Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[C:12]=1[Cl:19]>>[Cl:10][C:11]1[C:12]([Cl:19])=[C:13]([Cl:18])[C:14]([F:17])=[CH:15][C:16]=1[C:1]([Cl:5])([Cl:3])[Cl:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(Cl)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1cc(C(Cl)(Cl)Cl)c(Cl)c(Cl)c1Cl
Yield: 62.8 %

Procedure:
Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged, and 20.0 g (0.1 mol) of 1,2,3-trichloro-4-fluorobenzene was dropwise added under reflux. Thereafter, the mixture was reacted for 30 minutes. The reaction mixture was treated in the same manner as in Example 1 to obtain 19.9 g (yield: 62.8%) of 2,3,4-trichloro-5-fluorobenzotrichloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[CH:22]=2)[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]([CH3:12])[C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH:26]5[CH2:28][CH2:27]5)[NH:24][N:25]=4)[CH:17]=[CH:16][N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNCc1cccc2[nH]ccc12
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(Cc1cccc2[nH]ccc12)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A tube was charged with 116 (280 mg, 1.75 mmol), 53 (412 mg, 1.75 mmol), DIPEA (678 mg, 5.25 mmol) and IPA (5 mL), sealed and heated at 120° C. for 14 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 260 mg (41.4%) of I-40.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](Br)[N:6]([CH2:13][CH2:14][O:15][CH3:16])[N:5]=1>C(O)C>[Br:3][C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH:2][CH3:1])[N:6]([CH2:13][CH2:14][O:15][CH3:16])[N:5]=1
Reactant: CN
Reactant: COCCn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: CCO
Product: CNc1c([N+](=O)[O-])c(Br)nn1CCOC
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
Aqueous 40% methylamine solution (300 ml, 8.71 mol) was added to a solution of 3,5-dibromo-1-(2′-methoxyethyl)4-nitropyrazole (15 g, 0.483 mol) in ethanol (300 ml). The reaction mixture was stirred at 20-25° C. for 2 hours and then cooled to 0-5° C. for 30 minutes. The precipitate formed was filtered off and washed with a cold mixture of water/ethanol (1/1, 30 ml). The final amine product was obtained in the form of a yellow solid (4.6 g, 36%) after drying under reduced pressure.
Reaction SMILES: [H-].[Na+].C(O)C.[CH:6]1([C:11]([O:13]C)=O)[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>C1COCC1>[CH:6]1([C:11](=[O:13])[CH2:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: COC(=O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)CC(=O)C2CCCC2)cc1
Yield: 55.8 %

Procedure:
Sodium hydride (1.378 g, 59.9 mmol, 60% suspension in mineral oil) and ethanol (2.0 mL) were added to a solution of methyl cyclopentanecarboxylate (6.14 g, 47.9 mmol) and 1-(4-methoxyphenyl)ethanone (6.00 g, 40.0 mmol) in THF (200 mL). The mixture was heated to reflux for 11 h, quenched with water (100 mL) and acidified to pH˜2 with 1 N HCl. The THF solvent was evaporated in vacuo. The residue was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (25 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with hexanes and small amount of toluene and eluting with 0-15% ethyl acetate in hexanes, gave 1-cyclopentyl-3-(4-methoxyphenyl)propane-1,3-dione as yellow liquid (5.494 g, 56% yield). MS (ES+) m/z: 247 (M+H); LC retention time: 4.510 and 3.578 min, likely a mixture of keto and enol forms (analytical HPLC Method A).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[C:9]2[C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18](OCC)=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1>[Cl:3][C:4]1[C:9]2[C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[CH2:18][OH:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1Cc2c(CO)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 4 h

Procedure:
A solution of 0.39 g (17.9 mmol) of lithium borohydride in 40 ml of dry tetrahydrofuran is added dropwise to a hot solution of 5.2 g (16.2 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 180 ml of dry tetrahydrofuran. The mixture is stirred at the boiling point for 4 hours and subsequently treated dropwise at room temperature with 10.4 ml of 3 N hydrochloric acid. The mixture obtained is heated to boiling under reflux for 1.5 hours. The tetrahydrofuran is removed in vacuo, the aqueous residue is treated with concentrated ammonia until the mixture is basic and extracted three times with methylene chloride. The methylene chloride solution is dried over magnesium sulphate and evaporated in vacuo. After recrystallization from ethanol, the crystalline residue yields 7-chloro-4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 207°-208°.
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[CH2:6]([C@H:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:14]([C:16]#N)[OH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:29]>CCOCC>[CH2:6]([C@H:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:14]([C:16]([CH:1]1[CH2:3][CH2:2]1)=[O:29])[OH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: BrC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C#N
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)C1CC1

Procedure:
9.96 ml (124.5 mmol) of cyclopropyl bromide in 100 ml of ether were added dropwise within 30minutes to 3.03 g (124.5 mmol) of magnesium in 10 ml of abs. ether under slight reflux and the mixture was subsequently heated to reflux for 2 1/2 hours. Subsequently, 6.25 g (22.63 mmol) of tert-butyl [(1S,2R)-1-benzyl-2-cyano-2-hydroxyethyl]carbamate (EPA 0,266,950) were added dropwise thereto under reflux within 5 minutes and the mixture was heated to reflux for a further 2 1/2 hours. Finally, the mixture was left to cool (10°), 10% citric acid was added dropwise thereto and the mixture was extracted twice with ether. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. Chromatography on silica gel using a 9:1 mixture of toluene and ethyl acetate yielded tert-butyl [(1S,2R)-1-benzyl-2-(cyclopropylcarbonyl)-2-hydroxyethyl]carbamate as a pale yellow solid, MS: 246 (M-C3H9O)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O.Cl.[NH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[C:26](=[O:27])[CH2:25][N:24]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]=2[CH:16]=1
Reactant: NCC(=O)Cl
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1NCC(O)CO
Agent: Cl
Solvent: ClCCl
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.3 g of 5-chloro-2-[(2,3-dihydroxypropyl)-amino]-2'-fluorobenzophenone are dissolved in methylene chloride and treated under anhydrous conditions with 2.6 g of glycyl chloride hydrochloride. The mixture is stirred for 2 hours at room temperature, then the methylene chloride is extensively distilled off, whereupon the residue is stirred for 30 minutes with 3 N hydrochloric acid. The acidic aqueous solution is extracted with ether, subsequently made alkaline with 3 N sodium hydroxide or concentrated ammonia and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed on silica gel with ethyl acetate, there being isolated 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 117°-118°C. During the aforementioned reaction, there is formed as an intermediate 2-amino-4'-chloro-N-(2,3-dihydroxypropyl)-2'-(2-fluorobenzoyl)-acetanilide, which is not isolated.
Reaction SMILES: C[C:2]1[CH:3]=[C:4](Cl)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[CH3:18][NH:19][NH2:20].[CH2:21](O)CCC>>[CH3:21][C:3]1[CH:2]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:6]=[N:5][C:4]=1[N:19]([CH3:18])[NH2:20]
Reactant: CCCCO
Reactant: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1
Reactant: CNN
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)nnc1N(C)N

Procedure:
To an 8.0 g. portion of 5-methyl-6-(m-nitrophenyl)-3-chloropyridazine in 100 ml. of butanol is added 4.4 g. of methyl hydrazine. This reaction mixture is heated at reflux overnight and then cooled in an ice bath. The product which forms as a precipitate is collected by filtration, washed with butanol, water, dried and recrystallized from ethanol, m.p. 173°-174° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CN(C)C=O.C[O:11][C:12]1[CH:29]=[C:28]([O:30]C)[CH:27]=[CH:26][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=1[O:24]C)=[O:15]>O>[OH:11][C:12]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:24])=[O:15]
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2OC)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Temperature: 30 °C
Reaction time: 4.5 h

Procedure:
440 g (3.30 mol) of AlCl3 were stirred into 120 g (1.64 mol) of dimethylformamide in such a way that the temperature remained below 160° C. After cooling to 30° C., 60.5 g (0.20 mol) of 2,2',4,4'-tetramethoxybenzophenone were introduced into the mixture, which was easily stirrable. The mixture was stirred at about 50°-52° C. for 4.5 hours and then added to 1.8 l of water to which 3 g of active carbon had been added. The hydrolyzate was filtered at about 95° C., and then 65 g of concentrated hydrochloric acid were added to the filtrate. The precipitate was filtered off with suction at 25° C., washed with water and dried at 125° C. under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]([NH:41][CH:42]([C:48](O)=[O:49])[CH2:43][S:44][C:45](=[O:47])[CH3:46])(=[O:40])[CH3:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:48](=[O:49])[CH:42]([CH2:43][S:44][C:45](=[O:47])[CH3:46])[NH:41][C:38](=[O:40])[CH3:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)NC(CSC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-proline tert-butyl ester (0.85 g) and hydroxybenzotriazole (0.67 g) in methylene chloride (10 ml) chilled in an ice bath, dicyclohexylcarbodiimide (1.03 g) and N,S-diacetyl-D,L-cysteine (1.7 g) are added in that order. After fifteen minutes, the ice bath is removed and the mixture is stirred at room temperature overnight. The precipitate is filtered off and the filtrate is washed with 10% potassium bisulfate, water, saturated sodium bicarbonate and water. The organic phase is dried and concentrated to dryness in vacuo to give N,S-diacetyl-D,L-cysteinyl-L-proline tert-butyl ester as an oil. Rf =0.25 (silica gel, ethylacetate).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C1OC1C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:28])=[O:27])=[CH:24][CH:23]=1>C(O)C>[ClH:28].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][C:3]2[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=2)[C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(C(=O)C2CCNCC2)c1
Agent: CC1CO1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(C(=O)C2CCNCC2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
4-(3-aminobenzoyl)piperidine HCl (10.87 g (45.15 mmol)) was suspended in absolute ethanol (220 mL) in presence of propylene oxide (3.185 g, 3.84 mL, 54.84 mmol) at room temperature for 15 min. p-fluorobenzoyl chloride (8.93 g, 6.65 mL, 56.44 mmol) was then added dropwise. During the addition, a partial dissolution was observed before the formation of a thick precipitate. The temperature rose from 22° C. to 33° C. during the acylation. The suspension was post-agitated at room temperature for 4 h. Then, the precipitate was filtered, washed with ethanol (22 mL) and diethylether (40 mL). 15.38 g (94%) of 4-[3-(4-fluorobenzamidyl)benzoyl]piperidine HCl were obtained after drying at 50° C. under vacuum for 12 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:21][C:22]([C@@H:24]1[CH2:28][O:27]C(C)(C)[O:25]1)=O.O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([C@@H:24]([OH:25])[CH2:28][OH:27])[N:11]=2)=[N:6][CH:7]=1
Reactant: CC1(C)OC[C@@H](C(=O)CCl)O1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: OC[C@H](O)c1csc(Nc2ncc(Br)cc2Oc2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (0.5 g, 1.5 mmol) in ethanol (50 mL) was added (S)-2-chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.34 g, 1.9 mmol) and the reaction stirred at 80° C. for 1 hr. The reaction was poured into water (250 mL) and then filtered. The solid was triturated with ethyl acetate and methanol. The solid was suspended in ethyl acetate (500 mL) and washed with 1 N NaOH (500 mL). The organics were concentrated and the crude material was purified by chromatography using 3 to 10% MeOH/CH2Cl2 as eluent to give (R)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol (0.043 g, 0.10 mmol, 7%) (ABCI POS 426, 428 M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](C2C=CC=CC=2)(C2C=CC=CC=2)[O:14][SiH2]C(C)(C)C)[CH2:11][C@@H:10]([CH2:32][CH3:33])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([CH2:32][CH3:33])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@@H](C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of the compound obtained from step A (5.2 g, 10.8 mmol) in THF (20 mL) and acetic acid (1.36 mL, 2.2 equiv.) at 0° C. was added TBAF (1.0 M in THF, 17.8 mL, 1.65 equiv). The mixture was stirred at rt for 2.0 h. It was then diluted with ethyl acetate and washed with 5% KHSO4 and brine. Evaporation of solvent and a column chromatography (EtOAc: hexane=1:1) gave the desired product as viscous oil (yield, 95%). 1HNMR (400 MHz, CDCl3) δ 4.11 (m, 1 H), 3.78 (dd, 2 H), 2.63 (m, 1 H), 2.15 (dd, 1 H), 1.99 (m, 1 H), 1.82 (m, 1 H), 1.55 (s, 9 H), 1.54 (m, 1 H), 0.97 (t, 3 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:4]=1)=[O:28]
Reactant: CSc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
2-[4-(Methylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.28 g, 1.00 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (Ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.23 g, 77%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH2:34]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[N:25]([CH3:34])[CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OCC)c(OCC)c4)n3)cccc12
Reactant: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: CCOc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1OCC
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Ethyl 3-(7-{5-[3,4-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (100 mg) (D66), DABCO (13 mg) and N,N-dimethylformamide (4 mL) was added to dimethyl carbonate (10 mL) successively. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 150° C. for 2 h. After cooling the reaction, the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and then NaOH (27 mg) in water (5 mL) was added. The mixture was stir at 50° C. for 8 h. The organic solvent was evaporated off and the mixture was acidified with HCl (1 M) solution to pH around 1. Extracted with EtOAc (60 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 3-(7-{5-[3,4-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1-methyl-1H-indol-3-yl)propanoic acid (E42) (50 mg). δH (DMSO-d6, 400 MHz): 1.35-1.39 (6H, m), 2.61 (2H, t), 2.97 (2H, t), 3.63 (3H, s), 4.12-4.19 (4H, m), 7.15-7.22 (3H, m), 7.43 (1H, dd), 7.65 (1H, d), 7.78 (1H, dd), 7.79 (1H, dd), 12.06 (1H, br s). MS (ES): C24H25N3O5 requires 435; found 436.2 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:43]=4[CH:44]=[CH:45][CH:46]=[N:47]5)[CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCN(C[C@@H](O)COc3cccc4ncccc34)CC2)CC1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
1-(Piperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (71) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→1 00% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (200 mg) as a white solid. ESMS: MH+ 691.6
Reaction SMILES: NC(N)=O.[N-]=C=O.[Cl:8][C:9]1[CH:10]=[C:11]([N:16]=[C:17]=[O:18])[CH:12]=[C:13]([Cl:15])[CH:14]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[NH2:23]>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:18])[NH:23][C:22]2[CH:21]=[C:20]([Cl:19])[CH:26]=[C:25]([Cl:27])[CH:24]=2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: NC(N)=O
Agent: [N-]=C=O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)Nc1cc(Cl)cc(Cl)c1

Procedure:
The urea derivatives used as starting materials are obtained, for example, by the conventional reaction of an isocyanate with an amine. For example, reaction of 3,5-dichlorophenyl isocyanate with 3,5-dichloroaniline gives bis-(3,5-dichlorophenyl)-urea (melting point 294° C.).
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17](=[CH2:20])[CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:39]([O:57][C:58](Cl)=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].CCOCC>C(Cl)Cl>[CH2:39]([O:57][C:58]([O:19][CH2:18][C:17](=[CH2:20])[CH2:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: C=C(CO)COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(=O)OCCCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-[6-(triphenylmethoxy)hexyloxy]-2-metylenepropane-1-ol (from Preparation 46) (1.5 g) and pyridine (4.5 ml) in methylene chloride (15 ml) was cooled in an ice/water bath and octadecyloxycarbonyl chloride (1.3 g) was added. After stirring for 10 minutes at 0° C. the temperature was raised to 22° C. for 5 hours. Ether (15 ml) was added, and the mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was purified through a column of silica gel 60 (70-230 mesh, 15 g) eluting with ether/methylene chloride 1:1. Further purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/methylene chloride/pentane 1:1:3 as eluent.