Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>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.CC#N>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:13]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
Phenylboronic acid (732 mg, 6 mmol), 2-bromo-5-methylpyridine (1.03 g, 5.99 mmol), and Pd (PPh3)4 (350 mg, 0.303 mmol) were heated in 0.4 M K2CO3 (30 mL, 12 mmol) and CH3CN (30 mL) at 90° overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and ethyl acetate. The organic layer was separated, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 hexanes:ethyl acetate) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (m, 1H), 8.05 (m, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.68-7.71 (m, 1H), 7.37-7.50 (m, 3H), 2.34 (s, 3H); MS (APCI+) m/z 170 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C@H:20]2[CH2:25][CH2:24][C@@H:23]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])[CH2:22][C@H:21]2[CH2:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:16]1=[O:42])=[O:13].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([NH+:14]([O-:4])[C@H:15]1[CH2:19][CH2:18][N:17]([C@H:20]2[CH2:25][CH2:24][C@@H:23]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])[CH2:22][C@H:21]2[CH2:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)(=[O:33])=[O:34])[C:16]1=[O:42])=[O:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cccc(Cl)c3)C2=O)[C@H](CS(=O)(=O)c2ccc(Cl)cc2)C1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H]([NH+]([O-])C(=O)c3cccc(Cl)c3)C2=O)[C@H](CS(=O)(=O)c2ccc(Cl)cc2)C1
Reaction time: 1.25 h
Yield: 58.2 %

Procedure:
A solution of Example 86 (13.6 mg) in CH2Cl2 (1.5 mL) was cooled to 0° C., then 3-chloroperoxybenzoic acid (77%, 10 mg) was added portion-wise. The mixture was stirred for 1.25 h, then diluted with CH2Cl2 (400 mL), washed with satd NaHCO3 (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative HPLC to give the title compound (6.8 mg, 57%) as a white solid after lyophilization from MeCN/aqueous TFA. ESI MS m/z 596 [C28H35Cl2N3O5S+H]+.
Reaction SMILES: C1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][N:15]1[C:19]([OH:20])=[C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:17]([CH3:30])=[N:16]1.[C:31](Cl)(=[O:33])[CH3:32]>O>[CH3:14][N:15]1[C:19]([O:20][C:31](=[O:33])[CH3:32])=[C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:17]([CH3:30])=[N:16]1
Reactant: CC(=O)Cl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)Oc1c(C(=O)c2ccccc2Cl)c(C)nn1C
Yield: 82.2 %

Procedure:
In a mixture of 20 ml. of benzene and 0.51 g. of triethylamine is dissolved 1.25 g. of 1,3-dimethyl-4-(2-chlorobenzoyl)-5-hydroxypyrazole and 0.4 g. of acetyl chloride is added dropwise at room temperature with stirring. After completion of the dripwise addition, the mixture is stirred at room temperature for 3 hours. After completion of the reaction, water is added to the reaction mixture to dissolve the salts and an organic layer is separated. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The resulting oily substance is recrystallized from n-hexane to give crude crystalline substance. The substance is recrystallized from methanol to give 1.20 g. of the desired product as colorless prisms melting at 78°-79° C. Yield 82.2%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2N=C(N3CCNC(C4C=C5C(=CC=4)N(C)N=C5)C3=O)SC=2C=1C1C=CC(Cl)=CC=1)C(OCC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-n3ccnc(-c4ccc5c(cnn5C)c4)c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3=O)sc2c1-c1ccc(Cl)cc1
Product: Cc1cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid (5 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyrazin-1 (2H)-yl)benzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyrazin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C32H33ClN5O4S: 618.2 (M+H+); Found: 618.1 (M+H+). 1H-NMR 400 MHz, (CDCl3) δ 7.99 (m, 1H), 7.74-7.60 (m, 3H), 7.43-7.35 (m, 4H), 7.3-7.2 (m, 1H), 5.31 (s, 1H), 5.13 (m, 1H), 4.62-4.35 (m, 2H), 4.06 (s, 3H), 3.3 (m, 2H), 2.57 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].Br[C:9]1[C:10]2[S:32][CH:31]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:11]=2[S:12][C:13]=1[C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[C:48]([O-])([O-])=O.[K+].[K+].[Cl-].[Na+]>CN(C)C=O>[CH2:6]([O:5][C:1]([C:2]1[S:3][C:9]2[C:10]3[S:32][CH:31]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:11]=3[S:12][C:13]=2[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:48])=[O:4])[CH3:7]
Reactant: CCCCCCCCCCCCCCCc1csc2c(Br)c(C(=O)CCCCCCCCCCCCCC)sc12
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CS
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCCCCCCC)c(C(=O)OCC)sc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
ethyl thioglycolate (0.85 g, 0.77 mL, 7 mmol) was added to a mixture of 4 (4.5 g, 6.74 mmol), K2CO3 (1.86 g, 13.5 mmol), and N,N-dimethylformamide (DMF) (70 mL) at room temperature. The resulting mixture was stirred for 12 hrs at room temperature and another 12 hrs at 50° C. The mixture was then poured into an aqueous sodium chloride solution (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated, washed with saturated aqueous sodium chloride solution (4×150 mL), and dried over MgSO4. The crude product was obtained after evaporating off the solvent and used in the next step without further purification (4.2 g, 91% yield).
Reaction SMILES: [H-].[Na+].[CH3:3]CCCCC.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2.CI>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([N:29]([CH3:3])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2
Reactant: CCCCCC
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)N(C)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 0.23 g (5.7 mmol) of a 60 percent NaH/oil dispersion and 10 ml of hexane was stirred under N2 for 10 minutes. The hexane was decanted off, replaced with 20 ml of DMF and a solution of 2.0 g (4.1 mmol) of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(trifluoromethoxy)phenyl)propanamide in 20 ml of DMF was added dropwise over a period of 30 minutes. The mixture was stirred at ambient temperature for 1.5 hours when a solution of 1.45 g (10 mmol) of methyl iodide in 10 ml of DMF was slowly added. The mixture was stirred at ambient temperature for 2 days and then quenched by cautious addition of a few drops of acetic acid and then water. The mixture was poured into water, extracted with three portions of ether and the combined organic layers dried over MgSO4 and evaporated to dryness. The residue was taken up in hot methylcyclohexane, treated with charcoal and filtered and then allowed to cool to give 1.03 g (50 percent) of the above-named product as colorless crystals, m.p. 137°-139° C. (Compound 41)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[Br:21]N1C(=O)CCC1=O.CSC>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:21])=[CH:4][C:3]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(I)c(Oc2ccc3ccccc3c2)c1
Solvent: CSC
Solvent: ClCCl
Product: BrCc1ccc(I)c(Oc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
To a solution of [4-iodo-3-(naphthalen-2-yloxy)-phenyl]-methanol (0.085 g, 0.226 mmol) in CH2Cl2 (2 mL) at −15° C. was added a cold (0° C.) solution of N-bromosuccinimide (0.120 g, 0.68 mmol) in dimethyl sulfide (0.060 mL, 0.814 mmol) with stirring. The reaction mixture was allowed to warm to ambient temperature overnight, concentrated to dryness, and chromatographed (SiO2, 10% EtOAc:hexane) to give the title compound which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.C(OCC)(=O)C>[Si:23]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (22.1 g, 82.6 mmol) was dissolved in dry DMF (100 mL) under nitrogen. Imidazole (16.8 g, 248 mmol) was added and the mixture cooled to 0° C. tert-Butyldimethylsilyl chloride (13.1 g, 86.7 mmol) was added in small portions and then the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was diluted with 300 mL ethyl acetate and washed with water three times (500 mL, 200 mL, 200 mL). The organic extracts were washed one final time with brine and then dried over MgSO4, filtered and concentrated to give 29.5 g (99%) of desired product as a colorless oil. LC/MS (M-Boc+H)+ m/z=260.2. 1H NMR (CDCl3) δ 4.30-4.47 (m, 2H), 3.73 and 3.75 (s, 3H), 3.60 (m, 1H), 3.28-3.45 (m, 1H), 2.18 (m, 1H), 2.03 (m, 1H), 1.42 and 1.47 (s, 9H), 0.87 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[C:25](=O)[CH2:24][CH:23]2[CH2:27][CH:19]1[CH2:20][CH2:21][CH:22]2[O:28]C(=O)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:25][CH2:24][CH:23]2[CH2:27][CH:19]1[CH2:20][CH2:21][CH:22]2[OH:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC1CCC2CC1CC(=O)N2Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC1CCC2CC1CCN2Cc1ccccc1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Diisobutylaluminum hydride (1.5 mol/L in toluene, 21 mL) is added to a solution of acetic acid 2-benzyl-3-oxo-2-aza-bicyclo[3.3.1]non-6-yl ester (1.50 g, for synthesis see J. Chem. Soc. Perkin Trans. 1 1999, 1157-1162) in toluene (30 mL) cooled to −70° C. The cooling bath is removed and the solution is stirred at ambient temperature overnight. Then, another portion of diisobutylaluminum hydride (1.5 mol/L in toluene, 20 mL) is added and the solution is stirred for additional 4 h at room temperature. Then, the solution is poured into ice-cold water and the resulting mixture is extracted with ethyl acetate. The aqueous phase is acidified using 4 M hydrochloric acid and extracted one more time with ethyl acetate. The combined organic extracts are dried (Na2SO4) and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->2:1).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[Cl:33])N>C(#N)C>[Cl:33][C:32]1[CH:31]=[CH:30][C:28]([NH:16][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=2)=[O:15])=[CH:27][C:26]=1[C:25]([F:24])([F:34])[F:35]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 11 h
Yield: 76.8 %

Procedure:
To the dry N,N-dimethylformamide (45 ml) and 1-(4-hydroxyphenyl)urea (15 g, 0.0985 mol) solution were added triethylamine (34 ml, 0.24646 mol) and 3-trifluoromethyl-4-chloroaniline (19.28 g, 0.0985 mol) in one lot. This reaction mass was then agitated at 100° C. for 10-12 hours, quenched in water and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was back washed with water and dried over sodium sulfate. It was evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (100 ml) at ambient temperature, filtered and washed repeatedly with acetonitrile till the clear filtrate was obtained. The obtained cake was then suck dried for 10 minutes and vacuum dried at 50° C. to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (25 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[C:33]=1[CH3:34].[CH3:35][S:36]([O-:38])=[O:37].[Na+].CNCCNC.CS(C)=O>CCOC(C)=O>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[C:33]([CH3:34])=[C:2]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1c(Br)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(S(C)(=O)=O)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 110 °C

Procedure:
A mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 63, 100 mg, 0.180 mmol) sodium methyl sulfinate (55.2 mg, 0.541 mmol) and copper (II) triflate benzene complex (27.2 mg, 0.054 mmol) was flushed with nitrogen and capped, and was added N,N′-dimethyl ethylenediamine (0.12 mL, 0.108 mmol), and DMSO (0.60 mL). The mixture was heated to 110° C. for 36 h. After cooling to rt, the reaction mixture was diluted with EtOAc, filtered through silica gel, the filtrated was washed with water and brine, and concentrated. The residue was purified by reverse phase HPLC to provide the title compound as a racemic mixture. LC/MS: m/e 553.9 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 7.87 (1H, d), 7.63 (1H, d), 7.19 (2H, d), 7.13 (1H, d), 7.07 (1H, d), 7.02 (2H, d), 5.21 (1H, d), 4.45 (1H, d), 3.15 (3H, s), 2.87 (3H, s), 1.23 (9H, s). The racemic mixture was separated on a Chiracel OD-H column eluting with 20% EtOH in hexanes, at 8.0 mL/min. The faster eluting enantiomer E1 has a retention time of 15.7 min. The slower eluting enantiomer E2 has a retention time of 28.5 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:16][C:17]1[CH:28]=[CH:27][C:20]([CH:21]=NC(C)(C)C)=[C:19](F)[CH:18]=1.CS(C)=[O:32]>O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:27]2[CH:28]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=2[CH:21]=[O:32])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=Cc1ccc(Br)cc1F
Reactant: CS(C)=O
Reactant: CC1(O)CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(Oc2cc(Br)ccc2C=O)C1
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound from Step B (400 mg, 2.2 mmol) in DMSO (8 mL) was added 60% NaH (120 mg, 3.0 mmol). After 30 min, the title compound from Step A was added and the resulting mixture was heated at 125° C. for 1 h in a microwave reactor. An additional quantity of the title compound from Step B (100 mg) and 60% NaH (32 mg) were added to the reaction. Heating was then resumed at 125° C. for another 1 h in a microwave reactor. The reaction was diluted with H2O and extracted with EtOAc (3×) followed by methanolic EtOAc (2×). The organics were dried, then THF (5 mL), H2O (5 mL) and AcOH (3 mL) were added. After 18 h at rt, the reaction was diluted with H2O and extracted with CH2Cl2. The organics were dried and purified by PTLC to give the title compound as an off white solid (247 mg, 31%). 1H NMR (CDCl3): 10.36 (s, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.22-7.20 (m, 1H), 6.68 (d, J=1.6 Hz, 1H), 4.25 (d, J=9.2 Hz, 2H), 4.03 (d, J=9.8 Hz, 2H), 1.55 (s, 3H), 1.46 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:46])[CH2:20][CH2:21][C:22]2[N:23]=[N:24][N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:26]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].Cl.C(O)(C)C.C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:46])[CH2:20][CH2:21][C:22]2[N:26]=[N:25][NH:24][N:23]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CCc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O=CO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CCc3nn[nH]n3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-(2,4-dimethylphenyl)-4-(1-hydroxy-3-(2-trityl-2H-tetrazol-5-yl)propyl)-N-isobutylbenzenesulfonamide (20 mg, 0.029 mmol), at room temperature was treated with a solution of HCl (6N in isopropanol, 2 mL, 12.00 mmol) and isopropanol (2 mL). The reaction mixture was stirred at 20° C. for 2 hours, then the solvent evaporated in vacuo and the crude partitioned between ethyl acetate (5 mL) and water (5 mL). The organic phase was separated by hydrophilic frit then evaporated in vacuo to give a residue. LCMS analysis showed the reaction was incomplete, so the residue was re-dissolved in dichloromethane (DCM) (2 mL) and treated with formic acid (0.5 mL, 13.04 mmol). The solution was left to stand for 2 hours. The solvent was evaporated in vacuo then dissolved in a 1:1 mixture of MeOH and DMSO and purified by MDAP (Method F) to give the required product, 3.69 mg. LCMS (M+1) 444, RT 1.09 mins.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][C:2]=1[NH2:10].[H-].[Na+].Cl[CH2:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:17]=2[N:16]=1>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:17]2[N:16]=[C:15]([CH2:14][N:5]3[CH:6]=[N:7][C:8]4[C:4]3=[N:3][C:2]([NH2:10])=[N:1][CH:9]=4)[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=2[CH:26]=1
Reactant: Fc1ccc2nc(CCl)n(-c3ccccc3)c2c1
Reactant: Nc1ncc2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2ncn(Cc3nc4ccc(F)cc4n3-c3ccccc3)c2n1
Reaction time: 0.08 h
Yield: 46.5 %

Procedure:
To a stirred mixture of 9H-purin-2-ylamine (93 mg, 0.69 mmol) in DMF (1 mL) at RT and under a nitrogen atmosphere was added NaH (60% in mineral oil, 23 mg, 0.69 mmol). After 5 min, 2-chloromethyl-6-fluoro-1-phenyl-1H-benzoimidazole (150 mg, 0.575 mmol) in DMF (1 mL) was added. Stirring was continued for 18 h at RT. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 372 as a white solid (96 mg, 47%). LCMS (Method K): RT 3.17 min [M+H]+360.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.56 (1H, s), 8.00 (1H, s), 7.70-7.57 (6H, m), 7.16-7.07 (1H, m), 6.97 (1H, dd, J=8.93, 2.50 Hz), 6.43 (2H, s), 5.48 (2H, s)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:10][C:11]([Cl:18])([Cl:17])[CH2:12][O:13][C:14](Cl)=[O:15].[CH3:19][C:20]1[NH:21][C:22](=[O:26])[CH2:23][S:24][CH:25]=1>>[CH3:19][C:20]1[NH:21][C:22](=[O:26])[CH2:23][S:24][C:25]=1[CH:9]1[CH:8]=[CH:7][N:6]([C:14]([O:13][CH2:12][C:11]([Cl:18])([Cl:17])[Cl:10])=[O:15])[CH:5]=[C:4]1[C:1](=[O:3])[CH3:2]
Reactant: CC1=CSCC(=O)N1
Reactant: CC(=O)c1cccnc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Product: CC(=O)C1=CN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Yield: 42 %

Procedure:
A mixture of 3-acetylpyridine (2.18 ml), 2,2,2-trichloroethylchloroformate (3.44 ml) and 5-methyl-2H-1,4-thiazin-3(4H)-one (1.29 g) was treated in the same manner as described in Example 2 (i) to give the titled compound (1.77 g, yield 42%) as pale yellow crystals. Ethyl acetate-n-hexane (=1:1) was used as a developing eluant.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:41])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:40])[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[C:26]1[O:27][C:28]([C:29]([F:32])([F:30])[F:31])=[C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([OH:42])=[O:2])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)=[O:41])=[O:23])[N:25]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[2-(2,6-dichloro-phenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (459 mg, 0.733 mmol) was put into THF/water (50 mL, 3:1) solvent, and NaOH (146.54 mg, 3.663 mmol) was added thereto. The mixture was stirred for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain the desired compound (434 mg, 97%) as a white solid.