Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]([F:13])[C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[Br:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[CH:18][C:17]=1[S:25](Cl)(=[O:27])=[O:26].[OH:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[NH2:33]>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([NH:33][C:32]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:30]([OH:29])[CH:31]=2)(=[O:10])=[O:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[Br:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[CH:18][C:17]=1[S:25]([NH:33][C:32]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:30]([OH:29])[CH:31]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)c(F)c1F
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1Br
Reactant: COc1ccc(N)cc1O
Product: COc1ccc(NS(=O)(=O)c2cc(Br)c(F)c(F)c2F)cc1O
Product: COc1ccc(NS(=O)(=O)c2cc(F)c(F)c(F)c2Br)cc1O

Procedure:
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene and 1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)amino-sulfonyl]benzene were prepared in a manner similar to that described above, beginning with a mixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example B) and 2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example C) and 3-hydroxy-4-methoxyaniline. The two isomeric compounds were separated by column chromatography (silica gel; ethyl acetate:hexanes, 1:4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Product: C[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 2,2-dimethylpropanoyl chloride (18 mg, 150 μmol). Yield 17 mg (74%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]([CH3:7])[C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([C:14](=[O:61])[C@@H:15]([CH2:46][CH2:47][C:48]([F:60])([F:59])[C:49]([F:58])([F:57])[C:50]([F:56])([F:55])[C:51]([F:54])([F:53])[F:52])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]2[CH2:42][C:41]3[CH:40]=[C:39]([O:43][CH3:44])[CH:38]=[CH:37][C:36]=3[C@@H:35]3[C@@H:26]2[C@H:27]2[C@@:31]([CH2:33][CH2:34]3)([CH3:32])[C@@H:30]([OH:45])[CH2:29][CH2:28]2)[C:3]1=[O:62].[OH-:63].C([N+](CCCC)(CCCC)CCCC)CCC.OO>COCCOC>[OH:45][C@H:30]1[CH2:29][CH2:28][C@H:27]2[C@H:26]3[C@H:35]([CH2:34][CH2:33][C@:31]12[CH3:32])[C:36]1[CH:37]=[CH:38][C:39]([O:43][CH3:44])=[CH:40][C:41]=1[CH2:42][C@H:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([CH2:46][CH2:47][C:48]([F:59])([F:60])[C:49]([F:58])([F:57])[C:50]([F:56])([F:55])[C:51]([F:52])([F:53])[F:54])[C:14]([OH:61])=[O:63].[CH3:1][N:2]1[C@@H:6]([CH3:7])[C@@H:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:4][C:3]1=[O:62]
Reactant: [OH-]
Reactant: COc1ccc2c(c1)C[C@@H](CCCCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C(=O)N(C)[C@@H](C)[C@H]1c1ccccc1)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OO
Solvent: COCCOC
Product: COc1ccc2c(c1)C[C@@H](CCCCCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Product: C[C@H]1[C@@H](c2ccccc2)NC(=O)N1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %
Yield: 100 %

Procedure:
(4S,5R)-3,4-Dimethyl-1-[(2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl]-5-phenylimidazolidin-2-one (445 mg, 0.50 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (5 ml) under nitrogen atmosphere and then cooled to 0° C. To this solution, tetra-n-butylammonium hydroxide solution (40% w/w, 649 mg, 1.0 mmol) and aqueous hydrogen peroxide (30% w/w, 113 mg, 1.0 mmol) were added, and the resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was quenched with saturated aqueous sodium thiosulfate, acidified with saturated aqueous potassium bisulfate, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure using an evaporator and the resulting residue was purified by silica gel column chromatography (Wako gel C-200, eluent: ethyl acetate/n-hexane=4/6→8/2) to give (2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid (360 mg, Yield 100%) and (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one (93 mg, Yield 98%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[NH:1][C:2]([CH3:7])([CH2:3][CH2:4][OH:5])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(N)CCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a 150-mL round-bottomed flask was added 3-amino-3-methyl-butan-1-ol (2.18 mL, 19.39 mmol, Tyger Sci. Inc) and Na2CO3 (3.08 g, 29.1 mmol) (1 M in water) and the solution was cooled to 0° C. Benzyl chloroformate (3.03 mL, 21.33 mmol, Sigma-Aldrich) was added dropwise and the mixture was stirred at 0° C. for 2 h. The mixture was extracted with EtOAc (100 mL×3) and the combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 10-50% EtOAc in Hex) to give benzyl(4-hydroxy-2-methylbutan-2-yl)carbamate (3.33 g, 14.03 mmol, 72% yield) as a clear oil. MS (ESI, pos. ion) m/z: 238.1 (M+1).
Reaction SMILES: Cl.CO.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:9]=[C:10]([CH3:16])[C:11]=1[O:12]COC>O>[OH:12][C:11]1[C:10]([CH3:16])=[CH:9][C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[CH:7][C:6]=1[O:5][CH3:4]
Reactant: COCOc1c(C)cc(N2CCOC2=O)cc1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(N2CCOC2=O)cc(C)c1O
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
10% hydrochloric acid (5 ml) was added to a methanol solution (5 ml) of 3-(3-methoxy-4-methoxymethoxy-5-methylphenyl)oxazolidin-2-one (0.48 g, 1.79 mmol) and the mixture was stirred at 50° C. for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extracted material was dried over magnesium sulfate, and thereafter concentrated to dryness under reduced pressure to obtain 3-(4-hydroxy-3-methoxy-5-methylphenyl)oxazolidin-2-one (434 mg) as a light yellow powder.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[CH:17]=[CH:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:13]2[C:14]([C:30]([F:32])([F:33])[F:31])=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:17]=[CH:16]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1

Procedure:
The mixture of cis-4-tert-butylcyclohexanol (30.4 mg, 0.000195 mol), (R)-4-(6-hydroxy-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (50.5 mg, 0.000162 mol) and triphenylphosphine (51.1 mg, 0.000195 mol) in tetrahydrofuran (2 mL, 0.02 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0383 mL, 0.000195 mol) was added dropwise and was stirred and refluxed for 3 hours. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (22.2 mg, 30%). LCMS: Rf=2.41 min (450.46, M+1, 70%; 491.47, M+ACN, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.25 (dd, J=8.7, 1.4 Hz, 1 H), 7.91 (d, J=9.0 Hz, 1 H), 7.79 (d, J=2.0 Hz, 1 H), 7.52 (dd, J=9.3, 2.3 Hz, 1 H), 7.34 (d, J=9.3 Hz, 1 H), 5.98 (br. s., 1 H), 4.45 (d, J=8.6 Hz, 1 H), 4.41 (d, J=8.6 Hz, 1 H), 4.38-4.26 (m, 1 H), 2.19 (d, J=13.1 Hz, 2 H), 1.89 (d, J=10.0 Hz, 2 H), 1.87 (s, 3 H), 1.59-1.48 (m, 2 H), 1.21-1.05 (m, 3 H), 0.89 (s, 9 H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23](Cl)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3].[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(N(CC)C(C)C)(C)C>C(O)CCC>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:30][CH2:29][C:28]4[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=4[O:26][CH3:25])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 80 °C

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 2,4-dimethoxybenzylamine (1.2 mL, 7.8 mmol) in 1-butanol (18.6 mL) was treated with N,N-diisopropylethylamine (1.4 mL, 7.8 mmol) and heated at 80° C. for 22 h; HPLC/LC MS indicated ˜90% conversion to the desired product. The volatiles were removed and the yellow-brown paste was taken up in CH2Cl2 (90 mL) and washed with water (2×30 mL) and brine (1×45 mL). The separated organic layer was dried (Na2SO4) and concentrated in vacuo to afford an orange oil. Purification by column chromatography (2×22 cm silica; 0-50% EtOAc/Hex) afforded the title compound (2.23 g, 72%) as a pale yellow glass/foam: MS (ESI+) for C24H29N7O4 m/z 480.5 (M+H)+; MS (ESI−) for C24H29N7O4 m/z 524.3 (M+HCO2)−; HPLC purity >95% (ret. time, 3.551 min).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2C)c1OC
Yield: 94.3 %

Procedure:
Sodium hydride (50%, 1 g), ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (6.2 g) and methyl iodide (4.1 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]propionate (6.1 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)C.[O-]CC.[Na+].C(OC(C)C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][CH:28]1[CH2:29][CH2:30][CH:25]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11]4[S:12][C:8]([C:5]5[CH:6]=[CH:7][C:2]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:3][CH:4]=5)=[N:9][N:10]=4)=[CH:14][CH:15]=3)[CH2:20][CH2:21]2)[CH2:26][CH2:27]1
Reactant: CC1CCC(N2CCN(c3ccc(-c4nnc(-c5ccc(I)cc5)s4)cc3)CC2)CC1
Reactant: CCOC=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2nnc(-c3ccc(N4CCN(C5CCC(C)CC5)CC4)cc3)s2)cc1

Procedure:
To a suspension of 1-[4-[5-(4-iodophenyl)-1,3,4-thiadiazol-2-yl]phenyl]-4-(4-methylcyclohexyl)piperazine (2 g) in DMF (40 ml) was successively added ethyl formate (0.56 ml), dichlorobis(triphenylphosphine)palladium(II) (0.52 g) and 20% sodium ethoxide ethanol solution (4.43 ml) with stirring and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was added diisopropyl ether (600 ml). The resulting precipitate was collected by filtration. The precipitate was dissolved THF (200 ml), insoluble materials were filtered off and solution was concentrated in vacuo. The resulting residue was washed with acetonitrile, and dried to give ethyl 4-[5-[4-[4-(4-methylcyclohexyl)-1-piperazinyl]phenyl]-1,3,4-thiadiazol-2-yl]benzoate (1.07 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH:10]([NH:12][C:13]1[NH:17][N:16]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[N:14]=1)=[O:11].S(Cl)(Cl)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([C:15]2[N:14]=[C:13]([NH:12][CH:10]=[O:11])[NH:17][N:16]=2)(=[O:19])=[O:20])=[CH:4][C:3]=1[CH3:9]
Reactant: O=CNc1nc(S(=O)(=O)Cl)n[nH]1
Reactant: Cc1cc(N)ccc1Br
Solvent: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(NS(=O)(=O)c2n[nH]c(NC=O)n2)ccc1Br

Procedure:
A mixture of 4-bromo-3-methylaniline (3.72 g, 20 mmol) and 5-formamido-1,2,4-triazole-3-sulfonyl chloride (2.10 g, 10 mmol) in 50 mL of acetonitrile was refluxed under nitrogen until all of the sulfonyl chloride has been consumed (approximately 1 hr). The mixture was cooled and filtered. The precipitate was dispersed in 200 mL of 1% aqueous HCl solution and filtered again to yield the title compound as a white solid, 3.0 g (84%) m.p. 282°-284° C., M+ -Br at 280.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OC)=O.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl.O>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:39])=[O:38])=[CH:33][CH:32]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCCS(=O)(=O)c1ccc(N)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)CCCC(=O)OCC)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 100 mg; 0.43 mmol) in DCM (5 ml) was treated with triethylamine (0.1 ml; 0.72 mmol) and methyl chloroformate (0.060 ml; 0.78 mmol). After stirring at 0° C. for 30 minutes, ethyl 4-(4-aminophenylsulfonyl)butanoate (Intermediate 48, 125 mg; 0.46 mmol) was added. After stirring at 0° C. for 5 minutes and RT for 1 hour water was added and the mixture passed through a hydrophobic frit. The solvent was removed in vacuo and the residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give ethyl 4-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)phenylsulfonyl)butanoate. The intermediate was redissolved in ethanol (3 ml) and treated with 10% sodium hydroxide solution (2 ml). After stirring at RT for 18 hours the mixture was acidified to pH 3 with dilute HCl and EtOAc added. The organic phase was removed in vacuo and the aqueous phase extracted with EtOAc. The combined organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with diisopropyl ether and allowed to dry to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([CH2:10][NH2:11])[CH2:6][C:7]([OH:9])=[O:8])[CH3:3].C(N(CC)CC)C.C[Si](C)(C)Cl.C(=O)([O-])OC1C=CC=C([CH:32]([O:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH3:33])C=1[N+]([O-])=O.C(O)(=O)CC(CC(O)=O)([C:49]([OH:51])=[O:50])O>ClCCl>[C:35]([O:34][CH:32]([O:51][C:49]([NH:11][CH2:10][CH:5]([CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:6][C:7]([OH:9])=[O:8])=[O:50])[CH3:33])(=[O:39])[CH:36]([CH3:37])[CH3:38]
Reactant: CC(C)C(=O)OC(C)c1cccc(OC(=O)[O-])c1[N+](=O)[O-]
Reactant: CC(C)C[C@H](CN)CC(=O)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a stirred suspension of pregabalin (2) (150 mg, 0.94 mmol) in anhydrous dichloromethane (10 mL) at 0° C. was added triethylamine (0.26 mL, 1.88 mmol) and trimethylchlorosilane (0.24 mL, 1.88 mmol). After stirring for 15 min at 0° C., a solution of x-isobutanoyloxyethyl-p-nitrophenyl carbonate (111) (267 mg, 0.94 mmol) in dichloromethane (3 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was acidified with citric acid and extracted with dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. After filtration and evaporation, the crude product was purified by silica gel chromatography, eluting first with dichloromethane to remove nitrophenol, then with 30% ethyl acetate in dichloromethane to afford 130 mg (48%) of the title compound as a mixture of two diastereomers. 1H-NMR (CDCl3, 400 MHz): δ 0.90 (m, 6H), 1.70 (m, 8H), 1.46 (d, J=5.6 Hz, 3H), 1.66 (1H, m), 2.15 (m, 1H), 2.33 (m, 2H), 2.53 (m, 1H), 3.12 (m, 1H), 3.29 (m, 1H), 5.08 (t, J=6.0 Hz, 1H), 6.79 (m, 1H).
Reaction SMILES: COC(=O)C1C=CC=C(C2C=NC(N)=C(C3SC4C=CC=CC=4N=3)C=2)C=1.C[O:28][C:29](=[O:52])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39]([NH2:51])=[C:40]([C:42]3[S:43][C:44]4[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=4[N:46]=3)[CH:41]=2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[NH2:51][C:39]1[N:38]=[CH:37][C:36]([C:33]2[CH:32]=[CH:31][C:30]([C:29]([OH:52])=[O:28])=[CH:35][CH:34]=2)=[CH:41][C:40]=1[C:42]1[S:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cc1
Agent: COC(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1-c1nc2ccccc2s1

Procedure:
Following the procedure for 3-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-benzoic acid methyl ester, the title compound was prepared from 4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-benzoic acid methyl ester (1.2 g, 3.3 mmol) and K2CO3 (1.5 g, 11 mmol) in dioxane/H2O (5:1, 30 mL). 1H NMR (400 MHz, DMSO-d6): δ=13.0 (very brs, 1H), 8.62 (d, J=2.2 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.19-8.13 (m, 3H), 8.12 (d, J=7.8 Hz, 1H), 8.04-8.00 & 7.88-7.84 (AA′BB′, 4H), 7.57 (ddd, J=1.0, 7.0, 8.0 Hz, 1H), 7.49 (ddd, J=1.0, 7.4, 8.0 Hz, 1H). MS(ES+): m/z=348.08 (100) [MH+]. HPLC: tR=3.29 min (polar—5 min, ZQ2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][N:3]=1.[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>[Pd].COCCOC>[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2-c2ccccc2)C1
Reactant: OB(O)c1ccccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)ncc2-c2ccccc2)C1
Yield: 88.4 %

Procedure:
A mixture of (S)-tert-butyl 3-(2-chloro-5-phenylpyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.153 g, 0.408 mmol), 2-hydroxyphenylboronic acid (0.169 g, 1.24 mmol), palladium catalyst (0.013 g, 0.020 mmol) and 1 M aqueous Na2CO3 (0.82 mL, 0.82 mmol) in DME (4 mL) was refluxed for 24 hours. After cooling, water (50 mL) was added and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to give the title compound as an oil (0.156 g, 89%).
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:12])([CH3:11])[C:8]#[C:9][CH3:10].Cl[CH2:14][C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=1>C1COCC1>[CH3:20][N:19]1[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]=[C:15]1[CH2:14][CH2:10][C:9]#[C:8][Si:7]([CH3:12])([CH3:11])[CH3:6]
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
n-BuLi (1.35 mL, 3.39 mmol, 2.5 M) was added to a solution of trimethyl-prop-1-ynyl-silane (0.55 mL, 3.69 mmol) in THF (1 mL) at −78° C. After 2 hours, a solution of 2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) in THF (8 mL) was added to the reaction mixture at −78° C. then the reaction mixture was stirred for 30 min. at −78° C. and 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to yield 1-methyl-2-(4-trimethylsilanyl-but-3-ynyl)-1H-benzoimidazole (178 mg, 0.69 mmol, 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C([C:54]3[N:58]([CH3:59])[CH:57]=[N:56][CH:55]=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:54]3[N:58]([CH3:59])[CH:57]=[N:56][CH:55]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4)cc3F)c2s1
Reactant: Cn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4)cc3F)c2s1
Yield: 5 %

Procedure:
Following the procedure described for compound 5b (example 2, step 6) but substituting amine 9 for compound 18, title compound 5e was obtained in 5% yield. MS (m/z): 502.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][NH:39][CH2:40][CH2:41][CH2:42][OH:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:39]([CH2:40][CH2:41][CH2:42][OH:43])[CH2:38][C:29]2[CH:30]=[CH:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:26])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OCCCNCc1ccc2ccccc2n1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CN(C)c1cccc(N(CC(=O)N(CCCO)Cc2ccc3ccccc3n2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 3-[(quinolin-2-ylmethyl)-amino]-propan-1-ol