Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH2:25][CH2:26][C:27](=[O:30])[NH:28][N:29]=4)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]=O.[OH-].[K+]>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[C:26]([CH3:31])[C:27](=[O:30])[NH:28][N:29]=4)=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: O=C1CCC(c2ccc(NC(=O)CCN3CCC(c4ccccc4)CC3)cc2)=NN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc(NC(=O)CCN3CCC(c4ccccc4)CC3)cc2)n[nH]c1=O

Procedure:
4.0 g (10 millimoles) of 6-[p-(3-(4-phenylpiperid-1-yl)-propionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone in 15 ml of ethanol were refluxed with 1.5 ml of 37% strength formalin solution and 40 ml of 4% strength ethanolic KOH for 3 hours. Insoluble material was filtered off under suction, after which the mother liquor was evaporated down and the product was recrystallized from isopropanol. 2.2 g of 6-[p-(3-(4-phenylpiperid-1-yl)-propionylamino)-phenyl]-4-methyl-3(2H)-pyridazinone were obtained as pale beige crystals of melting point 239°-240° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[H][H]>[Pd].C1(C)C=CC=CC=1.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1F
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1F

Procedure:
A solution of 6.44 g of 8-(3,4-difluorophenyl)-1,4-dioxa-7-spiro[4.5]decene, 1 ml of triethylamine and 125 ml of toluene/acetone (vol. 4:1) was hydrogenated with 1 g of palladium/carbon (10%) at room temperature and normal pressure until the hydrogen uptake came to a standstill. The catalyst was filtered off from the reaction mixture and the filtrate was concentrated. There were obtained 6.30 g of colourless, solid 8-(3,4-difluorophenyl)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][CH2:10][C:11]([OH:13])=O.C([N:18](C(C)C)CC)(C)C.N[N:25]([CH:33]=[NH:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[NH:18]=[C:33]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH:34][C:11](=[O:13])[CH2:10][CH2:9][C:2]1[C:1]([CH3:14])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C)c(CCC(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N(N)C=N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CCC(=O)NC(=N)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.6 %

Procedure:
3-Mesitylpropionic acid (4.40 g; 23 mmol), diisopropylethylamine (14.8 g; 115 mmol), tert-butyl amino(imino)methylcarbamate (4.40 g; 28 mmol), and 1-hydroxybenzotriazole monohydrate (4.22 g; 28 mmol) were dissolved in N,N-dimethylformamide (92 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (10.5 g; 28 mmol) was added thereto, and the mixture was stirred for 17 hours at room temperature. To the reaction solution, ethyl acetate (300 mL) was added, and the mixture was washed with 10% aqueous citric acid solution, brine, saturated aqueous sodium bicarbonate solution, and then brine. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting oily substance was crystallized from diethyl ether/diisopropyl ether, collected by filtration and dried to give 7.10 g of the title compound (yield 93%).
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[C:3]1(/[CH:2]=[CH:1]/[C:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]3[NH:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: C(=Cc1ccncc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-styrylpyridine (4.0 g, 22.1 mmol) and 2-chloromethylbenzimidazole (3.7 g, 22.1 mmol) in dimethylformamide (20 ml) was heated at 110°-120° C. under a nitrogen atmosphere for 1.5 hours. The mixture was cooled to room temperature, diluted with ethanol (380 ml) and carefully treated with sodium borohydride (880 mg, 23.2 mmol). The mixture was stirred at room temperature for 2 hours, then heated at reflux for 1 hour before stirring at room temperature overnight. The ethanol was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and sodium carbonate (half saturated, 100 ml). The phases were separated and the aqueous was extracted with ethyl acetate (2×100 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a reddish gummy residue which was purified by flash chromatography (eluting with 5% methanol in dichloromethane) to give a yellow gummy solid. The gum was triturated with ethyl acetate and recrystallised from ethyl acetate to give the title compound as a mustard solid (912 mg, 13%). M.p. 225°-227° C. (EtOAc); (Found: C, 79.74; H, 6.89; N, 13.47. C21H21N3 requires C, 79.97; H, 6.71; N, 13.32%); δH (DMSO-d6) 2.37 (2H, br s, tetrahydropyridinyl CH2), 2.69 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.17 (2H, br s, tetrahydropyridinyl CH2), 3.83 (2H, s, NCH2Ar), 5.91 (1H, s, CH=CR), 6.48 (1H, d, J 16.2 Hz, CHCHPh), 6.91 (1H, d, J-16.2 Hz, CHPh), 7.13-7.22 (3H, m, ArH), 7.29-7.33 (2H, m, ArH), 7.42-7.47 (3H, m, ArH), 7.54 (1H, m, ArH), and 12.31 (1H, br s, NH); m/z (CI+, NHs) 316 (M+1)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:8][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 5 h
Yield: 74.3 %

Procedure:
To a solution of 4.64 g (0.04 mol) of hexanoic acid and 5.75 g (0.05 mol) of N-hydroxy succinimide in 100 mL distilled DMF, 10.3 g (0.05 mol) of DCCI was added. The mixture was cooled with an ice-water bath and stirred for 5 h. The dicyclohexyl urea (DCU) precipitate was removed by filtration, and the DMF solvent was removed by vacuum rotary evaporation. The yellow oil residue was washed with water and hexane to yield a white solid, which was vacuum dried at 78° C. to give 6.34 g (74% ) of N-hexanoyloxy succinimide. IR (KBr): 1816 cm−1 (ν(C═O) of ester), 1745-1786 cm−1 (ν(C═O) of imide). 1H-NMR (DMSO-d6, ppm): 0.86 (3H, —CH3), 1.31 (4H, —(CH2)2CH3), 1.62 (2H, —CH2CH2COO—), 2.64 (2H, —CH2COO—), 2.80 (4H, —COCH2CH2CO—).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.S(Cl)([Cl:12])=O>CN(C=O)C.C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)ccn1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: ClCc1cc(Cl)ccn1

Procedure:
A solution of 4-chloro-2-hydroxymethylpyridine (430 mg), thionyl chloride (0.43 ml) and DMF (1 drop) in chloroform (20 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated to obtain the title compound (0.44 g) as a tan powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH3:17][S:18]([Cl:21])(=[O:20])=[O:19]>ClCCl>[ClH:21].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: Fc1ccc(NCc2cccnc2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1F
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 11 g. portion of 3-(2,4-difluorophenylaminomethyl)pyridine was dissolved in 50 ml. of dichloromethane, and 4.6 ml. of methanesulfonyl chloride was added. The mixture was stirred at ambient temperature overnight. A solid had formed, which was filtered from the mixture. The filtrate was partially evaporated under vacuum, producing more solid which was removed and discarded. The filtrate was chromatographed over silica gel, eluting first with dichloromethane, then with dichloromethane:ethyl acetate, and finally with dichloromethane:methanol. The product-containing fractions were combined and evaporated to produce 1.9 g. of the desired product in the free base form. That product was dissolved in dichloromethane, with stirring, and hydrogen chloride was bubbled through the solution. Some solid formed. The mixture was diluted with 250 ml. of diethyl ether and filtered. The solids were washed with diethyl ether and dried under vacuum to obtain 2 g. of the desired product, m.p. 203°-206°.
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[CH:44]=[CH:43][CH:42]=[CH:41][C:28]=1[O:29][P:30](=[N:32][C@@H:33]([CH3:40])[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[O:31].CO>C1COCC1>[CH:37]([O:36][C:34](=[O:35])[C@@H:33]([N:32]=[P:30]([O:29][C:28]1[CH:41]=[CH:42][CH:43]=[CH:44][C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:31])[CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccccc1Cl
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccccc1OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (42 mg, 151 μmol) prepared in Preparation 6 in THF (8.00 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (377 μl, 377 μmol) dropwise. The mixture was stirred at room temperature for 15 min. followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(phenoxy)phosphorylamino)propanoate (755 μl, 377 μmol). The reaction mixture was stirred at room temperature for 1 hr, followed by the addition of THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (189 μl, 189 μmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(phenoxy)phosphorylamino)propanoate (378 μl, 189 μmol). The reaction mixture was then stirred at room temperature for 2 h. Methanol (2 mL) was added to quench the reaction, The mixture was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) and dried in vacuo to give the title compound as a light-yellow solid (18 mg, 22%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 5 h
Yield: 87.1 %

Procedure:
A mixture of 4-bromoaniline (100 g, 563.9 mmol) and 2-ethoxymethylene-malonic acid diethyl ester (126.9 g, 575 mmol) was heated to 90° C. Then, the resulting brown mixture was stirred for 5 h. After cooling to room temperature, the reaction mixture was diluted with ethanol (˜200 mL) and cooled down in an ice-water bath to afford a hard solid. This mixture was then heated to break down the hard solid and also to remove most of the impurities. After cooling the suspension in the refrigerator, the solids were collected by filtration and washed with cold ethanol. After drying in air, 168 g (87% yield) of 2-[(4-bromo-phenylamino)-methylene]-malonic acid diethyl ester was isolated as a white solid: mp 100-102° C. (lit. 100-101° C.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[NH2:6].[ClH:13].[H][H]>[Pd].C(O)C>[ClH:13].[CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: [H][H]
Reactant: CSc1cc(N)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CSc1cc(N)ccc1N

Procedure:
In a Paar hydrogenation bottle, a mixture of 3-methylthio-4-nitroaniline (7.7 g), 5% Pd/C catalyst (8.0 g), concentrated hydrochloric acid (7 ml) and ethanol (200 ml) is treated with hydrogen at 3.43 kg/cm2 for 45 minutes (until 0.8 kg/cm2 hydrogen is absorbed). The mixture is filtered through diatomaceous earth and the filtrate evaporated to dryness afford 3-methylthio-p-phenylenediamine hydrochloride. The salt is dissolved in water, the solution made alkaline (pH 9-10) with 50% sodium hydroxide and the diamine extracted with methylene chloride (3×150 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness to afford 4.75 g of title product, a brown solid, which is used as is.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.C#C.[H][H]>O>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCC(O)CC
Reactant: [H][H]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred solution of 9.81 g. (0.10 moles) of 4-hydroxy-1-hexyne and 33.5 g. (0.12 moles) of triphenylmethyl chloride in 100 ml. of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successsively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, λ mas. 3290 (acetylene hydrogen), 1600, 1030 and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17]O)=[CH:8][CH:7]=1.O.C(OCC)(=O)C>O1CCOCC1>[F:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][Br:2])=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(Cc2ccccc2CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
Phosphorus tribromide (6.4 ml, 67.3 mmol) was added dropwise to a solution of [2-(4-fluorobenzyl)phenyl]methanol (5.2 g, 24.05 mmol) in dioxane (125 ml). The reaction mixture was stirred for 1 hour at room temperature. Another portion of phosphorus tribromide (6.4 ml, 67.3 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. Water (60 ml) was added at 0° C. The reaction mixture was stirred for 30 min. Ethyl acetate (100 ml) was added. The phases were separated. The aqueous phase was washed with 1 N hydrochloric acid (100 ml). The combined aqueous phases were extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane 1:3 as eluent, to give 5.96 g of 2-(4-fluorobenzyl)benzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1cccs1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1cccs1
Yield: 74.8 %

Procedure:
38.6 g of ethyl 3-(4-fluorobenzoylamino)-3-(2-thienylcarbonyl)propionate, 100 ml of dimethylformamide and 20.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 27.4 g of ethyl 2-[2-(4-fluorophenyl)-5-(2-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C@@H:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH2:11])=[CH:4][CH:3]=1.[O:20]([CH2:24][CH2:25]Br)[CH2:21][CH2:22]Br.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C@H:10]([N:11]2[CH2:25][CH2:24][O:20][CH2:21][CH2:22]2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)Nc1ccc(Br)cc1
Reactant: BrCCOCCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)[C@@H](Cc1ccccc1)N1CCOCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
To a solution of N-(4-bromophenyl)-D-phenylalaninamide (500 mg) in N,N-dimethylformamide (5 mL) were added 1,1′-oxybis(2-bromoethane) (545 mg) and diisopropylethylamine (607 mg) and the mixture was stirred at 50° C. for 6 hours. After being cooled to 5° C., the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford (2R)—N-(4-bromophenyl)-2-morpholin-4-yl-3-phenylpropanamide (430 mg) as a powder.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1)#[N:2].C(OC([N:19]1[CH2:24][CH2:23][O:22][C@@H:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=O)(C)(C)C>>[ClH:32].[Cl:32][C:27]1[CH:26]=[C:25]([C@@H:21]2[O:22][CH2:23][CH2:24][NH:19][CH2:20]2)[CH:30]=[CH:29][C:28]=1[NH:31][C:9](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Product: Cl
Product: N#Cc1ccc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2Cl)cn1

Procedure:
In analogy to example 79, step a) using 6-cyano-3-pyridinecarboxylic acid (CAS 70165-31-0) instead of 4-cyanopicolinic acid (CAS 640296-19-1) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 341.1 ([M+H]+)
Reaction SMILES: N[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N+:5]([O-:12])=[N:4][N:3]=1.N([O-])=[O:14].[Na+].Cl>>[OH:14][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N+:5]([O-:12])=[N:4][N:3]=1
Reactant: O=N[O-]
Reactant: Nc1nn[n+]([O-])c2ccccc12
Agent: Cl
Agent: [Na+]
Product: [O-][n+]1nnc(O)c2ccccc21

Procedure:
The amino-benzotriazine N-oxide (16) is diazotized with NaNO2/HCl and the intermediate diazonium salt (not shown) is hydrolysed to form the hydroxybenzotriazine N-oxide compound (17). Reaction of the hydroxybenzotriazine N-oxide compound (17) with phosphorus oxychloride in the presence of a non-interfering base such as N,N-dimethylaniline gives the chlorobenzotriazine N-oxide compound (18). The chlorination reaction is typically carried out with heating, for example at reflux temperatures.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:21]1([C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[N:21]1[CH2:22][CH2:23][N:24]([C:9]([C:8]2[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=2[O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:11])[CH2:25][CH2:26]1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nc4ccccc4o3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example 2.3) and 2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].Br[CH:8]([CH3:12])[C:9](Cl)=[O:10].[C:13]([OH:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>O.C(N(CC)CC)C>[C:13]([S:20][CH:8]([CH3:12])[C:9]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:10])(=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(=S)c1ccccc1
Reactant: NCCC(=O)O
Reactant: CC(Br)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: CC(SC(=O)c1ccccc1)C(=O)NCCC(=O)O

Procedure:
8.9g (0.10 mol) of β-alanine was dissolved in 100 ml of water. To the solution was added 20 ml of triethylamine and then was added dropwise 22.2g (0.13 mol) of 2-bromopropionylchloride over one hour while stirring and ice-cooling. The mixture was stirred for a further 2 hours. To the mixture was added the filtrate which had been prepared by neutralizing 19.5g (0.14 mol) of thiobenzoic acid with an aqueous KOH and filtering the solution, followed by stirring overnight. Crystals precipitated were recovered by filtration, washed with water and dried to give 20.8g of N-(2-benzoylmercaptopropionyl-β-alanine. After recrystallization from benzene, the product had a melting point of 94° - 97°C.
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOC2CCCC2)cc1
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (15 mL) at ambient temperature under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 1.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 4-methoxybenzenesulphonyl chloride (2.95 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the organic phase was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate : hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (2.771 g, 79%) as an oil. H1-NMR (chloroform-D3): 1.61 (m, 8H), 3.87 (s, 3H), 4.57 (m, 1H), 6.67 (s, 1H), 6.99 (m, 2H), 7.83 (m, 2H). MS(ESI): 294 (M+Na).