Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N-:12]=[N+:13]=[N-].[Na+]>O.Cl>[N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:12]=[N-:13]
Reactant: Nc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1
Reaction time: 0.75 h

Procedure:
A solution of NaNO2 (5.7 g, 82.5 mmol)) in water (20 mL) was added dropwise to a solution of aniline (3.06 g, 33 mmol) in 4M HCl (330 mL) at 0-5° C. After stirring the mixture at this temperature for 45 min, a solution of NaN3 (429 g, 66 mmol) in water (20 mL) was slowly added to the mixture at the same temperature. Stirring was continued for 30 min below 5° C. and then for overnight at room temperature. The reaction mixture was extracted with diethyl ether (50×3), washed with water and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude liquid was purified by silica gel column chromatography using hexane/EAC 0-5% as eluent. Yield: 1.70 g (43%). IR (neat) 2925, 2093, 1933, 1620, 1492, 1295, 1175 cm−1; 1H NMR (400 MHz, CDCl3) δ7.10-7.21 (m, 2H), 7.22-7.24 (m, 1H), 7.42-7.46 (m, 2H); 13C NMR (CDCl3) δ 140.02, 129.72, 124.88, 109.00.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]2)=[CH:3][CH:2]=1.[CH3:21][O:22][C@:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:27]([F:30])([F:29])[F:28])[C:24](O)=[O:25].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:24](=[O:25])[C@@:23]([O:22][CH3:21])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:27]([F:29])([F:30])[F:28])[CH2:9]2)=[CH:3][CH:2]=1
Reactant: O[C@@H]1CCC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Reactant: CO[C@](C(=O)O)(c1ccccc1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@](C(=O)O[C@@H]1CCC[C@H](Oc2ccc(-c3ccccc3)cc2)C1)(c1ccccc1)C(F)(F)F
Temperature: 36 °C

Procedure:
A mixture of (1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclohexanol from Step C (1 eq) with (S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C. over night. The reaction mixture was cooled and concentrated to dryness. Reconstituted in: ether and washed with HCl 1N, and NaHCO3. Dry over MsSO4 and concentrated in vacuo to give a crude that was purified by silica gel chromatography to give a diastereomeric mixture which was separated using chiral HPLC
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([C:42]2[CH:43]=[C:44]([CH2:53]OS(C)(=O)=O)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=2)[CH:38]=[CH:39][C:40]=1[F:41].CN1CCNCC1>>[F:34][C:35]1[CH:36]=[C:37]([C:42]2[CH:43]=[C:44]([CH2:53][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=2)[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CN2CCN(C)CC2)c1=O
Yield: 79.1 %

Procedure:
Following the procedure of Example 1 (10), 6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 79.1%).
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:14]2[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[N:7]1)(=O)C.Cl>CO.O1CCCC1.O>[CH3:16][O:15][C:11]1[C:10]([C:17]([F:20])([F:18])[F:19])=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:6][N:7]=[CH:8]2
Reactant: COc1ccc2c(cnn2C(C)=O)c1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2[nH]ncc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
A 6N-aqueous sodium hydroxide solution (3.8 ml, 23 mmol) was added dropwise to a solution of 1-acetyl-5-methoxy-4-(trifluoromethyl)-1H-indazole (493 mg, 1.91 mmol) in a mixture of methanol (3.8 ml) and tetrahydrofuran (3.8 ml) at room temperature and stirred at room temperature for 5 hours while maintaining the temperature. The resulting reaction solution was adjusted to pH 8 to 9 by dropwise addition of 12N-aqueous hydrochloric acid solution (1.5 ml) and then a 1N aqueous hydrochloric acid solution (about 2 ml), and distilled under reduced pressure to remove the organic solvent. The white precipitate formed was diluted with water, filtered, washed with water, and then dried under reduced pressure to obtain 5-methoxy-4-(trifluoromethyl)-1H-indazole (400 mg, 97%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:38]C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>C(O)=O>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C
Solvent: O=CO
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1

Procedure:
320 mg (0.50 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and 6 ml of formic acid are reacted analogously to Example 2d to form the title compound which is used further directly.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].O([CH2:22][C:23]([F:26])([F:25])[F:24])S(C(F)(F)F)(=O)=O.O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A stirred solution of 3-fluoro-4-nitrophenol (200 mg, 1.3 mmol) in dimethylformamide (3 ml) at 0° C. under argon was treated portionwise with sodium hydride (60 mg of 60% oil dispersion, 1.5 mmol) and maintained for 20 minutes. The mixture was treated with trifluoroethyl triflate (325 mg, 1.4 mmol), then allowed to warm to room temperature and stir overnight. The yellow solution was treated with water (40 ml) and brine (5 ml) and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4) and concentrated under vacuum to leave the title compound as a yellow oil (280 mg, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br>CN(C)C=O.C(OCC)C.O>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][N:9]1[CH:8]=[C:7]2[C:11]([CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6]2)=[N:10]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(Cn1cc2ccc([N+](=O)[O-])cc2n1)OC

Procedure:
To a stirred suspension of 6-nitroindazole (10 g, 61 mmol) and K2CO3 (9.31 g, 67.5 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added bromoacetaldehyde dimethylacetal (8.0 mL, 67.5 mmol) and the reaction was heated to 55 C for 18 ours. The mixture was allowed to cool and was diluted with diethyl ether (30 mL) and H2O (60 mL). The layers were separated and the aqueous was extracted with additional diethyl ether (3×30 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to an orange oil. The residue was purified by MPLC (SiO2, 9:1 Hx:Ethyl acetateto 4:1 Hx:EtoAc) to yield the titled product as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.31 (m, 6 H), 4.67 (d, J=5.42 Hz, 2 H), 4.91 (t, J=5.42 Hz, 1H), 7.82 (m1 H), 7.99 (m, 1 H) and 8.63 (s, 2 H); MS (ESI) 252 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Br:30][C:31]1[N:32]=[C:33]([Sn](CCCC)(CCCC)CCCC)[S:34][CH:35]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O1CCOCC1>[Br:30][C:31]1[N:32]=[C:33]([C:2]2[S:3][C:4]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)=[C:9]([C@H:18]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=3[N:6]=2)[S:34][CH:35]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(Br)cs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(Br)cs3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
In a 5 mL microwave reaction tube, (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (240 mg, 0.5 mmol), 4-bromo-2-(tributylstannyl)thiazole (0.25 mL, 1.5 eq.), Pd(PPh3)4 (84 mg, 15%) and CuI (14 mg, 15%) were charged, then 4 mL dioxane was added. The reaction mixture was purged N2, then heated to 100° C. for 3 hour. LC-MS of reaction crude showed desired product mass. The reaction crude was partitioned using ethyl acetate and brine. The organic layer was concentrated and purified via CombiFlash column (0-50% ethyl acetate/hexane) to give desired product. LCMS-ESI+: calc'd for C25H25BrClN2O3S2: 565.9, found. 567.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[S:3]([CH3:6])(=[O:5])=[O:4].O.O.Cl[Sn]Cl.[OH-].[Na+]>Cl>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: CN(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CN(c1ccccc1N)S(C)(=O)=O

Procedure:
50.2 g of N-methyl-N-(2-nitrophenyl)methanesulfonamide, prepared by the procedure of Example 5, is added to 220 ml of concentrated HCl and contacted with 183.3 g of SnCl2.2H2O. The mixture is heated on a steam bath for one hour. The reaction mixture is treated with enough 5-10% NaOH to raise the pH to 9 while maintaining the temperature of the mixture less than 25° C. The crude reaction mixture is then extracted with CH2Cl2. The CH2Cl2 extracts are dried with MgSO4 and then filtered and concentrated on a rotary evaporator. The solid product obtained (38.1 g), m.p. 138°-139° was used without further purification in the next step.
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[N:6](CC2C=CC(OC)=CC=2OC)[C@H:5]1[C:20]([O:22][CH3:23])=[O:21])=[N+:2]=[N-:3].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[Na+].[Na+]>>[N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[C:20]([O:22][CH3:23])=[O:21])=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1[C@@H](N=[N+]=[N-])C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Product: COC(=O)[C@@H]1NC(=O)[C@@H]1N=[N+]=[N-]

Procedure:
A degassed solution of 3.8 g (0.012 mole) of methyl cis-3-azido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate was treated with potassium persulfate and sodium monohydrogen phosphate as described in Preparation 2 to give methyl cis-3-azido-4-oxoazetidine-2-carboxylate which was purified by chromatography on silica gel with benzene-ethyl acetate as eluant.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[C:5]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24]>C(O)(C(F)(F)F)=O.CCOCC>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[C:5]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3ccccc3)ccc2C2(CCCC2)C1=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(-c3ccccc3)ccc2C2(CCCC2)C1=O
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
1,1-Dimethylethyl N-((4′-hydroxy-2′-oxo-6′-phenyl-spiro[cyclopentane-1,1′-naphthalen]-3′-yl)carbonyl)glycinate (115 mg, 257 μmol) was dissolved in TFA (2 mL) at ambient temperature. The reaction was stirred for 30 minutes and was then concentrated to give an oil, dissolved in ether, concentrated again to give an amorphous solid, precipitated with ether, filtered, washed with ether, and dried in a vacuum oven to give the title compound (21 mg) as a white solid. MS (m/z)=392 (M+H)+. Calculated for the C23H21NO5 391.14.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][N:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:4][N:3]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: Nc1ncc(-c2cccc3c2CC(=O)N3)cn1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cnc(N)nc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-(2-Aminopyrimidin-5-yl)-1,3-dihydroindol-2-one (89 mg) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (98 mg) to give the title compound.
Reaction SMILES: C([C@:4]1([OH:41])[C@@H:9]([CH2:10][OH:11])[O:8][C@:7](C(=O)C)([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:29])=[C:17]([CH2:23][C:24]([O:26]CC)=[O:25])[C:18](=[O:22])[O:19]3)=[CH:14][CH:13]=2)[C@:6](C(=O)C)([OH:33])[C@@:5]1(C(=O)C)[OH:37])(=O)C.[OH-].[K+].Cl>CO>[C@@H:7]1([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:29])=[C:17]([CH2:23][C:24]([OH:26])=[O:25])[C:18](=[O:22])[O:19]3)=[CH:14][CH:13]=2)[O:8][C@H:9]([CH2:10][OH:11])[C@H:4]([OH:41])[C@H:5]([OH:37])[C@H:6]1[OH:33]
Reactant: CCOC(=O)Cc1c(C)c2ccc([C@@]3(C(C)=O)O[C@H](CO)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@]3(O)C(C)=O)cc2oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(CC(=O)O)c(=O)oc2cc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a stirred solution of 7-(tetraacetyl-β-galactosyl)-4-methylcoumarin-3-acetic acid, ethyl ester (3) (422 mg, 0.712 mmol) in methanol was added 6.8M KOH (5 mL) and the solution was stirred overnight at room temperature. The solution was neutralized by the addition of 1N HCl and evaporated to dryness under reduced pressure. The residue was dissolved in water (10 mL) and desalted using C18Sep Pack Cartridges in 10×1 mL portions. The C18Sep pack Cartridge (Waters Part No. 65910) was washed with methanol (3 mL) and water (3 mL) before the sample was applied in 1 mL. The cartridge was then washed with water (3 mL) to remove any salt followed by metahnol (3 mL) which eluted the desired product as determined by TLC (silica gel, acetone:20 mM NaOAc 9:1). The methanol washes were pooled and evaporated under reduced pressure and the while solid obtained was recrystallized from ethanol/water to give 170 mg (0.43 mmol, 60%) of 4 as white crystals: m.p. 186°-188° C.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[S:24]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25]1>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:30][CH2:29][C:26]1[CH:27]=[CH:28][S:24][CH:25]=1)[C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:17])([F:18])[F:16])=[O:7])([O-:23])=[O:22]
Reactant: NCc1ccsc1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: O=C(c1ccc(NCc2ccsc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (125 mg, 0.359 mmol) and 3-thienylmethylamine (49 mg, 0.431 mmol) in 3 mL of EtOH containing TEA (0.075 mL, 0.539 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24]>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc23)CC1
Yield: 72.2 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.1 mg (0.09 mMol) 3-trifluoromethylbenzoic acid, 8.7 mg (72%) of the title compound were recovered.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]#[C:7][C:8]2([CH3:22])[CH2:13][CH2:12][C:11]3[C:14]([CH3:21])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]=3[O:9]2)[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:10]2[O:9][C:8]([C:7]#[C:6][C:4]3[C:3]4[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=4[S:1][CH:5]=3)([CH3:22])[CH2:13][CH2:12][C:11]=2[C:14]=1[CH3:21])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1csc3ccccc13)O2
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#Cc1csc3ccccc13)O2

Procedure:
A mixture of 0.3 g of rac-2-[(benzo[b]thiophen-3-yl)ethynyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 20 ml of pyridine and 1 ml of acetic anhydride was allowed to sit at room temperature over night and was then evaporated to dryness under reduced pressure. The residue was crystallized from hexane to yield 0.25 g of colorless crystals with m.p. 99°-101°.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[OH:7])[C:3]2[S:13][CH:14]=[C:15]([CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[OH:17])[C:2]1=2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[S:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[O:7])[C:3]2[S:13][CH:14]=[C:15]([C:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[O:17])[C:2]1=2
Reactant: OC(c1ccsc1)c1csc2c(C(O)c3ccsc3)csc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(c1ccsc1)c1csc2c(C(=O)c3ccsc3)csc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of thieno[3,2-b]thiophene-3,6-diylbis(thiophen-3-ylmethanol) in dichloromethane at 0° C. was added pyridinium chlorochromate. The mixture was allowed to warm up at room temperature and stirred for 4 hours. The mixture was then filtered through celite. The solvent was evaporated and the resulting product was purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10](OC)[CH2:11][N:12]=2)=[CH:4][C:3]=1[CH:15](Br)Br.C1CCN2C(=NCCC2)CC1.N1CC[O:32]CC1.CC(C)([O-])C.[K+].Cl>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH:15]=[O:32]
Reactant: C1COCCN1
Reactant: COC1CN=C(c2ccc(Br)c(C(Br)Br)c2)O1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ncco2)ccc1Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 72.3 %

Procedure:
A 1 L round bottom flask was charged with 2-[4-bromo-3-(dibromomethyl)-phenyl]-5-methoxy-oxazoline (27.8 g, 67.1 mmol), DBU (24.1 mL, 161.2 mmol) and morpholine (56.4 mL, 646.7 mmol). The mixture was heated at 60° C. for 2.5 hours. HPLC indicated the starting material had disappeared. The reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath. The stirring stopped. Potassium tert-butoxide (1 M in THF, 350 mL) was added dropwise in 0.5 hours. The stirring started after ˜20 mL of potassium tert-butoxide THF solution was added. The reaction mixture was warmed up to RT and stirred at RT for 5 hours. It was put aside in a −40° C. freezer for 13 hours and then was stirred at RT for another 2 hours. The reaction mixture was cooled to −10° C. to 0° C. in an ice/acetone bath. HCl (6N, cold, 214 mL) was added dropwise in 15 minutes. The mixture was stirred at 0° C. to RT in 0.5 hours. It was transferred to a 2 L separatory funnel, diluted with EtOAc (300 mL) and water (300 mL). The aqueous layer was separated and extracted with EtOAc (300 mL×2). The organic layers were combined and the combined organic phase was washed with brine/1N HCl mixture (200 mL/30 mL ), brine/water mixture (200 mL/30 mL×2) and brine (230 mL×2). It was dried over MgSO4 (50 g) for 0.5 hours and concentrated to 21.3 g of semi solid. The crude semi solid was dissolved in warm THF (60 mL). The THF solution was added dropwise to a mixture of refluxing cyclohexane (600 mL) and charcoal (3.6 g). The mixture was stirred without heat for 0.5 hours and was heated to reflux. It was filtered through a celite pad and the pad was washed with a hot mixture of cyclohexane/THF (90 mL/9 mL×3). The filtrate was concentrated to 14.1 g of yellowish white solid. The charcoal treated crude product was dissolved in cyclohexane (300 mL) at reflux. Crystallization occurred upon cooling to RT. The mixture was stirred at RT for 4 hours and then at 4° C. for 13 hours. The 2-[4-Bromo-3-(formyl)-phenyl]oxazole was collected by filtration and was suction dried at RT for 13 h. It was obtained as an off-white solid in 72.3% yield, HPLC area percent 99.8. The 1H NMR and mass spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl>[N:8]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C1

Procedure:
10 g of azetidine-3-carboxylic methyl ester hydrochloride and then 23 ml of triethylamine are added to 150 ml of CH2Cl2. The mixture is cooled and 13.5 g of benzyl chloroformate are added. After leaving overnight at AT, washing is carried out with water and then with HCl (N). After drying, concentrating to dryness and purifying by chromatography on silica (eluent: heptane-AcOEt (gradient from 0% to 50%)), 13.1 g of the expected compound are obtained.