Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[CH3:14]C(C)([O-])C.[K+].[F:20][C:21]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C=O)C>[F:20][C:21]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:22]=1[CH2:23][N:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COC(=O)c1cc2ccncc2[nH]1
Reactant: Fc1cc(I)ccc1CBr
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccncc2n1Cc1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 45.9 %

Procedure:
To a suspension of methyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.81 g, 4.26 mmol) in DMF (15 ml) was added potassium tert-butoxide (0.72 g, 6.39 mmol). After the resultant red-brown suspension had been stirred for 40 minutes, a solution of 2-fluoro-4-iodobenzyl bromide (2.01 g, 6.39 mmol) in DMF (5 ml) was added dropwise over 10 minutes. The suspension was then heated to 60° C. for 35 minutes before stirring at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the resultant residue partitioned between dichloromethane (40 ml) and water (30 ml) and the organic layer separated. The aqueous layer was extracted with dichloromethane (2×25 ml) and the combined organic extracts were washed with brine (30 ml) dried over magnesium sulphate, then concentrated in vacuo to provide a residue. The residue was purified by flash chromatography (Si-SPE, dichloromethane:ethyl acetate 100:0 to 50:50 to 0:100 then dichloromethane:methanol 90:10 to 80:20) gave the title compound as a pale cream solid (0.83 g, 46%). LCMS (method B): RT=2.58 min, M+H+=425.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[CH:15][C:14]([C:27]([F:30])([F:29])[F:28])=[N:13]2)=[CH:8][CH:7]=1.O.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[CH:15][C:14]([C:27]([F:28])([F:29])[F:30])=[N:13]2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Acetyl chloride (0.31 g) was added dropwise to an ice-cooled solution of 1-(4-hydroxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (1 g) in pyridine (10 ml). The mixture was stirred at 5° C. for 3 hours, poured into water, and acidified with hydrochloric acid. The precipitates were filtered and purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1) to give a yellow powder of 1-(4-acetoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (0.9 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:42])[CH3:41])=[CH:16][N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:37].[ClH:37].[ClH:37].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:32]=[C:33]([Cl:39])[C:34]([OH:38])=[C:35]([Cl:37])[CH:36]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:42])[CH3:41])=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(N)C2)nc1
Product: Cl
Yield: 98 %

Procedure:
Following general procedure IV-2, tert-butyl[1-(5-{[3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (0.20 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (31 mg, 30% over two steps) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.38 (s, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.25 (d, J=2.6 Hz, 1H), 7.92-7.86 (m, 1H), 7.58 (s, 2H), 7.24 (d, J=9.5 Hz, 1H), 4.41-4.34 (m, 1H), 4.03-3.96 (m, 1H), 3.53-3.32 (m, 4H), 2.84 (s, 3H), 2.24-2.21 (m, 1H), 2.05-1.97 (m, 1H), 1.84-1.76 (m, 2H); ESI MS m/z 523 [M+H]+; HPLC 98.0% (AUC), tR=9.48 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([NH2:27])[CH:21]=[CH:20]2.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClCCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][NH:27][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=2)[CH:23]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccc2cc(Br)ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC[C@H](C)[C@@H](CNc1ccc2cc(Br)ccc2c1)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
((1S,2S)-1-Formyl-2-methyl-butyl)-carbamic acid tert-butyl ester (1.62 g, 7.5 mmol), and 6-bromo-naphthalen-2-ylamine (1.11 g, 5.0 mmol) were combined in DCE (10 mL). After stirring 5 min, NaBH(OAc)3 (2.33 g, 11 mmol) was added. The whole mixture was then stirred at r.t. for 18 h. The reaction mixture was transferred to a separatory funnel containing water (50 mL). The aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified via column chromatography on silica gel (10% ethyl acetate in hexanes) to afford {(1S,2S)-1-[(6-bromo-naphthalen-2-ylamino)-methyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (1.78 g, 85% yield) as an off-white solid. LC/MS (ESI) m/e 423.2 [(M+H)+, calcd for C21H29BrN2O2 421.4].
Reaction SMILES: [C:1]([CH2:8][C:9]([O:11][CH2:12][CH2:13][C:14]#[N:15])=[O:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17].N1CCCCC1.C(O)(=O)C>CC(O)C>[C:14]([CH2:13][CH2:12][O:11][C:9](=[O:10])[C:8](=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])#[N:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCC(=O)CC(=O)OCCC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCCCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-cyanoethyl hexanoylacetate (21.1 g, 100 mmol), 4-nitrobenzaldehyde (16.6 g, 110 mmol), piperidine (430 mg, 5.00 mmol) and acetic acid (300 mg, 5.00 mmol) in 350 ml of 2-propanol was stirred at room temperature for 48 hrs. The resulting white precipitate was filtered and dried in the air. The product, 2-[(4-nitrophenyl)methylene]-3-oxooctanoic acid 2-cyanoethyl ester was obtained as a white powder (25.2 g, 73% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10](O)(=[O:12])[CH3:11]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: NNc1ccc(I)cc1
Reactant: CC(=O)O
Product: CC(=O)NNc1ccc(I)cc1

Procedure:
A mixture of 10 g of 4-iodophenylhydrazine in 80 ml of acetic acid is refluxed for 5 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water, and the precipitate formed is filter-dried and washed with a propan-2-ol/PE (50/50; v/v) mixture. 9 g of the expected compound are obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:46]1[CH:55]=[C:54]2[C:49]([CH:50]=[C:51]([C:57]3[CH:58]=[N:59][CH:60]=[C:61]([F:64])[C:62]=3[CH3:63])[N+:52]([O-:56])=[CH:53]2)=[CH:48][N:47]=1.[CH:65]1([C:68]([NH2:70])=[O:69])[CH2:67][CH2:66]1>O1CCOCC1.ClCCl.CO>[CH:65]1([C:68]([NH:70][C:46]2[CH:55]=[C:54]3[C:49]([CH:50]=[C:51]([C:57]4[CH:58]=[N:59][CH:60]=[C:61]([F:64])[C:62]=4[CH3:63])[N+:52]([O-:56])=[CH:53]3)=[CH:48][N:47]=2)=[O:69])[CH2:67][CH2:66]1
Reactant: Cc1c(F)cncc1-c1cc2cnc(Cl)cc2c[n+]1[O-]
Reactant: NC(=O)C1CC1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)C3CC3)cc2c[n+]1[O-]
Temperature: 100 °C

Procedure:
A mixture of chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (28 mg, 0.035 mmol), cesium carbonate (227 mg, 0.69 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (19 mg, 0.035 mmol), 7-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide (100 mg, 0.35 mmol), and cyclopropanecarboxamide (59 mg, 0.69 mmol) in dioxane (2 mL) was heated at 100° C. for 8 hours in a vial sealed with a Teflon cap. The reaction mixture was diluted with dichloromethane (50 mL) and methanol (5 mL), filtered over Celite, and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% ACN in water w/0.1% NH4OH, 14 min) Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.14 (s, 2H), 8.63 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 2.12 (d, J=1.5 Hz, 3H), 2.08 (m, 1H), 0.86 (m, 4H). LCMS (Method E): RT=3.626 min, M+H+=339.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[Mg].[CH3:11][N:12]([CH3:23])[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[O:16][CH2:17][C:18]#N.CC[O:26]CC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:18](=[O:26])[CH2:17][O:16][C:15]2[CH:20]=[CH:21][CH:22]=[C:13]([N:12]([CH3:23])[CH3:11])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: CCOCC
Reactant: CN(C)c1cccc(OCC#N)c1
Agent: [Mg]
Product: CN(C)c1cccc(OCC(=O)Cc2cccc(Cl)c2)c1
Temperature: 0 °C

Procedure:
A solution of 10.0 g of 3-chlorobenzyl chloride in 75 ml of dry ether was added slowly to 2.25 g of magnesium powder in 75 ml of dry ether under nitrogen. The Grignard reagent was stirred at ambient temperature for one hour and then added to a solution of 5.47 g of 3-(dimethylamino)phenoxyacetonitrile in 200 ml of dry ether stirred at 0° C. The reaction was warmed to room temperature overnight and then quenched with of NH4Cl solution. The mixture was diluted with of water and the layers separated. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography (silica gel; 8:1 hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give 4.3 g of 1-(3-chlorophenyl)-3-[3-dimethylamino)phenoxy]-2-propanone, m.p. 82°-83° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]([NH2:15])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH3:3].CCCCCC.C(O)(C)C.C(NCC)C>>[CH3:3][N:2]([CH2:4][C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([NH2:15])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH3:1].[CH3:3][N:2]([CH2:4][C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([NH2:15])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CCc2ccc(N)cc2C1
Solvent: CCNCC
Solvent: CC(C)O
Solvent: CCCCCC
Product: CN(C)C[C@@H]1CCc2ccc(N)cc2C1
Product: CN(C)C[C@H]1CCc2ccc(N)cc2C1

Procedure:
7-[(Dimethylamino)methyl]-5,6,7,8-tetrahydronaphthalen-2-amine was optically resolved, using CHIRALPAK AD-H (20 mm×250 mm) (hexane/isopropanol/diethylamine=85/15/0.1) to obtain 237 mg of (7R*)-7-[(dimethylamino)methyl]-5,6,7,8-tetrahydronaphthalen-2-amine, and 243 mg of (7S*)-7-[(dimethylamino)methyl]-5,6,7,8-tetrahydronaphthalen-2-amine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(OCC)(=O)C>C1COCC1>[NH2:7][CH2:8][CH2:9][S:10]([C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)=[O:39]
Reactant: CC(C)(C)OC(=O)NCCSc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCS(=O)c1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C

Procedure:
A solution of [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester (from Example 39 above) (150 mg, 0.35 mmol) in THF (approximately 15 mL) was treated with mCPBA (Acros, 97 mg, 0.42 mmol, 75%) at 0° C. The reaction mixture was allowed to stir and warm up to room temperature overnight. The mixture was poured into ethyl acetate and washed successively with aqueous saturated Na2S2O3 and aqueous saturated K2CO3. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by HPLC (silica gel, 40% ethyl acetate in hexanes). The resulting intermediate was precipitated out of THF with excess of pentane. This material was then dissolved at 0° C. in 50% TFA in CH2Cl2 solution (10 mL) that contained H2O (0.5 mL) and stirred for 2 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and extracted with aqueous ammonium hydroxide. The organic layer was dried over Na2SO4, filtered and concentrated to an orange solid. This solid was dissolved in THF and precipitated with excess of pentane to give 5-(2-amino-ethanesulfinyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as an orange solid. (Yield 75 mg, 62%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC[C:8]1[CH:38]=[CH:37][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([C:24]4[N:25]=[C:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[S:27][CH:28]=4)=[CH:22][CH:21]=[C:20]([O:35][CH3:36])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1.[CH2:39]1COCC1>>[CH3:36][O:35][C:20]1[C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:37]=[CH:38][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:9][C:10]=3[CH3:39])[S:16][C:17]=2[C:23]([C:24]2[N:25]=[C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[S:27][CH:28]=2)=[CH:22][CH:21]=1
Reactant: C1CCNC1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Product: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(NC(=O)c3ccc(N4CCCC4)cc3C)nc12
Temperature: 25 °C
Yield: 87 %

Procedure:
0.032 g pyrrolidine (0.00045 Mol) and 0.075 g (4-chloromethyl-N-[4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-yl]-benzamide (0.00015 Mol) dissolved in THF (2 ml) were heated to reflux for 1 h. After cooling to room temperature and evaporation of the solvent the residue was triturated with water (7 ml). A precipitation formed, which was filtered, washed with water and dried yielding the title product as an off-white solid (87%); F.p.: 120-130° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[O:14]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C(O)(=O)C>N1C=CC=CC=1>[C:10]([O:9][C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[NH:1][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:22][CH:23]=1)=[O:29])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccsc1N
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccsc1NC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of t-butyl 2-amino-thiophene-3-carboxylate (0.6 g) in dry pyridine (20 ml) was added 4-phenoxyphenylisocyanate (0.84 g). The mixture was stirred for 48 h, then the dark coloured solution was poured into water (200 ml). The stirred mixture was acidified with acetic acid and a precipitate slowly solidified to give a brown solid. After about 1 hr, the solid was filtered off, dried in vacuo and recrystallised from acetonitrile, giving an off-white solid. MP=203-205° C. Yield=0.6 g (48.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:47]=[C:48]([C@@H:51]3[CH2:55][C@H:54]([CH3:56])[CH2:53][NH:52]3)[NH:49][CH:50]=2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:52]1[CH2:53][C@@H:54]([CH3:56])[CH2:55][C@H:51]1[C:48]1[NH:49][CH:50]=[C:46]([C:43]2[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=2)[N:47]=1)=[O:8])[CH:10]([CH3:12])[CH3:11]
Reactant: C[C@@H]1CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (103 mg, 0.59 mmol, Preparation 3) and HATU (270 mg, 0.71 mmol) were stirred in DMA (2 mL) for 10 min and then 4-(4-Bromo-phenyl)-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazole 2 HCl (224 mg, 0.59 mmol, Preparation 4) and N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) were added. The resulting mixture was stirred at RT overnight, diluted with ethyl acetate (50 mL), and washed with water (2×5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes)). Fractions with desired product were combined and concentrated to give the title compound (183 mg, 66% yield) (m/z): [M+H]+ calcd for C21H27BrN4O3 463.13; 465.12. found 465.3.
Reaction SMILES: C1C=CN=CC=1.F.[CH3:8][O:9][C:10](=[O:52])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][C@H:17]1[C@H:21]([Cl:22])[CH2:20][C@@H:19]([O:23][Si](C(C)(C)C)(C)C)[C@@H:18]1[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([O:44][Si](C(C)(C)C)(C)C)[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:33][CH:32]=1>CC#N>[CH3:8][O:9][C:10](=[O:52])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][C@H:17]1[C@H:21]([Cl:22])[CH2:20][C@@H:19]([OH:23])[C@@H:18]1[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[OH:44])=[CH:35][CH:36]=1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](c2ccc(C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)cc2)[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cl
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](c2ccc(C(O)C3CCCCC3)cc2)[C@H](O)C[C@H]1Cl
Reaction time: 1 h
Yield: 232.6 %

Procedure:
HF-pyridine (0.60 mL) was added to a 0° C. CH3CN solution of chloride 6-2 (24 mg, 20%) and the mono TBS derivative (36 mg, 36%). The reaction was stirred for 1 h, and then was quenched by addition of saturated NaHCO3 solution. The mixture was extracted with dichloromethane (3×30 mL) and the combined dichloromethane solution dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (20% ethyl acetate/hexanes) gave the title diol 6-3 (37 mg, 93%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[OH:8])=[O:6])[CH:2]=[CH2:3].[OH-].[Na+].Cl[C:19](OCC)=[O:20]>O1CCOCC1.O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([N:7]2[C:5](=[O:6])[N:4]([CH2:1][CH:2]=[CH2:3])[C:19](=[O:20])[O:8]2)=[CH:14][CH:13]=1
Reactant: C=CCNC(=O)N(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Allyl-3-(4'-chlorophenyl)-3-hydroxyurea (6.0 g.) was dissolved in cooled dioxane (50 ml.) and a solution of sodium hydroxide (1.3 g.) in water (15 ml.) was added thereto. Ethyl chloroformate (3.2 g; 2.9 ml.) was added dropwise at 10°-15° C. with stirring and the stirring continued for about 1/2 hour after the addition was completed. The reaction mixture was poured into cold water (300 ml.), stirred and filtered to separate the precipitate. The precipitate was recrystallized from ethanol and dried in vacuo at room temperature to yield 2-(4'-chlorophenyl)-4-allyl-1,2,4-oxadiazolidine-3,5-dione as white needle-like crystals melting 56°-57° C. and having the following elemental analysis as calculated for C11H9ClN2O3 :
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]#[N:6].C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:20]=[C:19]([C:34]([NH:36][NH2:37])=[O:35])[CH:18]=1>Cl.C(OCC)(=O)C.O>[C:5]([CH2:4][CH:3]=[N:37][NH:36][C:34](=[O:35])[C:19]1[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[N:20]=1)#[N:6]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: COC(CC#N)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CCC#N)c1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
3,3-dimethoxy propionitrile (0.35 g, 0.0015×2 mol) was dissolved in a 2N aqueous hydrochloric acid solution (about 10 ml). The obtained solution was stirred at a temperature of about 50 to 60° C. for about one hour. The solution was further mixed with benzene (about 10 ml) and 4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.50 g, 0.0015 mol), and then the resultant mixture was stirred at that temperature for about one hour. The obtained reaction solution was distributed in ethyl acetate-water The organic phase separated from the solution was successively washed with saturated sodium bicarbonate water and with saturated brine, and then dried with anhydrous sodium sulfate. Thereafter, the resultant solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([OH:18])[C:14]=3[CH:19]=2)=[CH:6][CH:5]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=3[CH:19]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (500 mg, 1.69 mmol), tert-butyl 2-bromoacetate (500 mg, 2.56 mmol) and cesium carbonate (1.65 g) were combined in 5 mL DMF and stirred at ambient temperature for 1 hour. The reaction mixture was diluted with 80 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-100% ethyl acetate in hexane gave tert-butyl 2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate (285 mg, 0.70 mmol).