:11].[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: C1COCCN1
Reactant: O=Cc1cccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3cccc(CN4CCOCC4)c3)cc2s1
Reaction time: 18 h

Procedure:
290 mg (3.32 mmol) of morpholine and 31 mg (0.50 mmol) of sodium cyanoborohydride are successively added to a solution of 80 mg (0.17 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 33A) in 1.0 ml of a 6:1 mixture of methanol and acetic acid. After 18 h at. 80° C., purification is carried out by preparative HPLC.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([C@H:30]([CH:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)[C:31]([O:33]CC5C=CC(OC)=CC=5)=[O:32])[CH2:20]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([C@H:30]([CH:43]5[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]5)[C:31]([OH:33])=[O:32])[CH2:20]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4cnc(-c5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(c3cnc(-c4ccccc4)s3)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
To 28 mg of α-(R)-(3-(S)-((4-(2-phenyl-thiazol-5-yl)-piperidine -1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (from Step C) were added 150 mg of anisole and 3 ml of triflouroacetic acid. The reaction was stirred at room temperature for 1 hr. The trifluoroacetic acid was evaporated under reduced pressure. The residue was purified by flash chromatography with 20% MeOH in EtOAc followed by 20% MeOH+2% NH4OH in EtOAc to give 24 mg of the title compound. LC-MS (Method A): Retention Time: 2.72 min. Mass Spectrum: 544 (M+H).
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[CH2:20]([O:22][CH:23]([O-])[O-])[CH3:21]>C(O)(=O)C>[F:1][C:2]1[C:15]([F:16])=[CH:14][C:5]([C:6]([C:8](=[CH:23][O:22][CH2:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1[N+](=O)[O-]

Procedure:
To 3 ml of acetic acid anhydrous were added 3 g (0.01 mol) of ethyl 4,5-difluoro-2-nitrobenzoylacetate and 2.44 g (0.016 mol) of ethylorthoformate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)occ1OCc1ccccc1
Yield: 56.9 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (7-05) (25.0 g, 56.92%) was synthesized as a brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (25 g, 108.22 mmol) and 3-chloro-benzenesulfonyl chloride (6-05) (22.98 mL, 162.33 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[Br:16]Br.Cl>O>[Br:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][C:5]2=[O:15].[Br:16][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH2:6][C:5]2=[O:15])=[CH:10][CH:11]=1
Reactant: O=C1CCCc2ccccc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C1CCCc2c(Br)cccc21
Product: O=C1CCCc2ccc(Br)cc21
Temperature: 77.5 °C
Reaction time: 0.08 h
Yield: 51 %
Yield: 42 %

Procedure:
A 500 mL three-necked flask fitted with an addition funnel, reflux condenser and thermometer was charged with aluminum chloride (33.34 g, 250 mmol) and heated to 75-80° C. 1-Tetralone (14.6 g, 13.3 mL, 100 mmol) was added dropwise over 10 min. The resulting brown slurry was stirred for 3 min before dropwise addition of bromine (19.21 g, 6.15 ml, 120 mmol) over 15 min. The mixture was stirred for 5 min and then poured into a mixture of ice (300 g) and 12N HCl (40 mL). The mixture was stirred until the aluminum chloride was dissolved and then diluted with water (200 mL). The mixture was extracted with diethyl ether (3×300 mL) and the combined organics were washed with water (2×300 mL), dried (sodium sulfate), filtered and evaporated in vacuo to give a dark brown mixture of 5- and 7-bromo-1-tetralone. The isomers were separated using silica gel flash chromatography (Biotage Flash 75, elution solvent 20/1 hexanes:MTBE) to yield 5-bromo-1-tetralone (11.59 g, 51%) and 7-bromo-1-tetralone (9.45 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][N:13]4[CH:19]=3)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.Br[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:28][CH:29]=2)[C:6]2[CH:7]=[C:8]([C:10]3[N:11]=[C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][N:13]4[CH:19]=3)[O:9][C:5]=2[CH:4]=1
Reactant: BrCc1csc(-c2ccccc2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Temperature: 22 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
In a 100 mL round-bottom flask, a suspension of 6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol (Example 39B, 0.190 g, 0.643 mmol) and 4-(bromomethyl)-2-phenylthiazole (Table of bromides, 0.180 g, 0.708 mmol) in DMF (5 mL) was purged under vacuum and N2 for 10 min. The reaction was treated with potassium carbonate (0.24 g, 1.737 mmol) and stirred at 22° C. for 18 hours, then diluted with DCM and washed with water (1×), brine (1×). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 0% to 50% EtOAc in CH2Cl2) to give the impure title material (0.198 g, 66%). The solid was triturated in hot ethyl acetate to provide the pure title material (0.176 g). LC (Method A): 2.414 min. HRMS (ESI) calcd for C26H21N4O3S [M+H]+ m/z 469.1329. found 469.1379. 1H NMR (CDCl3, 400 MHz) δ ppm: 2.57 (s, 3H), 3.84 (s, 3H), 5.39 (s, 2H), 6.46 (d, J=1.96 Hz, 1H), 6.74 (broad d, 1H), 6.91 (d, J=9.1 Hz, 1H), 7.34 (s, 1H), 7.36 (s, 1H), 7.39-7.46 (m, 3H), 7.80 (d, J=9.1 Hz, 1H), 7.90-8.0 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][C:18]([OH:20])=O)[C:5]=2[CH:4]=1.O=S(Cl)[Cl:23]>CO.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(CCC(=O)O)c1ccccc1-2
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(CCC(=O)Cl)c1ccccc1-2
Reaction time: 2 h

Procedure:
3-(2-Methoxyfluoren-9-yl)propionic acid (1.6 g, 5.2 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. The reaction was monitored by TLC (silica RP-18, 70% methanol/water). The excess of thionyl chloride was removed under reduced pressure, the residue (an oil) was used for the next step without further purification.
Reaction SMILES: [C:1]([C:7]#[N:8])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CO[C:11]([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)[OH:16]>C(O)(=O)C>[C:11]([NH:8][C:7](=[O:16])[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)C#N
Reactant: O=S(=O)(O)O
Reactant: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)NC(=O)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.8 (0.25 mole) of pivaloyl cyanide, dissolved in 22 g (0.25 mole) of t-butyl methyl ether were added to a reaction mixture, which had been initially introduced into the reaction vessel, consisting of 37.5 g of concentrated sulphuric acid and 52.5 g of glacial acetic acid at 20° to 30° C. in the course of 30 minutes. After subsequently stirring the reaction mixture at room temperature for 2 hours, it was poured onto 125 g of ice and stirred thoroughly. The product which precipitated was filtered off, washed with water and dried. 40.8 g (87.5% of theory) of analytically pure trimethylpyruvic acid N-tert.-butylamide with a melting point of 65° C. and a content of >99% (determined by gas chromatography) were obtained.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12]C2C=C(OC)C(OC)=C(OC)C=2)[C:9]([OH:11])=[O:10])[CH:2]=1.N[C@@H](C[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[C:38]=1[O:47][CH3:48])C(O)=O>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:41]2[CH:42]=[CH:37][C:38]([O:47][CH3:48])=[C:39]([O:45][CH3:46])[C:40]=2[O:43][CH3:44])[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Reactant: COc1ccc(C[C@H](N)C(=O)O)c(OC)c1OC
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)c(OC)c1OC

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using (S)-2-Amino-3-(2,3,4-trimethoxy-phenyl)-propionic acid. Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 408.2 [M+H]+; HPLC: single peak at tR=9.42 min (System 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=O)=[N:9][N:8]=[N:7]1)=[O:5])[CH3:2].C[O-:17].[Na+].CO.CS(O)(=O)=O.P([O-])(O)(O)=O.[Na+].[C:32]1(C)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([N:6]1[C:10]([C:11]2[O:13][C:14]3[CH:15]=[CH:35][CH:36]=[CH:37][C:32]=3[C:33](=[O:17])[CH:34]=2)=[N:9][N:8]=[N:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1
Reactant: C[O-]
Reactant: CCOC(=O)c1nnnn1C(=O)OCC
Agent: CS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)n1nnnc1-c1cc(=O)c2ccccc2o1
Reaction time: 5 h

Procedure:
To a solution of 1.01 g (2.50 mmol) of 3-[4-(4-phenyl-1-butoxy)benzoyl]-amino-2-hydroxyacetophenone and 0.669 g (3.12 mmol) of ethyl N-ethoxycarbonyltetrazol-5-carboxylate dissolved in 10 ml of toluene was added 1.45 g (7.5 mmol) of 28 % sodium methylate/methanol solution at room temperature, and the mixture was kept at 40° C. for 5 hours. To the resulting reaction mixture was added dropwise 1.22 g (12.7 mmol) of methanesulfonic acid at 40° C., and the mixture was kept at 60° C. for 5 hours. Then, 5% aqueous sodium dihydrogenphosphate and toluene were poured into the reaction mixture, followed by phase separation, washing with water, and concentration under reduced pressure. The residue was recrystallized from toluene to give 1.1 g of 2-(N-ethoxycarbonyltetrazol-5-yl)-4-oxo-4H-benzopyran. Yield, 77%; m.p., 154°-157° C. (decomp.).
Reaction SMILES: I([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](CC([O-])=O)[C:4]=1[CH2:13][C:14]([O-:16])=[O:15])=O.[C:17]([OH:20])(=[O:19])[CH3:18]>>[C:3]1([O:20][CH2:17][CH2:18][CH2:7][CH2:8][CH2:3][CH2:4][CH2:5][CH3:6])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:17]([O:16][C:14](=[O:15])[CH3:13])(=[O:19])[CH3:18]
Reactant: O=Ic1cccc(CC(=O)[O-])c1CC(=O)[O-]
Reactant: CC(=O)O
Product: CC(=O)OC(C)=O
Product: CCCCCCCCOc1ccccc1

Procedure:
To a mixture of 50 g of iodosobenzenediacetate obtained above, 30 g of octyl phenyl ether, 70 g of acetic anhydride and 725 ml of glacial acetic acid was dropwise added 8 g of concentrated sulfuric acid while cooling with an ice bath over a period of one hour. One hour after, a solution containing 31 g of sodium bromide dissolved in 150 ml of water was dropwise added thereto and the white powder thus-deposited was collected to obtain 42 g of iodonium bromide salt.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH2:19]([NH:24][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CCN
Reactant: CC[K]
Reactant: O=C(O)C1OC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)NCCC(C)C
Yield: 52.4 %

Procedure:
Following the procedure of Example 1, monoethyl potassium epoxysuccinate (1.5 g) was successively treated with oxalyl chloride (1.04 g) and isoamylamine (2.3 g) to give 0.9 g of ethyl N-isoamyl-2,3-epoxysuccinamate (Compound No. 17) as colorless needles melting at 59°-61° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C([OH:11])C=C.N1C=C[CH:15]=[CH:14][CH:13]=1.Cl>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:6][CH2:13][CH:14]=[CH2:15])=[O:11]
Reactant: C=CCO
Reactant: c1ccncc1
Reactant: O=C(Cl)CCCBr
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)CCCBr
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Bromobutryl chloride (18.6 g) was treated with allyl alcohol (5.8 g) in the presence of pyridine (8 g) in dry dichloromethane at 0° C. for 0.5 hours. The solution was treated with aqueous HCl and warmed to room temperature. The organic layer was separated, washed with saturated aqueous brine, dried (MgSO4) and evaporated to give the title compound as a colourless oil, 19.7 g, 95% yield
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20](O)=[O:21])[CH2:9]2)=[C:4]([F:23])[CH:3]=1.S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([Cl:26])=[O:21])[CH2:9]2)=[C:4]([F:23])[CH:3]=1
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2F)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(4-Bromo-2-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (2.5 g, 6.3 mmol) prepared in Step 4 was added to thionyl chloride (30.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(4-bromo-2-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C@@H:13]([CH3:27])[CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C@@H:29]1[CH2:34][O:33]C(=O)[CH2:30]1>>[CH2:9]([NH:8][C:34](=[O:33])[C:29](=[CH2:30])[CH2:28][C@H:10]([OH:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:12][C@@H:13]([CH3:27])[CH2:14][CH2:15][O:16][Si:17]([CH:18]([CH3:19])[CH3:20])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[CH2:12][CH2:13][CH3:14]
Reactant: CC(C)[Si](OCC[C@H](C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: C[C@@H]1COC(=O)C1
Product: C=C(C[C@H](O)[C@H](C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC

Procedure:
In a manner analogous to that described in Example 72g), the title compound is obtained starting from 3.2 g of 2(S)-tert-butoxycarbonylamino-4(R)-methyl-6-triisopropylsilyloxyhexanal (Rf (D)=0.36), which is prepared by processes analogous to those described in Examples 72h to 72n), starting from (S)-3-methylbutyrolactone, and is purified by FC over 400 g of silica gel (mobile phase gradient from E to B), the two stereoisomers being separated. This gives the title compound (diastereomer I): Rf (A)=0.58; and diastereomer II: Rf (A)=0.47.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.C([O-])([O-])=O.[K+].[K+].O.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:32](=[S:34])=[S:33]>C(O)C>[CH2:24]([S:34][C:32]([N:2]1[C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: S=C=S
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccccc1
Yield: 52.3 %

Procedure:
In the same manner as described in Example 16, (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (21.6 g), K2CO3 (13.8 g), water (550 ml), ethanol (550 ml), carbon disulfide (6 ml) and benzyl bromide (14 ml) are reacted and treated. The residue is purified by silica gel column chromatography (solvent, chloroform:methanol=10:1) to give the title compound (20 g, 52.3%) as powder.
Reaction SMILES: C(O)(=O)C.[OH:5][CH:6]1[CH2:9][NH:8][CH2:7]1.[C:10](Cl)(=[O:28])[CH2:11][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][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[C:10]([N:8]1[CH2:9][CH:6]([OH:5])[CH2:7]1)(=[O:28])[CH2:11][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][CH2:25][CH2:26][CH3:27]
Reactant: OC1CNC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC(O)C1
Temperature: 0 °C

Procedure:
Stir a suspension of 6.31 g of 3-hydroxyazetidine acetate in 150 ml dry pyridine until a solution results. Add 15.8 g stearoyl chloride at room temperature during ten minutes and stir for 21 hours at room temperature. Pour into 450 ml of an ice-water mixture, and extract once with 300 ml ethyl ether and then twice with 250 ml portions chloroform. Wash the combined extracts with three 150 ml portions of water, dry over anhydrous sodium sulfate and remove the solvents in vacuo. Stir the residue in 250 ml hexane and filter the resultant solid. Recrystallization from hexane affords pure 1-octadecanoyl-3-hydroxyazetidine, m.p. 86°-87.5° C.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)([OH:12])[CH3:11].O>C(Cl)Cl>[OH:12][C:10]([C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)([CH3:11])[CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(O)(CN)c1ccc(I)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(I)cc1
Temperature: 0 °C
Yield: 19.4 %

Procedure:
Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4-iodophenyl)propan-2-ol (2.77 gm, 0.01 mol) in 125 mL CH2Cl2 while stirring at 0° C. under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H2O and the layers were separated. The organic layer was washed once with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide the intermediate title compound (744 mg, 19%) as a solid material. FDMS 382 (M*).
Reaction SMILES: [O:1]=[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].N([CH2:38][CH3:39])(CC)CC.[C:40](=[O:48])([O:44][CH:45](Cl)[CH3:46])[O:41][CH2:42][CH3:43].[Na+].[I-]>CC(C)=O>[CH2:42]([O:41][C:40]([O:44][CH:45]([O:27][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[NH:23][C:2](=[O:1])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH:42]([O:41][C:40]([O:48][CH2:38][CH3:39])=[O:44])[CH3:43])=[O:10])=[O:5])[CH3:46])=[O:48])[CH3:43]
Reactant: CCOC(=O)OC(C)Cl
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Reactant: CCN(CC)CC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)OC(C)OC(=O)c1ccccc1NC(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)OC(C)OC(=O)OCC
Yield: 43 %

Procedure:
The compound 11 (2.0 g, 4.7 mmol) and dry N(C2H5)3 (1.13 g, 11.2 mmol) were stirred in dry acetone (60 ml) at room temperature for 30 minutes. The mixture was treated with ethyl 1-chloroethyl carbonate (1.70 g, 11.2 mmol) and NaI (1.67 g, 11.2 mmol) and heated under reflux for 23 hours. After completion of the reaction, the precipitate was removed, and the solvent was removed frcm the filtrate. The residue was extracted with benzene, washed with saturated aqueous solution of NaHCO3 and saturated solution of NaCl and dried over anhydrous Na2SO4 . The solvent was evaporated to give a colorless viscous product. The resultant product was dissolved in developing solvent and purified by silica gel column chromatography (developing solvent: benzene:ether=95:5) to give the desired compound as white solid (1.34 g, crude yield, 44%). The solid was dissolved in methanol at room temperature, treated with water, and cooled with a solution of dry ice in acetone. The precipitated solid was filtered by suction, followed immediately by drying under reduced pressure to give the desired compound as white crystal (970 mg, yield, 32%). m.p., 48°-51° C.