Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[I:9]N1C(=O)CCC1=O.O.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[I:9]
Reactant: Nc1cncc(Cl)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cnc(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6-chloropyrazin-2-amine (10.0 g, 77 mmol) in DMSO (100 ml) was treated with 1-iodopyrrolidine-2,5-dione (20.84 g, 93 mmol). The reaction mixture was stirred at RT for 2 days and then added to water (800 ml). The pH was adjusted to pH 8-9 using a sat. NaHCO3 solution and the resulting suspension was filtered, washing with water (×3) and dried under vacuum to afford the titled compound as an orange solid;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (102 mg, 0.375 mmol) to afford the crude product (56 mg) as an off-white solid: ESI MS m/z 556 [C30H35ClFN3O4+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[C:17]3[C:12](=[C:13]([C:24]([OH:26])=O)[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1.C1C=CC2N(O)N=[N:34]C=2C=1.C(Cl)CCl.N>O1CCOCC1>[O:1]=[S:2]1(=[O:27])[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[C:17]3[C:12](=[C:13]([C:24]([NH2:34])=[O:26])[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Reactant: On1nnc2ccccc21
Agent: N
Solvent: C1COCCO1
Solvent: ClCCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
3-(1,1-Dioxido-4-thiepanyl)-5-phenyl-1H-indole-7-carboxylic acid (0.076 mmol), HOBT (10 mg, 0.074 mmol), EDC (15 mg, 0.078 mmol) were mixed together. A solution of 0.5 M NH3 in dioxane (1.5 mL) was added in, and the reaction was heated in a microwave at 120° C. for 10 minutes, then allowed to sit at room temperature overnight. The solvent was evaporated and the crude product was dissolved in DMSO and purified by Gilson HPLC (0.1% TFA, 10%-90% CH3CN, 10 minutes). The desired fractions were concentrated, giving 4 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:19][CH2:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH:22]1(B(O)O)[CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:22]1([N:16]2[CH:15]=[C:14]([C:13]3[C:12]([O:19][CH2:20][CH3:21])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=3[O:3][CH2:1][CH3:2])[CH:18]=[N:17]2)[CH2:24][CH2:23]1
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cn[nH]c1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnn(C2CC2)c1
Temperature: 25 °C

Procedure:
To a mixture of methyl 3,5-diethoxy-4-(1H-pyrazol-4-yl)benzoate (20 mg), cyclopropylboronic acid (24 mg) in THF (2 ml) were added Cu(OAc)2 (37 mg), pyridine (45 ul) and TEA (48 ul) at room temperature and irradiated with microwave at 120° C. for 15 min. After cooling to room temperature, the mixture was diluted with EtOAc, filtered through celite pad and the filtrate was evaporated under reduced pressure. The residue was purified by p-TLC (hexane/EtOAc) to give the title product as a colorless solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:13].[K+].[K+].[CH2:18](OC(=O)CBr)[C:19]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:19][CH2:18][O:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: OCCNCc1ccccc1
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a mixture of Compound 2 (355.8 mg, 2.353 mmol) and K2CO3 (565 mg, 4.09 mmol) in anhydrous CHCl3 (12 mL) at 0° C. was dropwise added Benzyl-2-bromoacetate (540 mg, 2.36 mmol) over 0.5 h. The reaction mixture was gradually warmed to room temperature and stirred for 36 h. The resulting reaction mixture was filtered while washing with CH2Cl2, and the filtrate was concentrated to give Compound 3. 1H NMR (CDCl3) δ 2.7 (t, 2H), 3.3 (s, 2H), 3.6 (s, 2H) 4.4 (t, 2H), 7.2-7.4 (m, 5H); 13C NMR (CDCl3) δ 48.49, 55.64, 61.59, 68.69, 127.67, 128.48, 128.87, 136.04, 167.37. HRMS (Positive ion FAB) Calcd for C11H13NO2 [M+H]+ m/z 192.0900. Found: [M+H]+ m/z 192.1032.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:23])([F:14])[F:24])=[CH:21][N:20]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Product: O=C(Nc1ccc(C(F)(F)F)cn1)c1ccc(F)c([N+](=O)[O-])c1
Yield: 100 %

Procedure:
The product from Example 172a was reacted with 5-trifluoromethyl-pyridin-2-ylamine (239 mg, 1.474 mmol) according to the procedure from Example 172b to provide the title compound (485 mg, 100%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Co].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Agent: [Co]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Solvent: CC(=O)CC(C)=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), cobalt acetylacetonate (1.3 mg, 1 mol %), and Xantphos (2.9 mg) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 14 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 17%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 10 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:45]([NH:47][NH2:48])=O.P(Cl)(Cl)(Cl)=O>C1COCC1.C(#N)C>[CH2:31]([O:30][C:24]1[CH:23]=[C:22]([CH:17]([N:13]2[C:14](=[O:16])[C:15]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12]2)[CH2:18][C:19]2[O:21][CH:45]=[N:47][N:48]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH3:32]
Reactant: NNC=O
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(C(Cc2nnco2)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC

Procedure:
Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-[1,3,4]oxadiazol-2-yl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by reacting 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (400 mg, 0.9 mmol), CDI (160 mg, 1.0 mmol) and formic hydrazide (0.09 g, 1.5 mmol) in THF (5 mL). The crude was then reacted with phosphorus oxychloride (0.18 mL, 1.9 mmol) in acetonitrile (15 mL). The product was obtained as a white solid (60 mg, 15% yield): mp 181-183° C.; 1H NMR (CDCl3) δ 0.86-0.92 (m, 2H, cyclopropyl CH2), 1.06-1.11 (m, 2H, cyclopropyl CH2), 1.45 (t, J=7.5 Hz, 3H, CH3), 1.58-1.68 (m, 1H, cyclopropyl CH), 3.66 (dd, J=5, 15 Hz, 1H, CHH), 3.85 (dd, J=10, 15 Hz, 1H, CHH), 3.87 (s, 3H, CH3), 4.03-4.11 (m, 3H, OCH2CH3+CHH), 4.43 (d, J=17 Hz, 1H, CHH), 5.86-5.91 (m, 1H, NCH), 6.85-6.90 (m, 2H, Ar), 6.96-7.01 (m, 2H, Ar), 7.43 (t, J=7.5 Hz, 1H, Ar), 8.35 (s, 1H, Ar), 8.41 (d, J=7.5 Hz, 1H, Ar), 10.41 (s, 1H, NH); 13C NMR (CDCl3) , 8.27, 8.29, 14.73, 16.16, 28.04, 46.36, 52.26, 55.98, 64.64, 111.53, 112.36, 116.80, 116.96, 117.80, 119.16, 129.54, 133.43, 138.06, 141.25, 148.84, 149.64, 153.34, 163.79, 169.50, 172.66. Analy. calculated for C25H25N4O5+0.1H2O: C, 64.47; H, 5.69; N, 12.07. Found: C, 64.50; H, 5.70; N, 11.69.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>>[F:1][C:2]1[N:3]=[C:4]([C:8]([OH:10])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cccc(F)n1
Agent: [K+]
Product: O=C(O)c1cccc(F)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a heterogeneous solution of 2-fluoro-6-methyl-pyridine (9.65 g, 86.8 mmol) in water (400 mL) was added potassium permanganate (31.6 g, 200 mmol), and the reaction was heated to approximately 100° C. After 30 minutes, additional potassium permanganate (16.5 g, 104 mmol) was added, and the reaction heated at 100° C. overnight. The reaction was filtered through celite to remove manganese salts. The mother liquor was washed with ethyl ether (200 mL×3), neutralized to pH 7, and concentrated down to approximately 100 mL total volume. The aqueous solution was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate, followed by 20% i-PrOH/CHCl3 (×3). The combined organic layers were dried over MgSO4 and concentrated. The solids were suspended in chloroform, sonicated, then filtered to remove remaining side products. The mother liquor was concentrated to give 5.47 g as a white crystalline solid, 45% yield. 1H NMR: consistent with structure. MS (ion spray) 140 (M−).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH2:11])=[N:7][CH:8]=1.Br[C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][N:21]2[CH3:24])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C>CN(C=O)C>[CH3:24][N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([NH:11][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:8][N:7]=3)[CH:23]=2)[CH:19]=[CH:20]1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Cn1ccc2ccc(Br)cc21
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(NCCc3ccc(C(F)(F)F)cn3)cc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine (200 mg, 1.05 mmol) was added 6-bromo-1-methyl-1H-indole (685 mg, 2.10 mmol), cuprous iodide (10 mg, 0.05 mmol) and cesium carbonate (685 mg, 2.1 mmol) under an argon atmosphere. Then DMF (400 μl) and 2-acetylcyclohexanone (28 μl, 0.21 mmol) were added and the reaction mixture was stirred for 4 h at 120° C. After cooling to ambient temperature the reaction mixture was separated between tert-butylmethylether (2×20 ml) and water (15 ml). The combined organic layers were washed with brine (15 ml) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (114 mg, 34%) as a light brown oil. MS m/e: 320.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[CH2:15]=[O:16]>>[OH:16][CH2:15][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[C:3]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: Cc1[nH]c(=O)ccc1-c1ccncc1
Reactant: C=O
Product: Cc1[nH]c(=O)c(CO)cc1-c1ccncc1

Procedure:
In another process aspect the invention comprises reacting 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone with excess formaldehyde at an acidic pH to produce 3-hydroxymethyl-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone.
Reaction SMILES: C(O[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])C.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][Mg]Cl.[C:30](=[O:33])(O)[O-].[Na+]>O1CCCC1>[CH2:12]([N:8]1[CH2:9][CH2:10][O:11][CH:6]([C:4]([OH:5])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:33][CH3:30])[CH2:23][C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH3:19])[CH2:7]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1C[Mg]Cl
Reactant: O=C([O-])O
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1CC(O)(Cc1ccccc1OC)C1CN(Cc2ccccc2)CCO1
Reaction time: 1 h

Procedure:
Add a solution of 4-benzyl-morpholine-2-carboxylic acid ethyl ester (1.12 g, 4.49 mmol) in tetrahydrofuran (5 mL) to a stirred solution of 2-methoxybenzylmagnesium chloride (54 mL, 0.25M solution in tetrahydrofuran, commercially available from Rieke Metals) at −10° C. under nitrogen atmosphere. After 1 hour, add a saturated aqueous solution of sodium bicarbonate and extract with diethyl ether. Combine the organic layers and extract with brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure to give a residue to be taken forward without further purification. MW 447.58; C28H33NO4; LCMS (12 minute method):m/z)=448.2 [M+H]+) RT 4.8 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[CH2:3]1)[CH3:9]
Reactant: CCN1CCCC(N)C1
Reactant: O=C1OC(=O)c2ccccc21
Product: CCN1CCCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
6.4 Grams of 3-amino-1-ethyl-piperidine and 7.4 grams of phthalic anhydride were heated together in an oil bath at 150° C. for 20 minutes. On cooling, the resulting solid was recrystallized twice from methanol to give 4.2 grams of the title compound. Melting Point: 155° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)C(C)C)C.[N:32]1([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:41][C:40]=2[C:51]([F:54])([F:53])[F:52])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O.ClCCl>[N:45]1([C:42]2[CH:43]=[CH:44][C:39]([CH2:38][N:32]3[CH2:37][CH2:36][N:35]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[CH2:34][CH2:33]3)=[C:40]([C:51]([F:54])([F:53])[F:52])[CH:41]=2)[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1cc(N2CCOCC2)ccc1CN1CCNCC1
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (126 mg, 0.420 mmol, 0.70 equiv), dichloromethane (20 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (204 mg, 1.21 mmol, 2.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (627 mg, 4.86 mmol, 8.00 equiv) were added at 0° C. The mixture was stirred for 2 h at room temperature. 4-[4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl]morpholine (200 mg, 0.610 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 57.4 mg (18% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.57 (d, J=8.7 Hz, 1H), 7.14 (s, 1H), 7.01-7.04 (m, 1H), 5.70-5.82 (m, 1H), 3.87 (t, J=4.8 Hz, 4H), 3.55-3.60 (m, 6H), 3.19 (t, J=4.8 Hz, 4H), 2.45-2.47 (m, 4H). LCMS (ESI, m/z): 524 [M+H]+.
Reaction SMILES: [CH:1]([N:4](C(C)C)[CH2:5]C)(C)C.CNC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH3:1][N:4]([CH3:5])[C:31]([CH:28]1[CH2:29][CH2:30][N:25]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
Diisopropylethylamine (0.35 ml, 2.0 mmol) was added in one portion to a stirred solution of dimethylamine (0.8 ml, 1.6 mmol) in DCM (2 ml) at room temperature. To this mixture was added 1-(4-nitro-benzenesulfonyl)-piperidine-4-carbonyl chloride (0.27, 0.8 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time, the mixture was diluted with DCM (20 ml) and washed sequentially by HCl (1M solution, 20 ml) and NaOH (1M solution, 20 ml) before being separated, dried (MgSO4), filtered and concentrated under vacuum to afford the title compound (0.17 g, 33% yield) as an off white solid. Tr=1.65 min m/z (ES+) (M+H+) 342.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)#[N:2].C(O)C.CC1CCCO1.[O-]CC.[Na+].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>>[C:13]([O:12][C:11]([NH:10][C:7]1[N:8]=[CH:9][C:4]([CH:3]([C:1]#[N:2])[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[N:5][CH:6]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CCO
Product: CCOC(=O)CCC(C#N)c1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
To tert-butyl 5-(cyanomethyl)pyrazin-2-ylcarbamate (0.32 g, 1.37 mmol) in a mixture solvent of ethanol/2-methyltetrahydrofuran (5 mL/5 mL) was added freshly prepared sodium ethoxide (1 M, 1.366 mL), and the mixture was stirred at 0° C. for 10 min, followed by addition of ethyl acrylate (145 ul, 1.366 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction was quenched at this point by adding sat. NaHCO3 (5 mL), and the reaction mixture was stirred for another 10 min, diluted with EtOAc (20 mL), filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), washed with pH 7.0 sodium phosphate buffer, and EtOAc layer was concentrated, and the light brown residual oil was purified by flash column eluted with gradient EtOAc/heptane (0-50%) to afford ethyl 4-(5-(tert-butoxycarbonylamino)pyrazin-2-yl)-4-cyanobutanoate (100 mg, 22% yield). LCMS (m/z): 279.2 (MH+-tBu), 0.86 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]([F:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]([F:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:23])=[CH:8]2
Reactant: COC(=O)Cc1ccc2ncccc2c1F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc2ncc(Br)cc2c1F

Procedure:
To a solution of (5-fluoro-quinolin-6-yl)-acetic acid methyl ester (2.0 g, 9 mmol) in CCl4 (20 ml) and pyridine (1.48 ml, 18 mmol) was added bromine (0.9 ml, 18 mmol) dropwise at 5° C. The solution was heated to reflux for 20 minutes. After cooling, the reaction was quenched by sat. aq. NaHCO3 and the mixture extracted with dichloromethane and concentrated. The residue was purified by flash column chromatography to return the title compound (1.8 g, 66%). 1H-NMR (CDCl3, 300 MHz): 8.9 (d, 1H), 8.5 (d, 1H), 7.8 (d, 1H), 7.6 (m, 1H), 3.9 (d, 2H), 3.7 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[N:8][CH:9]=1
Reactant: Cc1ccc(Oc2cccc(CCl)c2)nc1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(Oc2ccc(C)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-5-methylpyridine (2.0 g, 8.8 mmol) was treated neat with triethylphosphite (1.89 mL, 11 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (10-75%, EtOAc:CH2Cl2) to afford the title compound (1.75 g, 59% yield) as a thick oil.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])([O-:12])=[O:11]>O1CCCC1>[C:2]1([CH2:1][O:8][NH:9][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])(=[O:20])=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NOCc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A solution of 96.4 g of O-benzylhydroxylamine in 80 ml of tetrahydrofuran was added to a solution of 86.8 g of o-nitrobenzenesulfonyl chloride in 400 ml of tetrahydrofuran at 5°-10°. After stirring at ambient temperature for 16 hours the solvent was evaporated. The residue was washed with water, filtered and dried to give 112.6 g of N-(phenylmethoxy)-2-nitrobenzenesulfonamide, m.p. 148°-151°.