Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:5]2.ClS([N:23]=[C:24]=O)(=O)=O.CN(C=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:5]2[C:24]#[N:23]
Reactant: Cn1c(-c2cccnc2)cc2cc(Cl)cc(F)c21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)c(C#N)c2cc(Cl)cc(F)c21
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole (130 mg, 0.50 mmol) in dichloromethane (10 mL) at ambient temperature is added chlorosulfonyl isocyanate (282 mg, 2.0 mmol) and the mixture is stirred for 11 h, whereupon anhydrous DMF (1 mL) is added. After 1 h, the mixture is concentrated and the residue is purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (d, J=1.8 Hz, 3H), 7.46 (dd, J=12.4, 1.8 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.71 (dd, J=7.5, 4.4 Hz, 1H), 8.16 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.83 (dd, J=4.9, 1.6 Hz, 1H), 8.89 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 286.0558 [(M+H)+ Calcd for C15H10ClFN3: 286.0547].
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)C.IC.[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:36])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([O:34][CH3:35])[CH:24]=2)[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20](=[O:36])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33][CH3:1])=[O:32])=[C:25]([O:34][CH3:35])[CH:24]=2)[CH2:17][CH2:18]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: COC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Reaction time: 16 h

Procedure:
30 ml of diisopropylethylamine and 1.0 ml of iodomethane were added to a solution of 1.84 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy)-3-methoxycinnamamide (Example 172) in 50 ml methylene chloride. The solution was stirred for 16 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.38 g of N-(trans-4-methylcyclohexyl)4-(methoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: CC(O[C:6]([N:8](C)[C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)=O)(C)C.Cl>O1CCOCC1>[CH3:6][NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1
Reactant: COC(=O)[C@H]1CC[C@@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@H]1CC[C@@H](C(=O)OC)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A mixture of methyl cis-4-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]cyclohexanecarboxylate (˜10 g, crude product from above) and 1M HCl in dioxane (20 mL) was heated to 50° C. and allowed to stir overnight. The mixture was concentrated to give the 3 g of crude product. MS (ES+): m/e 172.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CC(C)=O.O.CCOC(C)=O>[Cl:24][CH2:23][CH2:22][CH2:21][N:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=c1oc2ccc([N+](=O)[O-])cc2n1CCCCl
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
5-Nitro-3H-benzoxazol-2-one (5.35 g, 29.7 mmol) in Acetone (300 mL) was treated with Potassium carbonate (6.99 g, 50.6 mmol) then 1-Bromo-3-chloropropane (10.0 mL, 101 mmol) was added. After 45 min, the mixture was heated to 55° C. overnight. The reaction was cooled, diluted with 100 mL water and 150 mL EtOAc. The layers were separated, the org. washed with brine (50 mL), dried over sodium sulfate, filtered through a ½″h×2″w pad of SiO2 and conc. in vacuo. to near dryness. The oily remainder was suspended in 100 mL 5% EtOAc:Hexane, resulting in precipitation of the product. The solids were triturated for 2 h to break up the solids, collected by filtration and washed with hexane (2×60 mL). After drying, 3-(3-Chloro-propyl)-5-nitro-3H-benzoxazol-2-one was isolated as yellow solids (7.52 g, 99%). 1H-NMR (DMSO): 8.27 (d, 1H, J=2.2 Hz), 8.10 (dd, 1H, J=2.2, 8.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 4.04 (t, 2H, J=6.7 Hz), 3.75 (t, 2H, J=6.5 Hz), 2.17 (m, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[OH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]2[C:25](=[O:26])[C:24]3[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]2=[O:31])[CH2:10][CH2:11]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
K2CO3 (19.4 g, 140.6 mmol) was added to a solution of trans-4-aminocyclohexanol hydrochloride (9.0 g, 59.35 mmol) in water (150 mL) followed by N-carbethoxy phthalimide (18.8 g, 85.96 mmol). A white precipitate was formed immediately. Stirring continued at RT for 1 h. The precipitate was filtered off, washed with water and dried to afford 12 g (84%) of 2-(4-hydroxy-cyclohexyl)-isoindole-1,3-dione.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=1[N:34]=[C:35]=[O:36]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:35]([NH:34][C:28]3[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:33])=[O:36])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Reactant: Cc1cccc(C)c1N=C=O
Product: Cc1cccc(C)c1NC(=O)Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
1-{2-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-3-(2,6-dimethyl-phenyl)-urea was prepared according to the procedure outlined in Example 60, starting with 2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (100 mg) and 2,6-dimethylphenyl isocyanate (0.040 mL). The resultant white solid was recrystallized using isopropyl alcohol. 1-{2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-3-(2,6-dimethyl-phenyl)-urea was isolated in 100% purity @ 254 nm; LCMS (APCI): 500 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[O:4][C:5]1[N:6]=[C:7]([O:38][CH2:39][CH2:40][CH3:41])[C:8]2[N:13]=[C:12]([C:14]3[CH:35]=[C:34]([CH3:36])[C:17]([O:18][CH2:19][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])=[C:16]([CH3:37])[CH:15]=3)[O:11][C:9]=2[N:10]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[O:4][C:5]1[N:6]=[C:7]([O:38][CH2:39][CH2:40][CH3:41])[C:8]2[N:13]=[C:12]([C:14]3[CH:35]=[C:34]([CH3:36])[C:17]([O:18][CH2:19][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[C:27]([OH:29])=[O:28])=[O:21])=[C:16]([CH3:37])[CH:15]=3)[O:11][C:9]=2[N:10]=1
Reactant: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)O)c(C)c3)nc12
Reaction time: 16 h

Procedure:
59 mg of tert-butyl(S)-1-(2-{4-[5-(2,5-difluorophenoxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidine-2-carboxylate were dissolved in 1.2 ml of dichloromethane, and 0.5 ml of trifluoroacetic acid was added. After 16 h at room temperature, the mixture was concentrated under reduced pressure and freeze-dried. This gave 53 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH2:12]([Si](C)(C)C)[C:13]#[CH:14].N1CCCCC1.CN(C=O)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]2[CH:12]=[C:13]([CH3:14])[O:8][C:7]=12
Reactant: OCc1cc(I)c(O)c(Cl)n1
Reactant: C#CC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2cc(CO)nc(Cl)c2o1
Temperature: 45 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) (4.6 g, 16 mmol), propargyl trimethylsilane (2 g, 17.8 mmol), bis(triphenylphosphine)palladium dichloride (156 mg, 0.21 mmol), cuprous iodide (122 mg, 0.64 mmol), and piperidine (3.52 mL, 26.6 mmol) are added to 25 mL DMF in a dry flask under N2. The mixture is warmed to 45° C. for 7 h, is stirred overnight at rt, and is diluted with 150 mL EtOAc. The mixture is washed with 4×50 mL 50% saturated 1:1 NaCl/NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo to an amber oil. The crude material is chromatographed over 40 g silica gel (230-400 mesh) eluting with 35% EtOAc/hexane to afford (7-chloro-2-methylfuro[2,3-c]pyridin-5-yl)methanol (C24) (44% yield). MS (CI) for C9H8ClNO2, m/z: 198 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[O:28][N:27]=[C:26]([C@@H:29]5[CH2:34][CH2:33][C@@H:32]([N:35]([O:39][CH2:40][C:41]6[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=6)[C:36]([Cl:38])=[O:37])[CH2:31][N:30]5C(OC(C)(C)C)=O)[N:25]=4)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>>[CH2:40]([O:39][N:35]([C:36]([Cl:38])=[O:37])[C@H:32]1[CH2:31][NH:30][C@H:29]([C:26]2[N:25]=[C:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[O:17])[CH2:19][CH2:20]3)[O:28][N:27]=2)[CH2:34][CH2:33]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1noc(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2nc([C@@H]3CC[C@@H](N(OCc4ccccc4)C(=O)Cl)CN3)no2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.6 %

Procedure:
A mixture of (2S,5R)-tert-butyl 2-(5-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)-1,2,4-oxadiazol-3-yl)-5-(benzyloxy(chlorocarbonyl)amino)piperidine-1-carboxylate (˜400 mg) and 4 N HCl/dioxane (5.0 mL) was stirred at rt for 2 hrs. The solvent was then removed under vacuum to give (9H-fluoren-9-yl)methyl 4-(3-((2S,5R)-5-(benzyloxy(chlorocarbonyl)amino)piperidin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (400 mg) as a white solid. ESI-MS (EI+, m/z): 642 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([O:33][CH3:34])[C:27]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([O:33][CH3:34])[C:27]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reactant: COc1c(CNC(=O)C(C)(C)C)ccc(Cl)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(CNC(=O)C(C)(C)C)ccc(Cl)c1C(=O)Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Yield: 32.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 60 mg, 0.19 mmol), 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid (Intermediate-43, 88 mg, 0.29 mmol), oxalyl chloride (55 mg, 0.44 mmol), DMF (1 drop) and DIPEA (74 mg, 0.57 mmol) in CH2Cl2 (2 mL) to afford 36 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.92 (d, J=7.8 Hz, 1H), 8.77 (s, 1H), 8.17-8.11 (m, 2H), 7.86 (m, 2H), 7.74 (m, 3H), 7.30 (m, 2H), 4.29 (d, 2H), 3.84 (s, 3H), 1.15 (s, 9H); MS (m/z): 587.17 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:30][C:31]([OH:33])=O)[CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1)#[N:2].C([N:36](CC)CC)C.[Cl-].[NH4+].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[N:4]([CH2:30][C:31]([NH2:36])=[O:33])[CH:5]=[C:6]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC(N)=O
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of (2-cyano-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrol-1-yl)acetic acid (95 mg, 0.2 mmol, 1 equiv.) and triethylamine (0.16 mL, 1.2 mmol, 6 equiv.) in 2 mL of DMF was added ammonium chloride (67 mg, 1.2 mmol, 6 equiv.) followed by PyBOP (113 mg, 0.22 mmol, 1.1 equiv.) After stirring overnight, the reaction was then filtered into an HPLC vial and purified by reverse phase HPLC (15-95% CH3CN/water+0.1% TFA). The desired fractions were combined and the CH3CN was removed. The aqueous was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 50 mg (53%) of the title compound as a yellow foam. MS m/z 458.22 (MH+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]2[C:8](=[C:9]([N+:29]([O-:31])=[O:30])[CH:10]=[C:11]([NH:22]C(=O)C(F)(F)F)[C:12]=2[N+:19]([O-:21])=[O:20])[C:7]=1[N+:32]([O-:34])=[O:33])=O.Cl>CO>[NH2:5][C:6]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]2[C:8](=[C:9]([N+:29]([O-:31])=[O:30])[CH:10]=[C:11]([NH2:22])[C:12]=2[N+:19]([O-:21])=[O:20])[C:7]=1[N+:32]([O-:34])=[O:33]
Reactant: O=C(Nc1cc([N+](=O)[O-])c2c([N+](=O)[O-])c(NC(=O)C(F)(F)F)cc([N+](=O)[O-])c2c1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Solvent: CO
Product: Nc1cc([N+](=O)[O-])c2c([N+](=O)[O-])c(N)cc([N+](=O)[O-])c2c1[N+](=O)[O-]

Procedure:
reacting said 2,6-di(trifluoroacetamido)-1,4,5,8-tetranitronaphthalene with methanol and dry hydrogen chloride to form 2,6-diamino-1,4,5,8-tetranitronaphthalene.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:47]=[C:48]2[N:52]([CH3:53])[C:51](=[O:54])[NH:50][C:49]2=[O:55])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CO.C(O)(=O)C>O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8](/[CH:47]=[C:48]2\[C:49](=[O:55])[NH:50][C:51](=[O:54])[N:52]\2[CH3:53])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=C2C(=O)NC(=O)N2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1ncc(/C=C2\C(=O)NC(=O)N2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
To a mixture of the E and Z-isomers of 5-[[2-butyl-3-[[2'-(N-triphenylmethyl-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-1-methyl-2,4-imidazolidinedione (0.400 g, 0.552 mmol ) was added methanol (50 mL) and glacial acetic acid (0.2 mL). This white heterogeneous mixture was refluxed for 3 hour in which time a solution formed. The solution was cooled to room temperature and diluted with water (5 mL) and hexanes (50 mL). The aqueous methanol fraction was evaporated in vacuo and then triturated with ethyl acetate. The insoluble residue was collected and determined to be the E-isomer. HPLC eluant 45%(0.1%TFA in H2O) 55% MeCN, RT 1.9[95%] MS (CI) 483 (M+1)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN1C(=O)CCC1.O.ClCCl>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: Clc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Oc2ccncc2)c2ccccc12
Temperature: 120 °C
Yield: 16.5 %

Procedure:
To a stirred mixture of 4-amino-1-naphthol hydrochloride (2.5 g, 12.8 mmol) and 4-chloropyridine hydrochloride (3.84 g, 29.2 mmol) in NMP (20 ml) was added potassium tert-butoxide (6.0 g, 53.47 mmol) slowly. The mixture was heated at 120° C. for 6 h, cooled to room temperature and diluted with water and dichloromethane. The combined organic extracts were washed with HCl (2N), saturated aqueous NaHCO3 and brine and dried (Na2SO4). Removal of the volatiles in vacuo afforded the product (0.5 g, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23].[CH2:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCCl.C(Cl)Cl>[CH2:28]([O:35][C:26](=[O:27])[NH:25][S:22]([C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])[C:6]([F:8])=[CH:7][C:2]=1[Cl:1])(=[O:24])=[O:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)N=C=O)c(Cl)cc2F)c1=O
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)NC(=O)OCc3ccccc3)c(Cl)cc2F)c1=O

Procedure:
With stirring, 0.6 g (1.4 mmol) of 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]benzenesulfonylisocyanate in 1,2-dichloroethane was added to a solution of 0.15 g (1.4 mmol) of benzyl alcohol in methylene chloride, and the reaction mixture was stirred overnight. Removal of the solvent and customary purification methods gave 0.4 g (52% of theory) of the title compound as a colorless solid (m.p.: 231-232° C.).
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])(=[O:4])[CH3:3].C(=O)([O-])O.[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[CH2:22]([O:21][C:19]([NH:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][O:5][C:2](=[O:4])[CH3:3])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 93.1 %

Procedure:
19.8 g (0.10 mol) of O-acetyl-L-homoserine hydrochloride are dissolved in 200 ml of water, and 35.0 g (0.42 mol) of sodium hydrogen carbonate are added at 0° C. 19.2 g (0.11 mol) of benzyl chloroformate are then added and stirring is carried out for 3 hours at room temperature. The mixture is then extracted twice using 100 ml of methyl isobutyl ketone each time, and the aqueous phase is adjusted to pH=2 using concentrated hydrochloric acid and extracted twice using 150 ml of methyl isobutyl ketone (MIBK) each time. The combined organic phases are washed with 50 ml of saturated sodium chloride solution and concentrated in vacuo. 27.5 g (93%) of N-benzyloxycarbonyl-O-acetyl-L-homoserine are obtained in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].CS([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)(=O)=O>>[F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)(=[O:7])=[O:6]
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)CCC(F)(F)F)CC1
Yield: 51 %

Procedure:
3,3,3-Trifluoropropylsulfonyl chloride (96 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (55 mg, 0.123 mmol, 51% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.78 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 4.19 (d, J=Hz, 1H), 3.82 (d, J=Hz, 1H), 3.73 (m, 1H), 3.18 (t, J=12.4 Hz, 1H), 2.82 (m, 1H), 2.78 (t, J=Hz, 1H), 1.80 (t, J=9.6, 2H), 1.43 (m, 2H), 0.97 (s, 6H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)(C)(C)C.Cl>ClCCl.C(O)C>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(5R)-3-(4-((3R)-3-(t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (532 mg, 1.2 mM), was dissolved in dichloromethane (10 ml), and treated with a solution of hydrogen chloride in ethanol (3.8M, 2 ml). After stirring 4 hours at ambient temperature, the precipitated hydrochloride of the product (230 mg) was filtered, and the filtrate diluted with diethyl ether to deposit more product (218 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[CH2:38][CH2:37][CH2:36][O:35][C:34]2[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:33]1=2>COCCOC.O.[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>[O:32]1[CH2:38][CH2:37][CH2:36][O:35][C:34]2[CH:39]=[C:40]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)[CH:41]=[CH:42][C:33]1=2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCCO2
Yield: 85.1 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (0.097 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.092 g (75%) of the title compound.