Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([Cl:22])=[O:5]
Reactant: CC(C)C(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)Cl)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-methyl-2-phenylbutyric acid (891 mg; 5.0 mmol) and a catalytic amount of dry dimethylformamide (ca. 10 uL) in 10 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (0.65 mL; 7.5 mmol) dropwise. After 1 hour, the mixture was concentrated in vacuo and used immediately for Step 2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[NH2:20][CH2:21][C@@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[Si:24]([O:23][C@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:21][NH:20][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A mixture of Intermediate 26 (0.33 g, 1.0 mmol) and Intermediate 2 (0.40 g, 1.2 mmol) in DMF (5 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.25 mL, 1.5 mmol) and catalytic potassium iodide. The mixture was heated overnight in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 12 g Isco RediSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound (0.53 g, 90%). ES/MS calcd. for C30H37F3N3O4Si+588.3. found m/z=588.4 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:14][CH3:15])[CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][S:2]([CH3:1])(=[O:4])=[O:3])=[C:9]([CH2:14][CH3:15])[CH:8]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1NS(C)(=O)=O
Reaction time: 1 h

Procedure:
Methane sulfonyl chloride (1.93 ml, 0.025M) was added to a solution of 4-bromo-2-ethylaniline (5.0 g, 0.025M) and pyridine (2.02 ml, 0.025M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a clear oil (4.77 g).
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][N:24]([CH2:26][C:27]([N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)=[O:28])[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([NH:36]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:34][CH:35]=1)[CH3:37])=[O:28])[CH3:23]
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Product: CN(C)CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[S:17][C:13]=2[C:12]=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: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3ccccn3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)c(-c3ccccn3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(pyridin-2-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (122 mg, 0.2 mmol) in THF (3 mL) and EtOH (1.5 mL). 1M NaOH (1.5 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to rt, and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product as a bright yellow powder. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.1 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.66 (d, J=4.7 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.23 (dd, J=11.1, 4.5 Hz, 1H), 8.02 (dd, J=8.9, 1.3 Hz, 1H), 7.76 (s, 1H), 7.75-7.68 (m, 1H), 7.65-7.53 (m, 5H), 5.26 (s, 1H), 4.14 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:8]([CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:6]=1)=[O:4].[CH3:32]I.[Na]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:8]([CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH3:32])[CH:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1cc(CCCCNS(=O)(=O)c2ccccc2)c2ccc(C(C)C)ccc1-2
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CCCCN(C)S(=O)(=O)c2ccccc2)c2ccc(C(C)C)ccc1-2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 6-Isopropyl-3-[4-(benzenesulfonylamino)butyl]-azulene-1-carboxylic acid methyl ester (0.50 g) in DMF (10 ml) was added to the suspension, and the mixture was stirred at 0° C. for 10 min. Then, methyl iodide (5 ml) was dropped into the solution of the sodium salt, and the mixture was stirred at the same temperature for 30 min. The reaction was quenched by the addition of saturated aqueous NH4Cl, followed by extraction with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, and dried over MgSO4. Removal of the solvent and the purification by silica gel column chromatography (ethyl acetate-n-hexane, 1:1) afforded the sulfonamide (0.51 g 99%) as a violet oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1F.CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH:16]([CH3:17])[CH3:18]
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: CC(C)OC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)OC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 91.4 μmol) was dissolved in DMF (190 μL). NaH (2.6 mg, 109.7 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (21.4 μL, 182.9 mmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (949 μL, 1.1 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt oil (29.5 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO2, 318.10. found 318.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CN
Product: CNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.3 g 1,4-difluoro-2-nitrobenzene are slowly added to 30 ml of a 40% aqueous methylamine solution while cooling with ice and the reaction mixture is stirred for 1 hour at ambient temperature. The precipitated product is suction filtered and recrystallised from water and ethanol. 6.3 g product are obtained as a solid. M.p=74-76° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]2[S:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[C:16]([CH3:17])[C:12]=2[CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:15]1[S:14][C:13]2[CH:22]=[CH:23][C:10]([Cl:9])=[CH:11][C:12]=2[C:16]=1[CH3:17])(=[O:20])=[O:19]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1Br
Yield: 18 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-chloro-3-methylbenzo[b]thiophene-2-sulphonyl chloride in 18% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153-155° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I.[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:10]([CH3:28])[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(c2ccccc2)NC(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccccc2)c2ccccc2C1(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-Benzyl-4-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (1.0 g, 2.8 mmol) in DMF (800 mL) is cooled to 0° C., then NaH (0.134 g, 3.35 mmol) is added. After the addition the mixture is stirred at 0° C. for 0.5 h. Then CH3I (0.79 g, 5.6 mmol) is added and the mixture is stirred at r.t. overnight. Then the mixture is poured into NH4Cl (30 mL) and is extracted with EtOAc, dried over Na2SO4 and concentrated to give product. This is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@H:18]3[CH2:23][OH:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@H:18]3[CH:23]=[O:24])[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:8]=1
Reactant: OC[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: ClCCl
Product: O=C[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 108.4 %

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-hydroxymethyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 29; 1.38 g, 2.5 mmol) in dichloromethane (6 ml) at room temperature was treated with Dess-Martin periodinane (1.07 g, 2.5 mmol) and stirred for 1 hour. The mixture was treated with 5% sodium hydrogen sulfite (50 ml) and saturated sodium hydrogen carbonate (30 ml) and stirred for 5 minutes. The organics were collected, washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow foam (1.24 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][CH:34]=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(=CC)C.Cl([O-])=[O:42].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][C:34]([OH:42])=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 16 mg (0.03 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example 121, Step O) and 1.0 mL (9.4 mmol) of 2-methyl-2-butene in t-BuOH (3 mL) was added a solution of 28 mg (0.31 mmol) of sodium chlorite and 4.6 mg (0.03 mmol) of sodium dihydrogenphosphate dihydrate in water (1.6 mL). The resulting mixture was stirred at room temperature for 2 h, and then was quenched with 1 M HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 35% MeCN in water to 60% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA provided the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:17]=2)[C:12]([C:31](=[O:33])[NH2:32])=[CH:11][N:10]=1>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)[C:12]([C:31](=[O:33])[NH2:32])=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(OCC(=O)O)cc1

Procedure:
A solution of tert-butyl 2-(4-(2-((1R,2S)-2-aminocyclohexylamino)-5-carbamoylpyrimidin-4-ylamino)phenoxy)acetate racemate (180 mg, 0.395 mmol) in TFA (4 mL) was stirred at room temperature for 2 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (60 mg). MS 401.2 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:33]2([CH3:34])[C@H:18]([C@H:19]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:22]([CH2:23][C@H:24]([CH2:26][CH2:27]2)[OH:25])=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([C@:24]1([OH:25])[CH2:26][CH2:27][C@@:28]2([CH3:29])[C:22](=[CH:21][CH2:20][C@@H:19]3[C@@H:30]2[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[CH2:23]1)=[O:3]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@](O)(C(=O)OCCl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
Chloromethyl chloroformate (1.96 g, 15.2 mmol) and cholesterol (5.0 g, 12.9 mmol) was dissolved in CH2Cl2 (10 ml). The solution was cooled. Pyridine (1.21 g, 15.3 mmol) was dripped into the stirred solution over 5 minutes. Heat was produced and the reaction gave a clear solution from a somewhat unclear starting solution. After 24 hours at room temperature, the mixture was diluted with CH2Cl2 (50 ml), washed with 0.5M HCl (50 ml) and water (3×25 ml). After treatment with MgSO4, the solution was evaporated to dryness.
Reaction SMILES: [OH:1][N:2]([CH:6](C1SC2C=CC(CC(C)C)=CC=2C=1)[CH3:7])[C:3]([NH2:5])=[O:4].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[CH:22]1>>[OH:1][N:2]([CH:6]([C:23]1[C:24]2[CH:29]=[C:28]([CH2:23][CH:24]([CH3:29])[CH3:25])[CH:27]=[CH:26][C:25]=2[S:21][CH:22]=1)[CH3:7])[C:3]([NH2:5])=[O:4]
Reactant: CC(C)Cc1ccc2sc(C(C)N(O)C(N)=O)cc2c1
Reactant: c1ccc2sccc2c1
Product: CC(C)Cc1ccc2scc(C(C)N(O)C(N)=O)c2c1

Procedure:
N-hydroxy-N-[1-(5-(2,2-dimethylethyl)benzo[b]thien-2-yl)-ethyl]urea. The desired compound was prepared according to the method of example 2, except using the material prepared as in step c, above, instead of benzothiophene. (R1 =NH2, A=CHCH3, X=S[2-isomer], Y=5-(CH3)3C).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([C:15]([C:17]2[C:26]([Cl:27])=[CH:25][C:20]([CH2:21][N:22]=[N+:23]=[N-:24])=[CH:19][C:18]=2[Cl:28])=[O:16])=[CH:13][CH:12]=1>C(O)C>[NH2:2][C:1]1[N:22]([CH2:21][C:20]2[CH:19]=[C:18]([Cl:28])[C:17]([C:15](=[O:16])[C:14]3[CH:29]=[CH:30][C:11]([Cl:10])=[CH:12][CH:13]=3)=[C:26]([Cl:27])[CH:25]=2)[N:23]=[N:24][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Yield: 41.2 %

Procedure:
A suspension of 2-cyanoacetamide (149 mg, 1.77 mmol) in ethanol (5 ml) was refluxed 20 minutes with sodium methoxide (93 mg, 1.72 mmol), cooled slightly, treated with 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl azide (450 mg, 1.32 mmol), and refluxed 1 hour. The mixture was cooled, evaporated under vacuum, and chromatographed on a column of silica gel (50 g), eluted with 19:1 (v/v) dichloromethane-methanol to provide 231 mg (41%) of 5-amino-1(4-[4-chlorobenzoyl]-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 198.5°-200° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10]C(C#N)=[C:6]([Br:12])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:15][C:16]([OH:18])=[O:17]>O.OS(O)(=O)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:15]([C:16]([OH:18])=[O:17])=[C:6]([Br:12])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C#N)c(Br)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(C(=O)O)c(Br)c1

Procedure:
A solution of the product obtained in step 2 (0.5 g, 2.23 mmol) in AcOH (2.5 mL), H2O (2.5 mL) and concentrated H2SO4 (2.5 mL) was refluxed for 5 h. After cooling, the reaction mixture was adjusted with 10 N NaOH to pH=10 and washed with AcOEt. The aqueous layer was acidified with concentrated HCl to pH=1 and then extracted with AcOEt. The organic phase was washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The crude product was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([CH3:33])[CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[CH2:36](OC(=O)C1C=CC(N)=CC=1C)[CH3:37]>>[CH2:36]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:34][CH3:35])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])=[CH:25][C:26]=1[CH3:33])[CH3:37]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)c(C)c3)cc21
Reactant: CCOC(=O)c1ccc(N)cc1C
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1C

Procedure:
4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methyl-benzoic acid, MS (ISP): m/e=515.0 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using 4-amino-2-methyl-benzoic acid ethyl ester and yielded 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methyl-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5([C:37]#[N:38])[CH2:36][CH2:35]5)[CH:29]=4)[CH:25]=3)[CH:16]=[CH:15][C:13]=2[N:14]=1.O1C=C(C(O)=O)N=C1.C(Cl)(=O)C(Cl)=O>CN(C)C(=O)C.CN(C)C=O.O1CCCC1>[C:37]([C:34]1([C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([NH:26][C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=2[CH3:40])[O:19][C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:10]([NH:9][C:6]([C:4]4[N:3]=[CH:2][O:1][CH:5]=4)=[O:7])[S:11][C:12]=3[CH:18]=2)=[O:39])[CH2:36][CH2:35]1)#[N:38]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=C(Cl)c1cocn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cocn1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 1,3-oxazole-4-carbonyl chloride synthesized above in N,N-dimethylacetamide (3 mL) was added N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) produced in Example A3(iv), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of 1,3-oxazole-4-carbonyl chloride synthesized in the same manner as in the above from 1,3-oxazole-4-carboxylic acid (30 mg, 0.265 mmol), oxalyl chloride (27 μL, 0.316 mmol), N,N-dimethylformamide (1 drop) and tetrahydrofuran (1 mL) in N,N-dimethylacetamide (1 mL), and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, diluted with 5% aqueous sodium hydrogencarbonate solution (200 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate/hexane to give the title compound (3.84 g, 75%) as a colorless solid.