Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[F:4][C:5]1[CH:6]=[C:7]([S:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1.[OH:25]OS([O-])=O.[K+].[OH2:31]>C(Cl)(Cl)Cl>[F:4][C:5]1[CH:6]=[C:7]([S:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)(=[O:25])=[O:31])[CH:8]=[CH:9][CH:10]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2cccc(F)c2)CC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2cccc(F)c2)CC1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 62.5 %

Procedure:
A mixture of basic alumina (3.0 g, 29.4 mmol) in water (0.6 mL) was stirred at 23° C. for 5 min. Next, ACN (12 mL) was added followed by a solution of tert-butyl 4-((3-fluorophenyl)thio)piperidine-1-carboxylate (1.115 g, 3.58 mmol) in CHCl3 (8 mL). Next, Oxone® (6.60 g, 10.74 mmol) was added and the reaction mixture was stirred at 60° C. for 19 h. The reaction mixture was cooled to 23° C., filtered, rinsed with CHCl3, and the filtrate was washed with water (10 mL). The organic layer was dried over Na2SO4, filtered, rinsed with CHCl3, and dried in vacuo. The crude residue was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a gradient of 10% to 100% EtOAc with 0.1% triethylamine in heptane on a 80 g silica gel column (Single Step™) gave tert-butyl 4-((3-fluorophenyl)sulfonyl)piperidine-1-carboxylate (0.769 g, 62.5%) as a white solid. ESI-MS m/z [M+Na]+ 365.9.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH2:6]([OH:10])[CH2:7][CH2:8][OH:9].C(COC)OC.[I:17]N1C(=O)CCC1=O>>[I:17][CH:4]1[CH2:5][O:1][CH2:2][CH:3]1[O:9][CH2:8][CH2:7][CH2:6][OH:10]
Reactant: OCCCO
Reactant: O=C1CCC(=O)N1I
Reactant: C1=CCOC1
Solvent: COCCOC
Product: OCCCOC1COCC1I
Temperature: 23 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a solution of freshly distilled 2,5-dihydrofuran (700 mg, 0.740 mL, 10 mmol), in a mixture of dry 1,3-propanediol/dimethoxyethane (1:1, 5 mL) at 0° C. under argon, were successively added NH4OAc (77 mg, 1 mmol), followed by N-iodosuccinimide (11 mmol, 2.47 g). The mixture was warmed to 23° C. and stirred for 12 h protected from light. The reaction was quenched by addition of sat. aq. Na2SO3 then diluted with water. The mixture was extracted with Et2O/EtOAc (1:1). The combined organic phase was dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using hexanes/EtOAc (4:1, 3:1 then 2.5:1) to give iodoalcohol 23 (1.2 g, 45%) as a pale yellow oil. TLC: Rf=0.3 (hexanes/EtOAc=1:1); 1H NMR (CDCl3, 400 MHz) δ 4.33 (m, 1H), 4.29-4.19 (m, 3H), 4.04 (dd, J=2.2, 9.8 Hz, 1H), 3.79 (dd, J=1.5, 9.8 Hz, 1H), 3.76-3.69 (m, 3H), 3.60 (m, 1H), 1.81 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 88.2, 76.1, 71.8, 67.9, 60.6, 32.3, 23.4.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([S:60](Cl)(=[O:62])=[O:61])=[CH:56][CH:55]=1>>[O:53]([C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])(=[O:62])=[O:61])=[CH:56][CH:55]=1)[CH3:52]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 65 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-methoxybenzenesulfonyl chloride as described in example 2, affording the title compound in 65% yield.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([Br:27])[CH:20]=3)(=[O:18])=[O:17])[CH:11]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:27][C:21]1[CH:20]=[C:19]([S:16]([N:12]2[CH:11]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]3[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]2=3)(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2c2ccccc2)cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=S(=O)(c1ccc(O)c(Br)c1)N1c2ccc(Br)cc2-c2ccccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A stirred suspension of 2-bromo-5-[(3-bromo-4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine (0.527 g, 0.9 mmol) and cyclohexene (2.05 g, 25 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (6 mL, 6 mmol). After stirring for approximately two hours at room temperature, the reaction was quenched with methanol (10 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous, sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude orange residue (0.5 g,). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl t-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of ethyl acetate-diethyl ether-hexane yielded the title compound (0.322 g, 0.56 mmol, 63%) as a homogeneous, colorless, crystalline solid, m.p. 237-239° C.;
Reaction SMILES: [N:1]1[CH:6]=C[CH:4]=[C:3]([B:7]([OH:9])[OH:8])[CH:2]=1.[O:10]=[C:11]1[NH:16][CH:15]=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[CH:12]1>>[N:16]1[CH:15]=[CH:14][C:13]([B:7]([OH:9])[OH:8])=[CH:12][CH:11]=1.[N:16]1[CH:4]=[C:3]([B:7]([OH:9])[OH:8])[CH:2]=[N:1][CH:6]=1.[O:10]=[C:11]1[NH:16][CH:15]=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[CH:12]1
Reactant: OB(O)c1cccnc1
Agent: NC(=O)c1ccc(=O)[nH]c1
Product: OB(O)c1ccncc1
Product: OB(O)c1cncnc1

Procedure:
The title compounds, Example 14, 15 and 16, were obtained using a procedure analogous to that described in Example 8, using pyridine-3-ylboronic acid (24 mg, 0.20 mmol), 5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (in Ex. 14, 100 mg, 0.15 mmol); pyridine-4-ylboronic acid (26 mg, 0.21 mmol), 5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (in Ex. 15, 105 mg, 0.16 mmol) and pyrimidin-5-ylboronic acid (13 mg, 0.10 mmol), 5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (in Ex. 16, 50 mg, 0.08 mmol), respectively, to afford the title compound Example 14 as a light brown solid (MS m/z: 661 (M+1); title compound Example 15 as a light yellow solid; and title compound Example 16 (MS m/z: 662 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-bromo-1-methoxy-4-(trifluoromethyl)benzene (825 mg, 3.23 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.23 mmol), potassium carbonate (1.34 g, 9.697 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloro-palladium(11) complex with dichloromethane (1:1) (158 mg, 0.193 mmol) in N,N-dimethylformamide (19 mL) was purged with argon. After 30 minutes, the reaction mixture was heated at 90° C. and stirred for 22 hours before cooling to room temperature and filtering through Celite™, washing with ethyl acetate. The filtrate was concentrated in vacuo to ˜quarter and partitioned between water (100 mL) and ethyl acetate (75 mL). The aqueous layer was extracted with ethyl acetate (2×75 mL). Combined organic layers were washed with water, aqueous lithium chloride solution, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by automated flash chromatography (24 g silica gel) eluting with hexanes:ethyl acetate (gradient 1:0 to 3:1, by volume) to afford the title compound as a clear oil, 1.1 g.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCOCC1.O>[CH2:21]([O:20][C:18]([NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCOc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Sodium hydroxide (222 mg) was added to a solution of 2-[4-(2-aminoethoxy)-phenyl]acetic acid (394 mg) (see DE-A-2250400) in 1,4-dioxane: water (1:1, by volume) (20 ml) at 0° C. The reaction mixture was stirred for 20 minutes then benzyl chloroformate (319 mg) was added to the mixture and the solution was stirred for 4 hours. Additional benzyl chloroformate (70 mg) was added to the reaction mixture and it was stirred for a further 1 hour. The solvent was removed under reduced pressure. The resulting solid was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and the product was extracted with ethyl acetate. The organic solution was dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-[4-(2-[benzyloxycarbonylamino]ethoxy)phenyl]acetic acid (375 mg) as a solid.
Reaction SMILES: [OH:1][NH:2][CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[C:27](OC(=O)C)(=[O:29])C>C1COCC1.C(O)=O>[CH:27]([N:2]([CH:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[OH:1])=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added a preformed mixture of formic acid (2 ml) and acetic anhydride (0.5 ml). The mixture was stirred at room temperature for one hour. The mixture was evaporated in vacuo and toluene (2×5 ml) was added and evaporated in vacuo. The residue was taken in CH2Cl2-methanol (6 ml, 9:1) and silica (1 g) was added. The mixture was stirred for 18 hours. The silica was filtered off and rinsed with CH2Cl2-methanol (9:1). The residue was purified on silica gel (eluant:CH2Cl2—MeOH 4%) to give the title compound as a light orange solid (220 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9].O.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[S:8]([OH:11])(=[O:10])([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(S(=O)(=O)O)cc1
Temperature: 200 °C

Procedure:
651.7 g (7.0 mol) of aniline in 1400 ml of o-dichlorobenzene were introduced into a 4 enamel stirring autoclave and 686.7 g (7.0 mol) of 100% sulphuric acid were added with stirring. The autoclave was then closed and the reaction mixture was heated to 200° C. with stirring. After 21/2 hours reaction time, the reaction mixture was cooled, poured into 1000 ml of water with stirring and neutralized with sodium hydroxide solution. Two liquid phases were obtained. After replenishing the aniline to the abovementioned value, the organic phase was added to a further batch. Pure p-sulphanilic acid was obtained from the aqueous phase by acidification using sulphuric acid. The yield amounted to 64.2%.
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].O1CCCC1>CN(C)C=O.C(#N)C>[C:11]1([NH:10][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(Nc2ccccc2)cc1
Temperature: -78 °C

Procedure:
In Scheme 1, Step A, a 2-(arylamino)-benzoic acid or diphenylamine (3) is prepared from the coupling of a suitable benzoic acid (1) and a suitable aniline (2) in the presence of a strong base, for example, lithium 1,1,1,3,3,3-hexamethyldisilazane (LiHMDS), in a polar aprotic solvent such as tetrahydrofuran, acetonitrile or dimethylformamide. For example, the aniline (2) and the benzoic acid (1) are dissolved in a suitable organic solvent and cooled to about −78° C. under nitrogen. The suspension is treated with an excess of a suitable base, such as LiHMDS, and allowed to warm to room temperature. The reaction is typically complete within about 2 hours to about 5 days. The resulting benzoic acid (3) can be isolated by removing the solvent, for example by evaporation under reduced pressure or by filtering the precipitated solid through Celite® and washing with a suitable solvent. The benzoic acid (3) can be further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=O.[C:24](O)(=O)C.N1CCCCC1.[C:34]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:20][C:21]([CH:24]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[C:34]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:22][CH:23]=1
Reactant: CC(=O)O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccccc1C=O
Reactant: COC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC(C)(C)C
Yield: 179.2 %

Procedure:
To a solution of [(5-methyl-2-phenyloxazol-4-yl) ethoxy] benzaldehyde (4.0 g, 13.1 mmol) in toluene were added acetic acid (0.41 ml, 6.5 mmol), piperidine (0.64 ml, 6.5 mmol) and tert-butyl methyl malonate (2.8 ml, 15.6 mmol). While removing water through Dean-Stark trap, the mixture was refluxed under heating for 1.5 hr. After completion of the reaction, toluene (30 ml) was added and the mixture was washed with water (20 ml×3) and saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=75:25) to give the title compound (5.4 g, yield 89%, 1:1 geometric isomer mixture) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]3)=[CH:3]1.[OH-].[Na+].[CH3:25]I>C1COCC1.O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:25])[N:5]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]3)[CH:3]=1
Reactant: CI
Reactant: O=C(O)c1cccc2cc(Cc3cc(=O)[nH]c(=S)[nH]3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(O)cc(Cc2ccc3c(C(=O)O)cccc3c2)n1
Reaction time: 15 h

Procedure:
2.30 g (7.37 mMol) 6-(6-oxo-2-thioxo-1,2,3,6-tetrahydro-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid are suspended in 160 ml THF. Then a solution of 452 mg (11.3 mMol) NaOH in 9 ml water is added, followed by 556 μl (8.93 mMol) methyliodide. After 15 h, the reaction mixture is concentrated in vacuo. The residue is used without further purification in Step 3.8. Pure title compound can be obtained by chromatography (Combi Flash; CH2Cl2→CH2Cl2/MeOH 7:1): TLC (CH2Cl2/MeOH 4:1): Rf=0.46.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:1][CH2:2][CH2:3][C:4]2([OH:7])[CH2:6][CH2:5]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCCC1(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice-cooled solution of 1-(2-hydroxyethyl)cyclopropanol (1.31 g) and pyridine (4 ml) in dichloromethane (20 ml) was added p-toluenesulphonyl chloride (4.7 g). The mixture was then stirred at room temperature under an atmosphere of nitrogen for 5 hours before being partitioned between ether (100 ml) and water. The organic layer was washed consecutively with 1N hydrochloric acid, water, 5% sodium hydrogen carbonate solution, and brine, and dried. Concentration in vacuo gave a residue which was purified by chromatography (150 g silica gel; 40% ethyl acetate in petroleum ether as eluant) to give the 1-(2-p-toluenesulphonyloxyethyl)cyclopropanol [E; n=1, R1 +R2 =--(CH2)2 --] as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([C:31]([OH:33])=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([C:31]([N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:33])[CH2:27]1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (1,594 mg), (R)-Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 1,270 mg, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,480 mg), dimethyl aminopyridine (1,030 mg) in 110 ml dichloromethane was stirred at room temperature overnight. After addition of water (75 mL), the mixture was extracted with ethyl acetate (100 mL 3). The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography on silica (33-50% ethyl acetate in hexane) and received as an oil: MS (m+1)=467.3.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc(C(F)(F)F)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1NCCC(=O)c1ccccc1
Yield: 93.6 %

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-6-trifluoromethyl-1-(tert-butyloxycarbonyl)indole (200 mg, 0.407 mmol) from above in methylene chloride. Add trifluoracetic acid and stir overnight at room temperature. Concentrate the reaction in vacuo, dilute with ethyl acetate and rinse with saturated sodium bicarbonate, dry over magnesium sulfate, filter and concentrate in vacuo to yield 3-[(phenacyl)methylamino]-2-carbethoxy-6-trifluoromethylindole as a foam (154 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[N:6]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH:7]=1
Reactant: C=CS(C)(=O)=O
Reactant: O=c1[nH]cc(Br)cc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CS(=O)(=O)CCn1cc(Br)cc(N2CCOCC2)c1=O
Yield: 98 %

Procedure:
Method 1 was followed using 5-bromo-3-morpholinopyridin-2(1H)-one (1.0 equiv.), (methylsulfonyl)ethene (1.2 equiv.) and cesium carbonate (1.2 equiv.) at room temperature to give 5-bromo-1-(2-(methylsulfonyl)ethyl)-3-morpholinopyridin-2(1H)-one in 98% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.92 (s, 3H) 3.09-3.23 (m, 4H) 3.53 (t, J=6.65 Hz, 2H) 3.78-3.96 (m, 4H) 4.32 (t, J=6.65 Hz, 2H) 6.69 (s, 1H) 7.23 (d, J=2.35 Hz, 1H). LCMS (m/z) (M+H)=365.1/366.9, Rt=0.57 min.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (78 mg, 79%), MS (ISP) m/z=399.4 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and isobutyric acid.