Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
16 g of carbazole was dissolved in 80 ml of N,N′-dimethylformamide. To this was added 18 g of N-bromosuccinimide and allowed the reaction to stir at room temperature overnight. The reaction mixture was poured into water and the precipitated white solid was filtered, washed with methanol and dried under vacuum to obtain 20 g of 3-bromocarbazole. It was further converted to its acetyl derivative by refluxing with acetic anhydride (3 vol) with traces of conc. sulfuric acid. Aqueous workup yielded an off-white solid, which was then washed with n-hexane and dried under vacuum to obtain 23 g 9-acetyl-3-bromocarbazole, quantitatively.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1-c1ccccn1
Temperature: 120 °C

Procedure:
To a mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (185 mg, 1 mmol) and 2-(tributylstannyl)pyridine (202 mg, 1.1 mmol) in DMF (4 mL) was added tetrakis(triphenylphosphine) palladium (0) (58 mg, 5% mmol). The reaction tube was sealed, the mixture was purged with N2 for 3 min and then heated at 120° C. under N2 for overnight. The reaction was cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica gel column chromatography (60% ethyl acetate in hexanes) to afford 2-(2,5-dimethyl-4-nitrophenyl)pyridine as a white solid. The obtained solid was dissolved in acetic acid/TFA (15 mL/200 uL). To this solution was added PtO2 (10% w/w). The reaction mixture was degassed and purged with H2 for several times and stirred under 1 atm. hydrogen gas overnight. The mixture was filtered and concentrated to afford 2,5-Dimethyl-4-(piperidin-2-yl)aniline as a yellow oil. ESMS m/z 205 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:21][C@@H:22]([CH2:52]O)[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:25]1.[CH:54](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:29][C:26]1[CH:27]=[CH:28][N:24]([CH2:23][C:22]([OH:21])([CH3:52])[CH3:54])[N:25]=1)[CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CC1CCOCC1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
A solution of 2-t-butoxycarbonylamino-3-(tetrahydropyran-4-yl)-propionic acid (2.61 g, 9.55 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 1.8 g, 11.6 mmol) in N,N-dimethylformamide (15 mL) was treated with N,N-diisopropylethylamine (2.58 g, 20 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (8.84 g, 20 mmol) and the resulting mixture stirred at room temperature for 12 h. At this time the mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and a concentrated ammonium chloride solution. The layers were separated and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica 120 g, 30% to 100% ethyl acetate/hexanes) which afforded [1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-2-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid t-butyl ester (3.2 g, 82%) as a white solid.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[NH:48]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[N:49]1>>[NH:48]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:42])=[N:49]1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cc[nH]n1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc[nH]n1
Yield: 72 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1H-pyrazol-3-yl)methanamine, the title compound was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.46 (t, J=5.0 Hz, 1H), 6.28 (s, 1H), 6.09 (s, 1H), 5.70 (br s, 1H), 4.60 (d, J=5.0 Hz, 2H), 4.43 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 436.2 (M+23).
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4]>>[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:4])=[O:1])([O-:5])=[O:4]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1[N+](=O)[O-]

Procedure:
From N-Boc-D-cHyp(Tosyloxy)-OMe (5.27 mmol, 2.50 g), powdered KOH (13.2 mmol, 0.74 g), and 2-nitrophenol (13.2 mmol, 1.83 g), held at reflux for 6 days, the 2-nitrophenyl ether of D-trans-hydroxyproline methyl ester (0.29 g, 14%) was obtained. Purification by column chromatography (silica ge, ethyl acetate/hexane mixtures) yielded no pure fractions. All fractions bearing product were combined and purified in three equal portions using the chromatotron (4 mm silica gel plates) and a mixture of ethyl acetate/CH2Cl2/hexane (2:9:9:) which was found to effect separation on TLC plates. The mixture of ethyl acetate/CH2Cl2 (2:9) will be referred to as mixture A or simply A.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH:40]([CH3:42])[CH3:41])[CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH:40]([CH3:41])[CH3:42])[C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:34][CH:35]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (41 mg, 0.13 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (46 mg, 0.13 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (51 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (58 mg, 78%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 7.30-7.22 (m, 4H), 5.11 (m, 1H), 3.80-3.40 (m, 13H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.14 (m, 3H), 1.03 (m, 3H), 0.68 (m, 3H). MS (APCI+) [M+H] +559.
Reaction SMILES: [C:1]([C:5]1[C:6]([SH:16])=[C:7]([CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(C1C=[C:23]([CH:27]=C(C(C)(C)C)C=1)[C:24]([OH:26])=[O:25])(C)(C)C.[C:34]1(C)C=CC(S(O)(=O)=O)=C[CH:35]=1>CO>[C:12]([C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[S:16][C:27]([CH2:23][C:24]([O:26][CH2:34][CH3:35])=[O:25])=[N:8][C:7]=2[CH:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(N)c(S)c(C(C)(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCOC(=O)Cc1nc2cc(C(C)(C)C)cc(C(C)(C)C)c2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 40 g of 3,5-di(t-butyl)-2-mercaptoaniline [prepared according to a literature procedure from 3,5-di(t-butyl)benzoic acid] and 75 mL of ethyl 3-(trimethoxy)propionate in 1.2 L of methanol containing 1.5 g of p-toluenesulfonic acid was stirred at r.t. for 18 h. Excess methanol was removed by rotary evaporation. The precipitated the solid was filtered and washed with cold methanol. The crude product was purified by flash chromatography on silica gel and eluted with heptane to give 20 g of ethyl 2-[5,7-di(t-butyl)benzothiazolyl]acetate. The latter was refluxed with 16 g of 1,1,7,7-tetramethyl-8-hydroxy-9-formyljulolidine in 200 mL of acetonitrile containing 4 mL of piperidine for 18 h. The reaction mixture was cooled and the precipitated bright orange solid was filtered to give 13 g of the desired dye C-545TB: m.p. 275-276° C.; Tg=140° C.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1.CCCCCC>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8]3=[N:13][S:25](=[O:27])(=[O:26])[CH2:24][CH2:23][N:9]3[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of 3-biphenyl-4-ylpyridin-2-amine (700 mg) in dehydrated THF (30 mL) was added to a mixture of sodium hydride (60%, 568 mg) and 2-chloroethanesulfonyl chloride (1390 mg) in dehydrated THF (30 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (652 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH3:10].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2.Cl>CN(C)C=O.CC(C)=O>[CH2:9]([C:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:10]
Reactant: CCC(=O)c1ccccc1O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1c(C(=O)OC)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 1-(2-hydroxyphenyl)propan-1-one (10.0 g), methyl bromoacetate (5.11 mL) and acetone (100 mL) was added potassium carbonate (18.4 g), and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give a colorless oil. To a solution (150 mL) of the obtained oil in N,N-dimethylformamide was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.12 mL), and the mixture was stirred at 120° C. for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (7.14 g, 52%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(=O)c1cccc(CBr)c1
Yield: 95.2 %

Procedure:
3′-Methylpropiophenone (2.38 g; 16.1 mmol), N-bromosuccinimide (2.78 g; 16.1 mmol), and benzoyl peroxide (0.20 g) were added to carbon tetrachloride (60 ml), and the mixture was heated under reflux for 3 hours. The mixture was brought to room temperature, and insoluble matter was filtered off. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 3.48 g of the target compound as pale yellow oily, matter (yield: 95.2%). 1H-NMR (CDCl3, ppm); 1.23 (3H, t, J=1.89 Hz), 3.01 (2H, q, J=1.89 Hz), 4.53 (3H, s), 7.42˜7.70 (2H, m), 7.79˜8.13 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1.C1COCC1.N1CCC1>C(N(CC)CC)C>[F:20][C:21]1([F:25])[CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: FC1(F)CNC1
Agent: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CC(F)(F)C3)s2)noc1C(F)(F)F
Yield: 49 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3,3-difluoroazetidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine (containing and additional 1.1 eq to neutralize the azetadinyl hydrochloride salt) and azetidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried and then chromatographed on silica gel with EtOAc/hexanes (25 then 50%) as eluant to afford product as a colorless solid (43 mg, 49%). 1H NMR (CDCl3) 2.37 (s, 3H), 4.68 (br, 4H), 4.19 (br, 2H), 7.53 (s, 2H). 19F NMR −100.6, −63.1. LC/MS 6.42 min, [M+1]+ 353.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]1[S:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.Cl.[CH:22]([NH:25][OH:26])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[OH:26][N:25]([CH:22]([CH3:24])[CH3:23])[C:8]([C:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[S:4][C:3]=1[Si:2]([CH3:1])([CH3:16])[CH3:15])=[O:10]
Reactant: C[Si](C)(C)c1sc2ccccc2c1C(=O)O
Reactant: CC(C)NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)N(O)C(=O)c1c([Si](C)(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A mixture of 2-(trimethylsilyl)-3-benzothiophenecarboxylic acid (0.8 g, 3.2 mmol), made as in Example 14, and thionyl chloride (6 mL) was refluxed for 2 h. The excess thionyl chloride was removed under reduced pressure. The crude acid chloride was dissolved in 20 mL methylene chloride and added to a mixture of N-isopropylhydroxylamine hydrochloride (0.4 g, 3.6 mmol) and 4 g sodium bicarbonate in 20 mL methylene chloride and 20 mL water at 0° C. The resulting mixture was stirred at RT for 2 h. The organic layer was separated, washed with brine, dried, and concentrated in vacuo. The crude product was chromatographed on a silica gel column with 10% ethyl acetate/hexane to give 0.65 g of the title compound as a yellow solid, a 66.1% yield. m.p. 115-118° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 216 h
Yield: 21.7 %

Procedure:
4-BROMO-2,5-DIFLUOROBENZENESULFONYL CHLORIDE (10.0 g, 0.0345 mol) and 2-AMINOTHIAZOLE (3.80 g, 0.0379 mol) were mixed in Pyridine (40 mL, 0.5 mol). The reaction was allowed to stir at room temperature for 9 days. The reaction was concentrated in vacuo to a total volume of approximately 40 mL. The residue was triturated with 1N HCl (aq). Acetonitrile was added until the precipitate became free-flowing. The solid was collected by filtration and rinsed with acetonitrile then ethyl ether. The solid was dissolved in boiling acetonitrile and treated with activated carbon then filtered through a celite pad. The filtrate was reduced to ⅓ its original volume by distillation. The mixture was cooled to room temperature. The crystals were collected by filtration and rinsed with ethyl ether. Vacuum drying gave 2.66 g of off-white solid.
Reaction SMILES: [CH2:1]([N:5]([C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([CH3:15])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:18]=1[NH2:19]>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[CH:13]=[C:12]([NH:19][C:18]2[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=2[CH3:16])[N:11]=[C:10]([CH3:15])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCCCN(CC)c1cc(Cl)nc(C)n1
Product: CCCCN(CC)c1cc(Nc2c(C)cc(C)cc2C)nc(C)n1

Procedure:
A mixture of butyl-(6-chloro-2-methyl-pyrimidin-4-yl)-ethylamine (1.006 g, 4.42 mmol), and 2,4,6-trimethylaniline (3 ml) was heated at reflux overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 2.862 g of a brown oil. The oil was purified through silica gel column chromatography to give 981 mg (68%) of title compound as a yellow oil. 1H NMR (CDCl3) δ 0.80 (t, 3H), 1.1–1.3 (m, 2H), 1.3–1.5 (m, 2H), 2.17 (s, 6H), 2.27 (s, 3H), 2.41 (s, 3H), 3.2 (m, 2H), 3.36 (m, 2H), 4.66 (s, 1H), 6.90 (s, 2H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:25][N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1
Reactant: CI
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a stirred suspension of 640 mg (13 mmol) of sodium hydride (50% in mineral oil) in 20 ml of anhydrous dimethylformamide. After 1 hour at room temperature, 0.415 ml (6.68 mmol) of methyl iodide was added, and stirring at room temperature was continued for an additional hour. Nitrogen was then bubbled through the reaction mixture for 10 minutes and thereafter the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water, dried and evaporated in vacuo. Purification of the crude product by t.l.c. using hexane:ethyl acetate (80:20) afforded 1.439 g (69%) of the title compound, which was recrystallized from methylene chloride-hexane (mp 135.5°-136.5° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]3[CH3:27])[C:11]3[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[O:28]1CCOC[CH2:29]1.C(N(CC)CC)C.C(Cl)(Cl)=O.[CH2:45]([CH2:47][NH2:48])[OH:46]>C1(C)C=CC=CC=1>[C:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]3[CH3:27])=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH:48][CH2:47][CH2:45][OH:46])=[O:28])=[CH:7][CH:6]=3)=[N:13][C:12]=2[CH2:14]1)(=[O:20])[CH3:19]
Reactant: C1COCCO1
Reactant: NCCO
Reactant: CC(=O)N1CCc2c(nc(-c3ccc(N)cc3)nc2N2CCOC[C@@H]2C)C1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NCCO)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-1-(2-(4-aminophenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethanone (0.100 g, 0.000272 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0416 mL, 0.000299 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.1580 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added Ethanolamine (0.0986 mL, 0.00163 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.80 (d, J=5.5, 1H), 8.18 (dd, J=8.7, 3.1, 2H), 7.69 (s, 1H), 7.48 (d, J=8.5, 2H), 6.26 (s, 1H), 4.69-4.57 (m, 2H), 4.48 (d, J=18.7, 1H), 4.14 (s, 1H), 3.88 (d, J=9.4, 1H), 3.62 (ddd, J=22.1, 21.5, 8.2, 6H), 3.46 (t, J=5.7, 2H), 3.17 (dd, J=11.1, 5.5, 2H), 2.75 (s, 1H), 2.63 (s, 1H), 2.09 (d, J=27.2, 3H), 1.31-1.21 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[CH3:19])=[C:16]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:15]([C:32]#[N:33])=[N:14]1.[CH2:34]1[CH2:38][O:37]CC1.CCCCCCC.[C:46](OCC)(=[O:48])[CH3:47]>CN(C1C=CN=CC=1)C.O>[C:46]([O:23][CH2:22][CH:21]([O:24][C:38](=[O:37])[CH3:34])[CH2:20][N:18]([C:17]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:32]#[N:33])[C:16]=1[S:25]([C:28]([F:31])([F:29])[F:30])(=[O:26])=[O:27])[CH3:19])(=[O:48])[CH3:47]
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Reactant: CN(CC(O)CO)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCCCCCC
Product: CC(=O)OCC(CN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)OC(C)=O

Procedure:
To a mixture of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(2,3-dihydroxypropyl)(methyl)amino]-4-[(trifluoromethyl)sulfonyl]-1H-pyrazole-3-carbonitrile (0.20 g, 0.4 mmol) in THF (4 mL) acetanhydride (75 mg, 0.7 mmol) and DMAP (14 mg, 0.1 mmol) was added. The mixture was heated to reflux for 5 h. Extractive workup (heptane-ethyl acetate, water) gave the title product (Compound 02-06, 0.20 g) as an oil; 1H-NMR: 1.98 and 2.08 (COCH3), 3.05 (NMe), 3.05 and 3.15 (NCH2), 3.88 and 4.16 (CH2O), 5.11 (CHO), 7.85 (ArH) ppm; 19F-NMR: −64.2 (PhCF3); −79.5 ppm (SO2CF3).