Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1>>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CCCc1cnc(-c2ccc(Br)cc2)nc1
Product: CCCc1cnc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)nc1

Procedure:
Analogously to Example 9, by reacting 14.0 g of 2-(4-bromophenyl)-5-propylpyrimidine and 12.1 g of trifluoromethoxy-4-bromobenzene, the corresponding 2-(4'-trifluoromethoxybiphenyl-4-yl)-5-propylpyrimidine having C 125° SG 1110 SA 218° I is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:20][C:21](Cl)=[O:22])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1.[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>O1CCCC1>[CH2:26]([O:25][P:24]([C:21]([OH:22])=[CH:20][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:10]=1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: CCOP(OCC)OCC
Reactant: O=C(Cl)Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)=Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of 17.5 g of 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoleacetic acid chloride in 100 ml of tetrahydrofuran is cooled to 10° C. and combined with 9.8 ml of triethyl phosphite. The mixture is stirred for 3 hours at 10°-15° C., the solution is concentrated under vacuum, and the oily residue is crystallized from diisopropyl ether, thus obtaining 18.8 g (83.4%) of 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethenephosphonic acid diethyl ester, mp 96°-98° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22.5 g (149 mmol) 2,3-dihydro-benzo[1,4]dioxin-6-ylamine and 25 ml (179 mmol) triethylamine in 1 l diethyl ether is added at 12° C. within 10 minutes 20 ml (164 mmol) pivaloyl chloride dissolved in 250 ml diethyl ether. The temperature is kept between 12-16° C. The reaction mixture is stirred at room temperature for 1 hour. Then it is washed with 2× with 300 ml water, 2× with 150 ml 1N HCl and 2× with brine, dried with Na2SO4 and partially evaporated to a volume of 80 ml. This leads to a suspension. Hexane is added and the solid is filtered to give N-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2,2-dimethyl-propionamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:5]([Cl:16])=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=2)[N:3]=1.Cl.[F:26][C:27]1[CH:28]=[N:29][C:30]([C@@H:33]([NH2:35])[CH3:34])=[N:31][CH:32]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:5]1[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:7][C:2]([NH:35][C@H:33]([C:30]2[N:31]=[CH:32][C:27]([F:26])=[CH:28][N:29]=2)[CH3:34])=[N:3][C:4]=1[NH:17][C:18]1[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 86.6 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 29, 44.1 mg, 0.112 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 39.5 mg, 0.223 mmol), and DIPEA (0.062 ml, 0.352 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (48.6 mg, 87%). LC-MS, 501 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.01 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H), 8.21 (s, 1H), 5.60 (s, 1H), 5.04-5.06 (m, 1H), 3.76 (s, 3H), 2.80 (s, 3H), 2.70 (s, 6H), 1.59 (d, 3H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O.C1(C)C=CC=CC=1>[C:17]1([CH2:16][O:15][C:13]([NH:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH2:6][S:7][CH3:8])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
In a 2 L flask equipped with a mechanical stirrer and internal thermometer, sodium hydroxide (61.65 g, 1.541 mol) was dissolved in distilled water (1000 ml). To this solution, L-methionine (100.0 g, 0.670 mol) was added at room temperature. The solution was cooled in an ice bath (internal temperature 30° C.) and benzyl chloroformate (110 ml, 0.737 mol) was added over 10 minutes. After a 15 minute induction period, the internal temperature rose from 3° C. to 12° C. over 30 minutes and then dropped to 0° C. over 15 minutes. The reaction was stirred at 0° C. for 2 hours, during which time the initially cloudy reaction mixture became homogeneous. The ice bath was removed, and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was transferred into a separatory funnel and washed with hexane (2×300 ml). The aqueous layer was acidified with 6N hydrochloric acid to pH 5 and diluted with ethyl acetate (600 ml). The mixture was further acidified to pH 2. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×600 ml). The organic extracts were combined and washed with brine (750 ml), dried (magnesium sulfate), filtered and concentrated in vacuo to produce a light yellow oil. The crude product (oil) was dissolved in toluene (1500 ml), and the solution was concentrated to half of its volume. A second portion of toluene (750 ml) was added, and concentrated again such that 630 ml of toluene remained. This solution was stored at 5° C. overnight, during which time some of the product crystallized from solution. The solid was redissolved by warming to room temperature. Toluene (134 ml) was then added (a few seed crystals remained). With mechanical stirring, heptane (500 ml) was added in 30 ml portions at 10 minute intervals (approximately 3 hours total addition time). At this point, the product started to crystallize from solution. An additional portion of heptane (1020 ml) was added over 1.5 hours, and the resulting slurry was stirred for 2 hours. The product was collected by vacuum filtration, washed with 1:2 toluene:heptane (3×150 ml) and heptane (3×500 ml) and air-dried to give 158.6 g of title product as a white solid; m.p. 66° C.; [α]D =-1.5° (c=1, 95% ethanol). TLC (ethanol:water, 3:1) Rf =0.78.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(OC(C)C)(C)C.[C:20]([O:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30])(=[O:24])[C:21]([CH3:23])=[CH2:22].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCCCCC>[C:20]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:30])[O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: C=C(C)C(=O)OCCNC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 5.5 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
In a three-necked flask having an inner volume of 50 mL equipped with a thermometer and a stirring apparatus were charged 1.66 g (9.98 mmol) of 2-methyl-2-adamantanol, 2.0 mg of 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl, 6.7 g of isopropyl ether, and 1.66 g (10.5 mmol) of 2-methacryloyloxyethyl isocyanate. After the mixture was cooled by ice water to an inner temperature of 5° C., 290 mg (3.0 mmol) of methanesulfonic acid was added dropwise. After stirring the reaction mixture for 15 hours with the reaction temperature maintained at 5 to 6° C., 10 g of a saturated aqueous NaHCO3 solution was added dropwise with the inner temperature maintained at 10° C. or less and, after completion of the dropwise addition, the mixture was allowed to stand still for 30 minutes. The organic layer (upper layer) formed was separated and the aqueous layer (lower layer) was extracted twice with 10 g of isopropyl ether. All the separated organic layers were combined, washed with 10 g of distilled water, and the organic layer concentrated under reduced pressure to obtain 2.82 g of a concentrate. The concentrate was dissolved in 15 g of hexane at 30° C. and the solution was cooled to −10° C. at a rate of 10° C./hour. The crystals which precipitated were separated by filtration and the crystals obtained were dried under vacuum (26.7 Pa) at 30° C. for 2 hours to obtain 1.29 g (purity 98.2%, 3.94 mmol, yield: 39.5%) of 2-methyladamantan-2-yl (2-methacryloyloxyethyl)carbamate.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=O)=[O:14]>C(Cl)Cl.FC(F)(F)C(O)=O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([N:15]1[CH:20]=[CH:19][O:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23])=[O:14]
Reactant: COC(=O)[C@H](COCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1COC=CN1C(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.3 %

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester (13.6 g) in methylene chloride/trifluoroacetic acid (10:1/330 mL). Stir at room temperature for 2.5 hours and evaporate the solvent in vacuo. Purify by silica gel chromatography (35% ethyl acetate/hexane) and recrystallize (ethyl acetate/hexane) to give the title compound (8.52 g, 68%); mp 70°-72° C.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:24][C:25](=[O:52])[C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=2)[CH:36]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].C1COCC1>CO>[C:48]([C:45]1[CH:44]=[CH:43][C:42]([O:41][C:37]2[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=2)[CH2:34][NH:33][C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25]([NH:24][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[C:3]([OH:53])=[O:2])=[O:52])=[CH:47][CH:46]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1)NC(=O)c1cc(Cl)ccc1NCc1cccc(Oc2ccc(C(C)(C)C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(Oc2cccc(CNc3ccc(Cl)cc3C(=O)N[C@@H](Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)C(=O)O)c2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
The title compound was prepared following General Procedure C using (S)-2-{2-[3-(4-tert-Butyl-phenoxy)-benzylamino]-5-chloro-benzoylamino}-3-(4′-cyclohexyl-biphenyl-4-yl)-propionic acid methyl ester (135 mg, 0.19 mmol), LiOH(aq) (2.0 N, 0.22 mL, 0.44 mmol), THF (4 mL) and MeOH (1 mL). The mixture was stirred at 0° C. for 12 h. The product was obtained as off-white solid (115 mg, 0.16 mmol, 84% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([N:6]=[C:7]=[S:8])=[O:5].[CH3:10][NH:11][CH3:12].C1COCC1>>[CH3:10][N:11]([CH3:12])[C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:9])[CH3:1])=[S:8]
Reactant: CC(C)=CC(=O)N=C=S
Reactant: CNC
Solvent: C1CCOC1
Product: CC(C)=CC(=O)NC(=S)N(C)C
Yield: 84.9 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1b) using 3-methylbut-2-enoyl isothiocyanate (2 g, 14.2 mmol, Eq: 1.00) and dimethylamine solution 2M in THF (7.08 ml, 14.2 mmol, Eq: 1.00). Evaporation of the solvent afforded 1,1-dimethyl-3-(3-methyl-but-2-enoyl)-thiourea (2.239 g/84.9%) as a yellow oil which was used without further purification in the next step. MS: m/e=187.4 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.[Br-]>C(#N)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[Cl:31])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: Clc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [Br-]
Solvent: CO
Solvent: CC#N
Product: O=C1C(=O)N(Cc2ccccc2Cl)c2ccc(Br)cc21
Reaction time: 18 h
Yield: 102.7 %

Procedure:
Partially dissolve 5-bromoisatin (45 mg, 0.20 mmol) in acetonitrile (2 mL) and add 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polysteyrene (95 mg, 0.21 mmol, 2.2 mmol/g, Fluka) followed by adding 2-chlorobenzyl bromide (0.026 mL, 0.20 mmol). Stir 18 h and add additional base (50 mg) and bromide (0.010 mL) to drive reaction to completion after another 3 h. Dilute with MeOH and warm with heat gun to insure soluability. Filter off beads and concentrate the filtrate in vacuo to obtain 72 mg of the title compound as a dark orange solid. Use material in subsequent reaction without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:21]=[N:20][C:19]2[NH:18][C:17](=[O:22])[N:16]3[N:23]=[CH:24][N:25]=[C:15]3[C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:11][C:12]1[CH:21]=[N:20][C:19]2[N:18]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)[C:17](=[O:22])[N:16]3[N:23]=[CH:24][N:25]=[C:15]3[C:14]=2[CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]c2ncc(Br)cc2c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Temperature: 40 °C
Yield: 70 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (3.10 ml, 22.9 mmol) was added to a stirred solution of 9-bromopyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (3.02 g, 11.35 mmol) and potassium carbonate (4.71 g, 34.1 mmol) in 1-methylpyrrolidinone (60 ml) and the mixture was heated at 40° C. for 14 hours. The mixture was filtered, and the resulting solid was washed liberally with dichloromethane. The combined organics were concentrated under vacuum and the residue was triturated with ethyl acetate (40 mL) to afford 3.07 g (70%) of the benzylated product as a brown powder.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:11]([C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH:16]=[N:17][CH:18]=1)=O>>[CH3:3][O:2][N:4]=[CH:11][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH:16]=[N:17][CH:18]=1
Reactant: CON
Reactant: N#Cc1cccc(C#Cc2cncc(C=O)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=Cc1cncc(C#Cc2cccc(C#N)c2)c1
Yield: 74.6 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using methoxylamine hydrochloride (2.88 g, 34.45 mmol), potassium carbonate (2.97 g, 21.53 mmol) and 3-(5-formylpyridin-3-ylethynyl)-benzonitrile (1.00 g, 4.31 mmol), (prepared as described in EXAMPLE 90), to give the title compound (0.84 g, 75%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C.O>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[CH:6][N:5]2[CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc2c1ccn2CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1ccn2CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-bromopropyl)-4-nitro-1H-indole (8.18 g, 28.9 mmol) in anhydrous N,N′-dimethylformamide (200 mL) was added grounded potassium carbonate (12 g, 87 mmol) in portions. Then a solution of morpholine (12.6 g, 144.8 mmol) in N,N′-dimethylformamide was added dropwise. The mixture was stirred at 80° C. for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated to afford the product 4-(3-(4-nitro-1H-indol-1-yl)propyl)morpholine, which was used for the next step without purification.
Reaction SMILES: COC1C=CC(COC([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:36])[C@@H:18]([OH:35])[CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH2:12]2)=O)=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([NH:21][CH2:20][CH2:19][C@H:18]([OH:35])[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:36])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: COc1ccc(COC(=O)N2CCN(C(=O)[C@@H](O)CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(NCC[C@H](O)C(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Yield: 99.8 %

Procedure:
A 1.32 g of 1-(p-methoxybenzyloxycarbonyl)-4-((2S)-4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyryl)piperazine was added to a mixture of 15 ml of trifluoroacetic acid and 1.35 ml of anisole, followed by 1 hour of reaction at room temperature. After removing trifluoroacetic acid by evaporation under a reduced pressure, a residue was adjusted to basic with sodium hydroxide and extracted with chloroform, and the organic layer was washed with water and dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography to yield 0.91 g of 1-((2S)-4-(p-nitrobenzyloxycarbonyl)amino-2-hydroxybutyryl)piperazine as a syrup.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][NH:3]1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: COC(=O)c1c[nH]c(=O)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)c2ccccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of the product from part 3 (12.5 g) in 50 ml of POCl3 is stirred at 100° C. for about two hours then cooled and concentrated under vacuum. The residue is dissolved in 300 ml of CHCl3, and the resulting solution is washed with aqueous NaHCO3 and water, dried over Na2SO4, filtered and then concentrated to give the title compound, m.p. 53-55° C.
Reaction SMILES: [C:1]12([C:11](=[O:28])[CH:12](Cl)[C:13]([NH:15][C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[O:25][CH3:26])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:29][C:30]1([CH3:37])[O:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]12([C:11](=[O:28])[CH:12]([N:32]3[C:31](=[O:36])[C:30]([CH3:37])([CH3:29])[O:34][C:33]3=[O:35])[C:13]([NH:15][C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[O:25][CH3:26])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)C(Cl)C(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC1(C)OC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)C(C(=O)C12CC3CC(CC(C3)C1)C2)N1C(=O)OC(C)(C)C1=O
Yield: 79.7 %

Procedure:
A suspension of 16.28 g (0.04 mol) of [4], 5.17 g (0.04 mol) of 5,5-dimethyloxazolidine-2,4-dione, and 16.58 g (0.12) mol of anhydrous potassium carbonate in 380 mL of dried acetone was refluxed for 3 hours. Thin layer chromatographic analysis indicated that the reaction was complete. The reaction mixture was concentrated in vacuo to yield an orange-colored solid. It was dissolved in ethyl acetate and the organic layer was washed with HCl (10%) and brine until neutrality. The organic layer was dried, filtered, and concentrated to yield an oil which solidified upon standing. It was triturated in ligroin. The final dried product (15.92 g, 79.8%) gave one spot on TLC. All analytical data confirmed the assigned structure.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:20][C:21]([Cl:26])([Cl:25])[C:22](Cl)=[O:23]>ClCCl>[Cl:20][C:21]([Cl:26])([Cl:25])[C:22]([O:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])=[O:23]
Reactant: C=CCc1cc(C#N)ccc1O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1cc(C#N)ccc1OC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INT 25 (10.0 g, 62.8 mmol) in dichoromethane (450 mL) was added triethylamine (7.98 g, 79 mmol), followed by dropwise addition of trichloroacetyl chloride (14.42 g, 79 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to give INT 26 which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1CCl
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1CCl

Procedure:
A solution of 24 g (0.17 mol) of 2-chloromethyl-3-methylpyridine in 200 ml of methylene chloride ls treated while cooling with ice with a solution of 44 g (0.25 mol) of m-chloroperbenzoic acid in 200 ml of methylene chloride. The reaction mixture is heated under reflux for 2 hours and concentrated in a rotary evaporator. The residue is chromatographed on silica gel with ethyl acetate/methylene chloride (3:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. The 2-chloromethyl-3-methyl-pyridine 1-oxide obtained is processed directly.