Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:9][CH:8]=[CH:7][C:6]2[N:5]3[CH2:10][CH2:11][CH2:12][CH2:13][C:4]3=[C:3]([C:14]([O:16]CC)=[O:15])[C:2]1=2.Cl>C(O)C.[OH-].[Na+]>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]([OH:16])=[O:15])=[C:4]1[CH2:13][CH2:12][CH2:11][CH2:10][N:5]12
Reactant: CCOC(=O)c1c2c(n3c1CCCC3)C=CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c2n(c3ccccc13)CCCC2
Yield: 39.5 %

Procedure:
A solution of ethyl 6,7,8,9-tetrahydro-1 H-pyrido[1,2-a]indole-10-carboxylate (1.20 g, 0.0047 mole) in ethanol (50 ml) and 10% NaOH solution (50 ml) was heated under reflux for 4 hours. The reaction was then acidified with 1M HCl acid (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was separated and extracted with 10% Na2CO3 solution (120 ml) and the aqueous solution then re-acidified with 5M HCl acid and extracted into ethyl acetate (2×75 ml). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo to afford the title compound (D3) as a white solid (400 mg, 40%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH:1]([N:14]1[CH2:17][C:16]([C:20]([F:22])([F:21])[F:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(C(F)(F)F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 46.32 %

Procedure:
1-Benzhydrylazetidin-3-one (5.0 g, 1.0 eq.) was dissolved in THF (50 mL). Trifluoromethyl trimethylsilane was added at 5-10° C. The reaction mixture was stirred at 10° C. for 10 min. Tetrabutyl ammonium fluoride was then added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by chromatography (6% ethyl acetate-hexane) to give 3 g of 1-benzhydryl-3-(trifluoromethyl)azetidin-3-ol (Yield: 46.32%).
Reaction SMILES: C(=O)(O[C:4]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:9][O:8]C(C)(C)[O:6][CH:5]1C(C)(C)C)N.C(OC(=O)[NH:38]C1(CCC2C=CC(S(N3C4C(=CC=C(OC)C=4)C(C(=O)C4C=C(OC)C(OC)=C(OC)C=4)=C3)(=O)=O)=CC=2)COC(C)(C)OC1)(C)(C)C>>[NH2:38][C:4]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH2:9][OH:8])[CH2:5][OH:6]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Reactant: Cc1ccc(-c2ccc(CCC3(OC(N)=O)COC(C)(C)OC3C(C)(C)C)cc2)cc1
Product: Cc1ccc(-c2ccc(CCC(N)(CO)CO)cc2)cc1
Yield: 67 %

Procedure:
When the product of Step A was substituted for tert-butyl-5-(4-(6-methoxy-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-ylsulfonyl)-phenethyl)-2,2-di methyl-1,3-dioxan-5-ylcarbamate in Example 13, Step F, the similar process afforded the title compound in 67% yield, as colourless solid. 1H-NMR (CDCl3) 3.17-3.23 (m, 2H); 3.63 (s, 3H); 3.94-3.88 (m, 2H); 4.91 (d, 2H, J=12.36 Hz); 4.97 (d, 2H, J=11.94 Hz); 8.12 (tr, 4H, J=10.92 Hz); 8.66-8.88 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)=[O:13])=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(F)cc1
Yield: 9.7 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.00 g, 2.92 mmol) in 20 mL of dichloromethane and 4-fluoroaniline (0,657 g, 5.91 mmol) in 5 mL of pyridine. The crude product was triturated with hot ethanol-ethyl acetate mixture, filtered, and recrystallized from ethanol-DMF to yield 0.14 g of the title compound, mp 242°-244° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:44]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)(=[O:46])=[O:45])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3c(CNS(=O)(=O)c4ccccc4)csc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 48.1 %

Procedure:
To a solution of the product of Example 353E (16.9 mg, 0.038 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.012 mL, 0.083 mmol) and benzene sulfonyl chloride (0.006 mL, 0.042 mmol). The reaction mixture was stirred at 23° C. for 0.75 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (10.7 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (d, J=7.72 Hz, 2 H) 1.01 (m, J=7.54, 7.54 Hz, 1 H) 2.83 (d, J=6.99 Hz, 2 H) 4.07 (d, J=6.25 Hz, 2 H) 6.38 (bs, 1 H) 7.30 (s, 1 H) 7.41 (t, J=7.54 Hz, 1 H) 7.65 (m, 3 H) 7.86 (m, 3 H) 8.06 (d, J=8.82 Hz, 1 H) 8.15 (d, J=6.99 Hz, 1 H) 8.42 (t, J=6.25 Hz, 1 H) 14.43 (bs, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=O>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:18]1[NH:17][C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:5])=[O:4]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([CH3:11])[N:3]=1.[K].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Br)n1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: Cc1cc(Sc2ccc([N+](=O)[O-])cc2)cc(Br)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
1.0 g (0.00458 mol) of 2-bromo-6-methyl-4-nitropyridine and 0.885 g (0.00458 mol) of 4-nitrothiophenol potassium salt were dissolved in 10 ml of 1-methyl-pyrrolidone and stirred at 50° C. for 1 hr. The solvent was removed in a high vacuum and the residue was partitioned in water and ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4 and 1:3 and subsequently dried in a high vacuum. There was obtained 0.945 g (63%) of 2-bromo-6-methyl-4-(4-nitrophenylsulphanyl)-pyridine as yellow crystals; m.p.: 124-126° C.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([C@@:30]1([CH3:56])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N+:32]2[C@@H:50]([CH:53]3[CH2:55][CH2:54]3)[CH2:51][O:52][C:31]1=2)[CH:28]=[CH2:29]>O1CCCC1.O>[CH2:27]([C@@:30]1([CH3:56])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N:32]([C@@H:50]([CH:53]2[CH2:55][CH2:54]2)[CH2:51][S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:31]1=[O:52])[CH:28]=[CH2:29]
Reactant: CC(C)(C)S
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSC(C)(C)C)C2CC2)C1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-2-propanethiol (0.195 mL, 1.796 mmol, dried over activated 4 Å molecular sieves) was added to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 1.8 mL, 1.8 mmol) in anhydrous tetrahydrofuran (4 mL) at room temperature. The reaction mixture was heated at 60° C. After 15 minutes at 60° C., (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-α]pyridin-4-ium 4-methylbenzenesulfonate (1.00 g, 1.632 mmol, Example 1, Step F) was added as a solid. The reaction mixture was heated at 60° C. for 12 hours and then cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate thrice and the organics were pooled, washed with brine, dried over sodium sulfate, decanted and concentrated under a vacuum to provide a brown oil. Purification by flash chromatography (80 g SiO2 column, gradient elution of 10 to 60% ethyl acetate in hexanes provided the desired product as a colorless syrup.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])(=[O:22])C.[NH4+].C1(C)C=CC=CC=1>C(O)(=O)C>[OH:22][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(Cl)nc2)c[nH]n1-c1ccccn1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccc(O)nc2)c[nH]n1-c1ccccn1

Procedure:
50.0 mg (0.18 mmol) of the compound from Example 7 and 600 mg (7.74 mmol) ammonium acetate are heated at 180° C. as a suspension in 3 ml glacial acetic acid in a single mode microwave (Explorer from CEM) for 2 h. After a complete conversion is detected by analytical HPLC, toluene is added and the volatile components are distilled off azeotropically. The residue is taken up in water and the solid which remains is filtered off. The slightly brownish powder is subsequently washed with water and then with MTBE. After drying, 39 mg (84% of th.) of the title compound are obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[CH:8][C:7]=1[CH2:15][OH:16].C(N(CC)CC)C>ClCCl>[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[CH:8][C:7]=1[CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: OCc1cc2ccccn2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc2ccccn2n1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.149 g, 0.13 mmol) in dichloromethane (2 mL) was added to a solution of pyrazolo[1,5-a]pyridin-2-yl-methanol (0.148 g, 0.1 mmol) and triethylamine (0.303 g, 0.3 mmol) in dichloromethane (3 mL) at −10° C. under N2. After the addition was complete, the mixture was stirred at −10° C. for 1 h. Ice water (10 mL) was added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum to give methanesulfonic acid pyrazolo[1,5-a]pyridin-2-ylmethyl ester as a yellow oil, which was used for the next step without further purification. A solution of this material (0.22 g, 0.1 mmol) in dry dichloromethane (2 mL) was added to a solution of 1-methyl-4-phenyl-1,3-dihydro-imidazole-2-thione (0.190 g, 0.1 mmol) and DIPEA (0.303 g, 0.3 mmol) in dry DMF (3 mL) at −10° C. under N2. The mixture was stirred at 0° C. for 2 hours, and was then concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (50 mg, 15%). LC-MS: m/z=321.1 (MH+), tR=2.16 min, method F.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[O:13]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)[CH2:14]1.ON1C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([NH:46][C:47](=[O:60])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[CH:49]=2)[CH:42]=[CH:43][C:44]=1[CH3:45]>CN(C=O)C.O>[CH3:45][C:44]1[CH:43]=[CH:42][C:41]([NH:46][C:47](=[O:60])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([N:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)[CH:49]=2)=[CH:40][C:39]=1[NH:38][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH:15]2[CH2:16][CH2:17][O:13][CH2:14]2)[CH:20]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(O)c1cccc(OC2CCOC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCOC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.165 g) was added to a stirred mixture of 3-(tetrahydrofuran-3-yloxy)benzoic acid (0.15 g), 1-hydroxybenzotriazole (0.146 g) and DMF (5 ml) which had been cooled to 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and a solution of N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (0.224 g) in DMF (1 ml) was added. The reaction mixture was allowed to come to ambient temperature and was stirred for 16 hours. The reaction mixture was poured into water and the resultant solid was isolated and purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.228 g); NMR Spectrum: (DMSOd6) 1.99 (m, 1H), 2.18 (s, 3H), 2.25 (m, 1H), 3.17 (t, 4H), 3.72 (t, 4H), 3.88 (m, 4H), 5.13 (m, 1H), 7.11 (m, 2H), 7.21 (d, 1H), 7.39 (m, 5H), 7.56 (m, 2H), 7.79 (m, 2H), 9.83 (s, 1H), 10.11 (s, 1H); Mass Spectrum: M+H+ 502.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[F:24].CN([CH:28]=[O:29])C>C1COCC1.O>[Cl:16][C:17]1[C:18]([F:24])=[C:19]([C:20]([CH3:23])=[CH:21][CH:22]=1)[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)c(F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
(Reference: E. J. Org. Chem. 2005, 2116-2123) To a solution of 2,2,6,6-tetramethylpiperidine (0.642 mL, 3.80 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.162 mL, 3.46 mmol) dropwise. The resulting solution was stirred at −78° C. for 1 h and added 1-chloro-2-fluoro-4-methylbenzene (0.5 g, 3.46 mmol) dropwise. The solution was stirred for additional 0.5 h and then added DMF (0.536 mL, 6.92 mmol). The reaction was stirred at −78° C. for 1.5 h and at ambient temperature for 12 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine and concentrated. The residue was purified by silica gel chromatography to yield the desired product (43 mg, 7%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][O:36][CH:37]1[CH2:40][NH:39][CH2:38]1.C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:39]4[CH2:40][CH:37]([O:36][CH3:35])[CH2:38]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(OC)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride in DMF. [α]D20=+42.5° (c=0.44, CHCl3), ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[O:16][C:17]=2[CH2:18][CH2:19][C:20]([NH2:22])=O)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[O:16][C:17]=2[CH2:18][CH2:19][C:20]#[N:22])=[CH:11][CH:12]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(N)=O)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC#N)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Phosphorus oxychloride(585 mg) was added dropwise into a N,N-dimethylformamide solution (20 ml) of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide(840 mg) at room temperature. After stirring for 1 hour, the reaction mixture was poured into ice water, and neutralized with saturated sodium bicarbonate. The precipitating crystals are collected by filtration to give 4-(4-chlorophenyl)-5-(2-cyanoethyl)-2-(2-methyl-1-imidazolyl)oxazole(650 mg, 82%). This was recrystallized with acetone-isopropyl ether to give colorless prisms. mp 163-164° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=N3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35]O>[Pt]=O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:35]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: CO
Agent: O=[Pt]
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3c(c1)CCC(c1ccccc1)N3)n2C1CCCCC1
Yield: 37 %

Procedure:
A solution of Compound 203 (100 mg, 0.23 mmol) and platinum oxide (12 mg, 0.048 mmol) in methanol (5 mL) was hydrogenated at 40 psi for 3 h. The reaction was evaporated to dryness, and purified via HPLC. The resulting compound was then converted to the HCl salt using the standard method, yielding 40 mg (37% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[N+:11]([C:10]1[C:2]([O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:3][CH:4]=[C:5]2[C:9]=1[C:8](=[O:14])[CH2:7][CH2:6]2)([O-:13])=[O:12]
Reactant: O=C1CCc2ccc(O)c([N+](=O)[O-])c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1[N+](=O)[O-])C(=O)CC2
Temperature: 0 °C
Yield: 94.3 %

Procedure:
To a solution of 6-hydroxy-7-nitro-1-indanone (8.0 g, 41 mmol.) in N,N-dimethylformamide (50 mL) was added potassium carbonate (11.7 g, 82 mmol.). The mixture was stirred under ice-cooling, to which was added dropwise ethyl bromoacetate (5.5 mL, 50 mmol.). The reaction mixture was then stirred for one hour at room temperature, which was poured into ice-water, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting crystalline precipitate was collected by filtration and washed with hexane to afford the title compound (yield 10.8 g, 94%).
Reaction SMILES: C1(S)C=CC=CC=1.[H-].[Na+].[CH3:10][NH:11][C:12](=[O:55])[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([CH2:20][N:21]([CH2:34][C:35]([C:37]2[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:40]([OH:47])=[C:39]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:38]=2)=[O:36])S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[CH:15][C:14]=1[O:52][CH2:53][CH3:54]>CN(C)C=O.C(OCC)(=O)C>[CH3:10][NH:11][C:12](=[O:55])[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([CH2:20][NH:21][CH2:34][C:35]([C:37]2[CH:38]=[C:39]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:40]([OH:47])=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=2)=[O:36])=[CH:15][C:14]=1[O:52][CH2:53][CH3:54]
Reactant: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(Br)cc1C(=O)NC
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CNCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
After dissolving thiophenol (1.27 ml) in dimethylformamide (20 ml), sodium hydride (480 mg) was added. The mixture was stirred at room temperature for 30 minutes and then the N1-methyl-5-bromo-4-({{2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-oxoethyl}[(4-nitrophenyl)sulfonyl]amino}methyl)-2-ethoxybenzamide (2.95 g) was added. After stirring at room temperature for 1 hour, the mixture was diluted with ethyl acetate and washed with water and brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.75 g) as a light orange oil. (78% yield)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl>C1COCC1>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([N:16]2[CH2:17][CH2:18][N:19]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH2:20][CH2:21]2)[CH:4]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc(Cl)cc1N1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To a mixture of the product from step c) (0.34 g) and benzenesulfonyl chloride (0.11 ml) in THF (3 ml) was added triethylamine (0.42 ml) dropwise. After 5 min, further THF (3 ml) was added and the reaction stirred for 16 h. It was poured into 2M HCl and extracted with ethyl acetate. The organic layer was separated and washed with sat aqueous sodium bicarbonate solution, brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was stirred in THF (2 ml) and 4M NaOH (4 ml) for 16 h. After acidification to pH 3, the aqueous layer was extracted with ethyl acetate. The organic layer was separated and the solvent removed in vacuo. Purification by RPHPLC (symmetry column) gave the title product as a white foam (0.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]([NH2:14])=[O:13])(=[O:10])=[O:9].ClCC(N1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]([N:14]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:13])(=[O:10])=[O:9]
Reactant: O=C(CCl)N1CCOCC1
Reactant: NC(=O)CS(=O)(=O)c1ccccc1Br
Product: O=C(CS(=O)(=O)c1ccccc1Br)N1CCOCC1

Procedure:
The title compound was prepared in a manner similar to that described for 2-((2-bromophenyl)sulfonyl)acetamide using 2-chloro-1-morpholinoethanone in Step A. 1H NMR (600 MHz, DMSO-d6) δ 8.06-8.01 (m, 1H), 7.93-7.88 (m, 1H), 7.68-7.60 (m, 2H), 4.84 (s, 2H), 3.63-3.55 (m, 4H), 3.53-3.48 (dd, J=5.6, 4.0, 2H), 3.42-3.37 (d, J=5.2, 2H).