Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].Cl.[CH2:11]([C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH3:12].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:11]([C@H:13]1[CH2:18][N:17]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:26]([F:28])([F:29])[F:27])[C:30]([F:31])([F:32])[F:33])=[CH:21][CH:20]=1)[CH3:12]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC[C@H]1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 19 h
Yield: 17.2 %

Procedure:
2-Thiophenesulfonyl chloride (0.28 g, 1.5 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a stirring solution of 2-(4-((2S)-2-ethyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol hydrochloride (0.55 g, 1.5 mmol), Hünig's base (0.81 mL, 4.6 mmol), and DMF (7.7 mL) at room temperature. After 19 h, the reaction mixture was partitioned between EtOAc (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4) and purified via column chromatography (40 g of silica, 20 to 33% EtOAc in hexanes) to give 2-(4-((2S)-2-ethyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.13 g) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J=5.1 Hz, 1H), 7.59-7.49 (m, 3H), 7.19-7.13 (m, 1H), 6.83 (d, J=8.0 Hz, 2H), 3.77 (d, J=11.0 Hz, 3H), 3.49 (d, J=12.7 Hz, 1H), 3.32 (dt, J=3.1, 11.9 Hz, 1H), 3.24 (s, 1H), 2.74-2.51 (m, 2H), 1.89 (ddd, J=7.3, 9.3, 14.0 Hz, 1H), 1.60-1.47 (m, 1H), 0.94 (t, J=7.4 Hz, 3H); m/z (ESI, +ve ion) 503.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.679 μM; GK-GKRP EC50 (LC MS/MS)=1.37 μM.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[NH:6][C:5]1=[O:12])[C:2]#[CH:3].[I:13]N1C(=O)CCC1=O.CC(C)=O>C(Cl)(Cl)(Cl)Cl.O.[N+]([O-])([O-])=O.[Ag+]>[I:13][C:3]#[C:2][CH2:1][N:4]1[C:8](=[O:9])[C:7]([CH3:10])([CH3:11])[NH:6][C:5]1=[O:12]
Reactant: C#CCN1C(=O)NC(C)(C)C1=O
Reactant: O=C1CCC(=O)N1I
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)NC(=O)N(CC#CI)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(2-propynyl)-5,5-dimethylhydantoin (1 g, 60 mmole) in CCl4 (20 mL) at room temperature was added N-iodosuccinimide (1.6 g, 7.1 mmole). Dry acetone was added until all materials were dissolved. To the above clear solution was added silver nitrate (0.1 g, 0.58 mmole) and the reaction mixture was stirred at room temperature for 2 hr. The mixture was diluted with water (60 mL) and was extracted with ethyl acetate (3×50 mL). The organic layer was washed with saturated sodium chloride solution (75 mL) and dried with sodium sulfate. After filtering off drying agent and evaporating the solvents, a light yellow solid of 3-(3-iodo-2-propynyl)-5,5-dimethylhydantoin was obtained, 1.6 g (91%), mp=118°-126° C. An NMR spectrum also showed the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[ClH:1].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:30])=[CH:27][CH:26]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C(c1ccc(Cl)cc1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 L, 0.29 mmol) were dissolved in THF (2 ml) and stirred at room temperature. 4-Chlorobenzoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was quenched with H2O (200 mL). The resulting precipitate was filtered, and dried overnight under vacuum. The HCl salt was formed via dissolving the precipitate in MeOH (2 ml) and adding 1 M HCl/ether (2 equivalents), and cooling at 0° C. overnight. The resulting precipitate was filtered, and dried under vacuum to provide 18 (54 mg, 59% yield) as a yellow powder. LC-MS (M+H=346, obsd.=346).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH:10]1[CH2:12][O:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].C(OC)=O.CO>O>[CH3:1][N:2]([CH2:9][CH:10]([OH:11])[CH2:12][N:13]=[N+:14]=[N-:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CC1CO1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: CN(CC(O)CN=[N+]=[N-])c1ccccc1
Yield: 91.1 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 1.65 g of N-methyl-N-phenylaminomethyloxirane (prepared as described in Preparation 88), 3.29 g of sodium azide, 15 ml of methyl formate and 63 ml of an 8:1 by volume mixture of methanol and water were used, to give 1.9 g of the title compound as a pale yellow oil having an Rf value of 0.09 (on silica gel thin layer chromatography, using a 1:15 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:36])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:36])[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1)OCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl {[trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.49 g, 0.00374 mol) in DMF (0.6 mL) was added NIS (1.0 g, 0.0045 mol). The reaction mixture was stirred at 55° C. overnight then diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude mixture thus isolated was chromatographed over silica gel eluting with hexane→hexane:EtOAc 1:1 to afford 1.7 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]([F:19])([F:18])[F:17].[CH:21](OC)(OC)OC.FC(F)(F)C(O)=O>CO>[F:18][C:16]([F:19])([F:17])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:7]2=[N:6][C:5]([OH:20])=[CH:4][CH:3]=[C:2]2[N:1]=[CH:21]1
Reactant: Nc1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Reactant: COC(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Oc1ccc2ncn(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a solution of 5-amino-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (75.0 mg, 0.26 mmol) dissolved in MeOH was added trimethyl orthoformate (1.0 mL, 9.05 mmol) and catalytical amount of trifluoroacetic acid. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (78 mg). LCMS m/z=296.0 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ ppm 6.63 (d, J=8.6 Hz, 1H), 7.66 (m, 3H), 7.81 (d, J=7.6 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 10.60-11.20 (broad s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]([Mg]Br)[CH:19]=[CH2:20]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([CH:14]([CH3:16])[CH3:15])([OH:17])[CH2:20][CH:19]=[CH2:18])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)CCN[C@@H](C)c1ccc(Br)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of (S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (740 mg, 2.5 mmol) in THF (25 mL) was added dropwise allylmagnesium bromide (25 mL, 25 mmol) under N2 at −78° C. The reaction mixture was stirred at −78° C. for 2 h, quenched by addition of satd aq NH4Cl, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and filtered. The solvent was removed under vacuo to give 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg, 95% yield), which was used directly in the next step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[H][H].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Sc1ccccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Sc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
A dry 500 ml round bottom flask, equipped with a magnetic stirring bar and maintained under static argon atmosphere, was charged with sodium hydride (4.55 g, 113 mmol) in mineral oil (60% by weight) and dry THF (80 ml). To this well-stirred slurry, maintained at 0° C. in an ice bath, was added o-bromothiophenol (18.7 g, 99 mmol). Reaction was rapid with vigorous hydrogen evolution. After 15 min, tert-butyldimethylsilyl chloride dissolved in 35 ml of THF was added dropwise (15 min). The resulting mixture was stirred overnight, and the precipitated sodium chloride was filtered off. Volatile materials were first distilled under atmospheric pressure to provide the crude product (17 g) as a pale yellow oil. This was further purified by vacuum distillation under argon, bp 99°-100° C. (0.4 mm), to furnish o-bromo-(S-tert-butyldimethylsilyl)benzenethiol as a colorless liquid (14.4 g, 48% yield); HPLC: 96% pure. 1H NMR (300 MHz) was consistent with the structure:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]2)[CH3:1])=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CNC[C@H]1CC[C@H](CO)CC1
Product: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in examples 1.7, trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) was acylated with 4-chlorophenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] giving trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 311 (M+).
Reaction SMILES: [C]=O.[H][H].[CH3:5][C:6]1[C:11]2CO[C:14](=[O:15])[C:10]=2[C:9](O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)=[C:8]([CH2:29]/C=C(/CCC(O)=O)\C)[C:7]=1OC.C(C1CC2CC1CC2C=O)#[N:41]>>[C:29]([CH:8]1[CH2:7][CH:6]2[CH2:5][CH:9]1[CH:10]([CH:14]=[O:15])[CH2:11]2)#[N:41]
Reactant: N#CC1CC2CC1CC2C=O
Reactant: [H][H]
Reactant: COc1c(C)c2c(c(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: [C]=O
Product: N#CC1CC2CC(C=O)C1C2
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Next, the inside of the autoclave was sufficiently substituted by nitrogen, and then sufficiently substituted by a gas mixture having a volume ratio of carbon monoxide to hydrogen of 50/50. The same gas was injected until a pressure in the autoclave reached 0.6 MPaG, and the adjustment liquid was heated to 100° C. under stirring, thereby initiating a hydroformylation reaction. Since the pressure in the autoclave decreased with proceeds of the reaction, the gas mixture was continuously supplied so that the pressure was maintained at 0.6 MPaG, the temperature was adjusted so as to be maintained at 100° C., and the hydroformylation reaction was carried out for 6 hours. After the completion of the reaction, the gas mixture in the system was purged using nitrogen, and 276.7 g of a reaction liquid including 2-cyano-5-formyl bicyclo[2.2.1]heptane and 2-cyano-6-formyl bicyclo[2.2.1]heptane was obtained. An analysis showed that the reaction liquid contained 261.8 g (1.76 mol) of the compounds.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:49].[ClH:50].O1CCOCC1>CO.[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[ClH:50].[BrH:49]
Reactant: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCNC(=N)N

Procedure:
6.3 g of Z-Arg-Phe-Ser(tBu)-Gly-OCH3 hydrobromide (8.5 mmols) are dissolved in 350 ml of methanol and 2.9 ml of hydrogen chloride in dioxane (3.09 N, 8.9 mmols) are added. The mixture is hydrogenated in the presence of 1.2 g of 10 % strength palladium-charcoal at room temperature and atmospheric pressure. After completion of the hydrogen uptake the solution is filtered and evaporated and the resulting residue is dissolved in 30 ml of methanol and the solution stirred into 700 ml of ether. Thereby a yellowish paste is produced which is again dissolved and precipitated in the same manner.
Reaction SMILES: S(=O)(=O)(O)N.[C:6]1([S:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])=[O:22].[Na+].[OH2:25]>CC(C)=O>[C:6]1([S:12]([C:13]2[CH:20]=[CH:19][C:16]([C:17]([OH:22])=[O:18])=[CH:15][CH:14]=2)=[O:25])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(Sc2ccccc2)cc1
Reactant: [O-][Cl+][O-]
Reactant: O
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Sulphamic acid (0.272 g, 2.80 mmol) in 2 mL water was added to 4-phenylsulfanyl-benzaldehyde (0.2 g, 0.93 mmol) in 5 mL acetone at 0° C. After 5 minutes, sodium chlorite (0.338 g, 3.74 mmol) was added and the mixture stirred at 0° C. for 30 minutes. Sodium chlorite (0.676 g, 7.48 mmol) was then added and the resulting mixture was stirred at room temperature overnight. Water was then added and the resulting solid was filtered to afford 140 mg (60% yield) of 4-benzenesulfinyl-benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:38])[C:19]([C:35](O)=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[CH:16][C:15]=2[F:39])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:42](CC)CC)C.ClC(OC(C)=C)=O.[OH-].[NH4+]>ClCCl.C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:38])[C:19]([C:35]([NH2:42])=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[CH:16][C:15]=2[F:39])[CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(CC)CC
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)nc32)c(OC)c1
Agent: C=C(C)OC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C(N)=O)c(=O)c3cc(F)c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)nc32)c(OC)c1
Reaction time: 0.5 h

Procedure:
A suspension of EXAMPLE 75B (350 mg) and triethylamine (0.098 mL) in dichloromethane (4 mL) and THF (3 mL) at 0° C. was treated with isopropenyl chloroformate (0.077 mL), stirred for 30 minutes, treated with concentrated ammonium hydroxide (0.100 mL), stirred for 18 hours at ambient temperature, loaded onto a flash silica gel column, and eluted with a methanol/dichloromethane gradient.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[O:5][CH:6]=1.[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:11]([OH:10])[C:12]([Cl:15])([Cl:14])[Cl:13])=[O:8])[O:5][CH:6]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NC(=O)c1cc(Br)co1
Solvent: Cc1ccccc1C
Product: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Temperature: 95 °C

Procedure:
A mixture of 4-bromofuran-2-carboxamide 124 (0.85 g, 4.47 mmol) and chloral (0.78 mL) in xylene was heated at 95° C. for 1.5 hours. The mixture was concentrated to give 4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide 125 as a tan solid that was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH2:15])=[S:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH:18]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=O.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[S:14][C:18]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)CNC(=O)OCc1ccccc1
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2nc(CNC(=O)OCc3ccccc3)sc2-c2cccnc2)cc1
Reaction time: 2 h
Yield: 60.3 %

Procedure:
In 40 ml of acetonitrile was dissolved 1.12 g of benzyloxycarbonylaminothioacetamide. In the solution was suspended 2.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added while stirring 0.8 ml of triethylamine. The mixture was stirred for 2 hours under reflux. The resultant was left standing for cooling, then the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and, then, the solvent was evaporated off. The residue was recrystallized from ethyl acetate-isopropylether to give 1.3 g (yield 56%) of 2-(benzyloxycarbonylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 93°-94° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.C(S)C.COC1C=CC(C2SC3C=CC=CC=3C=2CC2C=CC(O)=CC=2)=CC=1>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Agent: COc1ccc(-c2sc3ccccc3c2Cc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.9 g. (0.12 mole) of sodium hydride in oil were added 13 g. (0.035 mole) of 2-(4-methoxyphenyl)-3-(4-methoxybenzoyl)benzothiophene (prepared as in Example 13) dissolved in DMF. The resulting mixture then was added to a cold solution of DMF containing 7.5 g. of ethyl mercaptan. The mixture was stirred at 70° C. for two hours and was monitored by TLC until little or no starting material remained. The total reaction time was about two hours. The mixture then was concentrated to dryness, water was added, and the aqueous mixture was acidified and extracted with ethyl acetate. The ethyl acetate extract was washed, dried over magnesium sulfate, and evaporated to a residue. The residue was recrystallized from benzene to obtain 9.1 g. (73 percent) of 2-(4-methoxyphenyl)-3-(4-hydroxybenzyl)benzothiophene, melting point 188°-189° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@H:45]([C:48]([OH:50])=O)[CH2:46][OH:47])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:51]([O:55][C:56](=[O:61])[NH:57][CH2:58][CH2:59][NH2:60])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@@H:45]([CH2:46][OH:47])[C:48]([NH:60][CH2:59][CH2:58][NH:57][C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:61])=[O:50])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.05 g (2.759 mmol) of HATU and 648.3 mg (5.016 mmol) of N,N-diisopropylethylamine are added to a solution of 600 mg (2.5 mmol) of N-[(benzyloxy)carbonyl]-L-serine in 25 ml of anhydrous DMF. After stirring at RT for 15 min, 442.0 mg (2.76 mmol) of tert-butyl(2-aminoethyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=O)(=[O:15])[CH3:14].Cl.[NH2:28][CH2:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1)=[O:31].ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O>[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([NH:28][CH2:29][C:30](=[O:31])[NH:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:34]=1)=[O:21])(=[O:15])[CH3:14]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: NCC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)NCC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
WSC.HCl (95.9 mg, 0.5 mmol) was added to a solution of 2-acetoxy-5-chlorobenzoic acid (59.1 mg, 0.28 mmol), 2-amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide hydrochloride (80.8 mg, 0.25 mmol) and 1-hydroxybenzotriazole (37.2 mg, 0.28 mmol) in N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:2→1:1) to give the title compound (83.7 mg, 69.3%) as a white crystal.