Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:15])=[C:7]([CH3:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]=[S:3].[NH3:16]>ClCCl>[CH3:14][C:7]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([NH:1][C:2]([NH2:16])=[S:3])[S:5][C:6]=1[CH3:15]
Reactant: CCOC(=O)c1c(N=C=S)sc(C)c1C
Reactant: N
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(N)=S)sc(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
To a solution of ethyl 2-isothiocyanato-4,5-dimethylthiophene-3-carboxylate (Example 50b) (1.21 g, 5.27 mmol) in dichloromethane (10 mL) was added ammonia (7 M in MeOH, 1.12 mL, 7.91 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 3 h, quenched with water and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The dark orange residue was purified by chromatography on silica gel (Gradient 0-50% EtOAc in Hexanes) to give the title compound (37.1 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H, J=7.1 Hz), 2.18 (s, 3H), 2.19 (s, 3H), 4.30 (q, 2H, J=7.1 Hz), 8.43 (s, 2H), 11.38 (s, 1H). MS 259 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH3:32]
Reactant: CCI
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a mixture of ethyl 7-[(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carboxylate (2.89 g), potassium carbonate (1.2 g) and N,N-dimethylformamide (25 ml) was added dropwise a solution of ethyl iodide (0.67 ml) in N,N-dimethylformamide (2 ml) under ice-cooling. The mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oil was crystallized from ethyl acetate-hexane, and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (2.16 g, yield 70%) as colorless prism crystals. melting point 148-149° C.
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][C:13]2[O:14][C:15]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][CH2:25][CH3:26])[C:16]=3[C:17]=2[CH3:18])=[CH:10][CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[O:14][C:15]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][CH2:25][CH3:26])[C:16]=3[C:17]=2[CH3:18])=[CH:27][CH:28]=1
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCCc1c(O)ccc2oc(Cc3ccc(O)cc3)c(C)c12
Reaction time: 0.25 h

Procedure:
Under nitrogen, ethanethiol (3.1 gm; 50 mmoles) was added dropwise over 5 minutes to a mixture of 99% sodium hydride (1.2 gm; 50mmoles) in dimethylformamide (100 mL). After stirring for 15 minutes, a solution of 2-(4-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (2.1 gm; 6.7mmoles) in dimethylformamide (DMF) (25 mL) was added in one portion. The mixture was refluxed for 1.5 hours, cooled, acidified with 20% citric acid and extracted with ether. The ether solution was washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting oil crystallised on standing at room temperature overnight. The crystals were slurried with hexane, filtered, washed with hexane, and air dried to yield 2-(4-hydroxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp. 138°-142° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([Cl:16])[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O1CCOCC1.Cl>O>[ClH:16].[CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1
Reactant: CN1CCNCC1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)c([N+](=O)[O-])c21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(N(C)C)c3c2[N+](=O)[O-])CC1
Yield: 83.7 %

Procedure:
A mixture of 3.3 g of 1-dimethylamino-7-chloro-6-fluoro-8-nitro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 3.1 g of 1-methylpiperazine and 25 ml of dioxane is refluxed for 3 hours. The solvent is stripped off in vacuo, the residue is suspended in 25 ml of H2O and the pH is brought to 1 with 10% strength hydrochloric acid. The precipitate is filtered off with suction in the cold and washed with a little cold 10% strength hydrochloric acid and ethanol. 3.6 g of 1-dimethylamino-6-fluoro-8-nitro-7-(4-methyl-1-piperazinyl)1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of decomposition point 292°-294° C. are obtained.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][NH2:12])=[CH:6][C:5]=1[Br:13].[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH:31]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>>[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1/[CH:31]=[N:12]/[O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:14])=[C:5]([Br:13])[CH:6]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cc2ccccc2n1Cc1ccccc1
Reactant: COC(=O)c1ccc(CON)cc1Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CO/N=C/c2cc3ccccc3n2Cc2ccccc2)cc1Br
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a solution of 4-aminooxymethyl-2-bromo-benzoic acid methyl ester (0.21 g, 0.81 mmol) and 1-benzyl-1H-indole-2-carbaldehyde (0.19 g, 0.81 mmol) in 10/5/3 tetrahydrofuran/ethanol/water (18 mL) was added 2.5 M sodium hydroxide solution (3 mL). This mixture was heated to reflux for 3 hours and then allowed to cool back to room temperature. The mixture was concentrated to approximately 1/4 volume and partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 1 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80 with 1% formic acid) to give 4-[({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino }oxy)methyl]-2-bromobenzoic acid (0.19 g, 51%) as an off-white powder. mp=148-149° C. 1H NMR (400 MHz, DMSO-d6); δ 13.35 (bs, 1H), 8.51 (s, 1H), 7.66 (m, 2H), 7.60 (d, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 7.21-7.15 (m,4H), 7.06 (t, 1H), 6.93 (s, 1H), 6.90 (d, 2H), 5.70 (s, 2H), 5.14 (s, 2H). Mass spec; (ES+) m/z 462.9, (ES−) m/z 461.3. Elemental analysis; Calculated for C24H19BrN2O3: C, 62.22; H, 4.13; N, 6.05. Found: C, 62.07; H, 4.38; N, 5.88.
Reaction SMILES: ClC(OCC)=O.[O:7]1[C:11]([C:12](O)=O)=[CH:10][CH:9]=[N:8]1.C(N(CC)CC)C.[NH2:22][C:23]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>O1CCCC1>[O:7]1[C:11]([C:12]2[NH:22][C:23]3[C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=3[N:32]=2)=[CH:10][CH:9]=[N:8]1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccno1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2nc(-c3ccno3)[nH]c12
Temperature: -10 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of 0.81 g (7.5 mmol) of ethyl chloroformate in 5 ml of tetrahydrofuran was added dropwise to a solution of 0.85 g (7.5 mmol) of isoxazole-5-carboxylic acid and 3.79 g (37.5 mmol) of triethylamine in 50 ml of tetrahydrofuran at −10° C. After stirring at −10° C. for 1 hour, 1.68 g (7.5 mmol) of 2,3-diaminobenzamide were added. The reaction mixture was stirred at room temp. for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate. The residue obtained after concentration in vacuo was taken up in 10 ml of glacial acetic acid and stirred at 100° C. for 60 minutes. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in isopropanol, and the precipitate produced with petroleum ether was filtered off, washed with petroleum ether and dried in vacuo at 35° C. 120 mg of yellow crystals were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCc1ccc(Cl)c(Cl)c1
Yield: 84.3 %

Procedure:
To a solution of 3,4-dichlorobenzylamine (3.97 g) and triethylamine (3.5 ml) in chloroform (80 ml) was added a solution of 2-nitrobenzenesulfonyl chloride (5 g) in chloroform (20 ml) at 0° C. with stirring and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed successively with diluted hydrochloric acid and water, and then dried. Evaporation of the solvent gave N-(3,4-dichlorobenzyl)-2-nitrobenzenesulfonamide (6.87 g).
Reaction SMILES: [OH-].[Na+].O.[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH3:6].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C(OCC)C>[Cl:10][CH2:11][C:12]([NH:4][C@H:5]([C:7]([OH:9])=[O:8])[CH3:6])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: C[C@H](NC(=O)CCl)C(=O)O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Into a 5-liter, 4-neck, round-bottom flask equipped with a mechanical stirrer, pH probe, thermometer, two 1-liter addition funnels and a nitrogen bubble were charged 157 g (3.93 mole) of sodium hydroxide and 1800 ml of water followed by 350 g (3.93 mole) of L-alanine. After all the solids dissolved, 600 ml of diethyl ether was added and solutions of chloroacetyl chloride (500 g, 4.43 mole) in 600 ml of diethyl ether and dilute sodium hydroxide (225 g in 500 ml water) were added concomitantly while maintaining the pH at about 11 and the temperature at about 0° C. by external cooling. The resulting mixture was allowed to warm to room temperature, and the ether layer separated. The aqueous layer was acidified with concentrated hydrochloric acid to pH 1 and extracted with four 1-liter portions of ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate and rotoevaporated to yield 550 g (85%) of 2-chloroacetyl-(L)-alanine as a white crystalline solid, melting point (mp) 93°-96° C. This material can be purified by recrystallization from ethyl acetate, but this is not necessary for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:27]=[CH2:28])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Yield: 68.4 %

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (3 g, 7.2 mmol), tributyl(vinyl)stannane (2.73 g, 8.64 mmol) and Pd(PPh3)4 (1 g, 0.87 mmol) in toluene (100 mL) was heated to reflux for 3 h. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by column chromatography to afford (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (1.8 g, 68%). 1H NMR (CDCl3): 1.32 (m, 1H), 1.46 (m, 3H), 1.65 (m, 1H), 1.84-2.22 (m, 5H), 2.78 (m, 1H), 3.51 (m, 2H), 5.12 (m, 1H), 5.59 (m, 2H), 6.54 (m, 1H), 6.78 (m, 1H), 7.07 (m, 1H), 7.16 (m, 1H), 7.18-7.32 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N+:43]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[NH2:52])([O-:45])=[O:44]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:52][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:46]=1[N+:43]([O-:45])=[O:44])=[O:9]
Reactant: Nc1cnccc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cnccc1[N+](=O)[O-])c1cc(Br)ccc1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Method C—Step a To a mixture of 5-Bromo-2-chlorobenzoic acid (5.00 g, 21.23 mmol) in DMF (40 mL), HATU (8.48 g, 22.29 mmol) and triethylamine (2.97 mL, 21.44 mmol) were added. After 30 min stirring at room temperature 4-nitro-pyridin-3ylamine (2.36 g, 16.99 mmol) was added, the reaction mixture stirred at 40° C. overnight and solvent removed. The crude was then diluted with EtOAc (40 mL) and washed first with saturated Na2CO3 solution (6×30 mL) then 1N HCl (3×30 mL). The organic layer was dried over Na2SO4, filtered and left standing. The precipitate obtained was filtered to get 4.75 g of the title compound (63%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C.Cl>[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: BrCc1ccccc1Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cc2ccccc2)CCCC1=O
Reaction time: 0.05 h
Yield: 36.5 %

Procedure:
40% Methanolic Triton B (0.95 mL, 2.1 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (510 mg, 2.1 mM) in 30 mL of DMF at −10° C. After 3 minutes, 2-benzylbenzyl bromide (548 mg, 2.1 mM) was added and the resultant mixture stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate and 1 N HCl, washed twice with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The reside was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 324 mg (36%) of the 9-[(2-benzylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.45-7.0 (m, 10H), 6.9 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.2 (s, 2H), 4.15 (s, 2H), 4.05 (s, 3H), 2.5 (m, 4H), and 2.1 (m, 2H). IR (KBr, cm−1) 1726, 1653, 1466, 1443, 1411, 1283, 1200, 1119, and 749. MS (ES) m/e 422, 424.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:46][C:47]([CH2:49][NH2:50])=[O:48])=[CH:41][CH:40]=1>ClCCl.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[NH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([C:18]([NH:50][CH2:49][C:47]([O:46][CH2:45][C:42]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1)=[O:48])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
A solution of WSC (34 g.) in dichloromethane (50 ml.) was added dropwise to a suspension of BOC-Leu-OH (46.2 g.), HOBT (1 g.) and H-Gly-OBzl.TosOH (74 g.) in DMF (100 ml.) and dichloromethane (200 ml.) with stirring at -5° C. for 1 hour. After 1 hour, the solution was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to remove dichloromethane. To the DMF layer was added water and the mixture was extracted with ethyl acetate (1 l.), and again with the same solvent (500 ml.). The ethyl acetate layer was washed with 1 N HCl, water, 5% sodium bicarbonate and water, in this order and dehydrated with sodium sulfate (anhydrous), then concentrated in vacuo to obtain oily BOC-Leu-Gly-OBzl (82 g.) Rf = 0.68.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:7][C:6]([CH2:10][C@H:11]([CH3:29])[CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[Si](CC)(CC)CC)([OH:9])[CH2:5][CH2:4]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([CH2:12][C@@H:11]([CH3:29])[CH2:10][C:6]2([OH:9])[CH2:7][CH2:8][C:3]([N:2]([CH3:36])[CH3:1])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:4][CH2:5]2)=[CH:14]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccccc2c1C[C@@H](C)CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Cc1c[nH]c2ccccc12)CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Reaction time: 4 h

Procedure:
A solution of (R)-4-dimethylamino-1-[2-methyl-3-(2-(triethylsilyl)-1H-indol-3-yl)propyl]-4-phenylcyclohexanol (175 mg, 0.34 mmol) in anhydrous tetrahydrofuran (30 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (109 mg, 0.34 mmol) and stirred for 4 h with reflux. The reaction mixture was then concentrated to low volume in a vacuum and the residue was purified by flash chromatography (10 g, 20×1.5 cm) with ethyl acetate/methanol (95:5).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([CH:25]1[CH2:27][CH2:26]1)[CH2:23][OH:24]>>[CH:25]1([CH:22]([NH:21][C:12]([C:10]2[CH:9]=[N:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:23][OH:24])[CH2:27][CH2:26]1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(CO)C1CC1
Product: O=C(NC(CO)C1CC1)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and β-amino-cyclopropaneethanol (CAN 776315-67-4, 78.94 mg, 0.53 mmol) as starting materials, and isolated (20 mg, 14.91%) as light brown solid; LC-MS (UV peak area, ESI) 97.84%, 368.9 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)(=[O:9])=[O:8].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(NCCCCO)c1cccc(Br)c1
Product: O=S(=O)(NCCCCO)c1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Using a method analogous to that described in Example 40, 3-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethylphenyl boronic acid were reacted to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][OH:28])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)c1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (1 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (943 mg). CHCl3 was used for recrystallization.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH2:10]Br.[OH:17][C:18]1[N:19]=[C:20]([S:36][CH3:37])[N:21]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([O:30][CH3:31])=[O:29])[C:22](=[O:24])[CH:23]=1>>[F:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH2:10][O:17][C:18]1[N:19]=[C:20]([S:36][CH3:37])[N:21]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([O:30][CH3:31])=[O:29])[C:22](=[O:24])[CH:23]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(SC)nc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(C)c(-n2c(SC)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of methyl 3-[4-hydroxy-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (1.0 g, 0.0033 mol) in DMF (10.0 mL) obtained from step 2, was added potassium carbonate (0.7 g, 0.005 mol) followed by the addition of 2,4difluorobenzyl bromide (0.8 g, 0.0039 mol) and stirred at 0° C. for 15 min. After stirring at room temperature for 30 min, DMF was distilled in vacuo and the residue was portioned between EtOAc (25 mL) and water (25 mL). The organic phase was washed with water, (2×20 mL), dried (Na2SO4) and concentrated. The resulting material was purified by flash chromatography using EtOAc/hexane (1:1 v/v) to afford the title compound (0.9 g, 64%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.08 (dd, 1H, J=8.4 Hz, & 1.6 Hz), 7.83 (d, 1H, J=1.6 Hz), 7.55 (m, 2H), 6.99 (m 2H), 5.64 (s, 1H), 5.48 (s, 2H), 3.89 (s, 3H), 2.50 (s, 3H), and 2.15 (s, 3H); ES-HRMS m/z 433.1016 (M+H calcd for C21H19N2O4SF2 requires 433.1028).