Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[S:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[S:4][N:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(N)sn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of 3-methylisothiazol-5-amine (1.00 g, 6.64 mmol) and pyridine (1.30 ml, 7.97 mmol) in tetrahydrofuran (22 ml) was added 2,2,2-trichloroethyl chloroformate (1.10 ml, 7.97 mmol) with ice-cooling and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (767 mg, 39.9%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:25])[O:4][C:5]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=2)=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11].[H][H].O1CCO[CH2:30][CH2:29]1>CCO.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:13]([C:5]3[O:4][C:3](=[O:25])[C:2]([CH3:1])=[C:7]([O:8][CH2:9][O:10][CH3:11])[C:6]=3[CH3:12])=[CH:17][C:16]=2[CH:18]=1.[CH3:1][C:2]1[C:3](=[O:25])[O:4][C:5]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([NH:22][CH2:29][CH3:30])=[CH:18][C:16]=3[CH:17]=2)=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: C1COCCO1
Reactant: COCOc1c(C)c(-c2cc3cc([N+](=O)[O-])ccc3o2)oc(=O)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccc2oc(-c3oc(=O)c(C)c(OCOC)c3C)cc2c1
Product: COCOc1c(C)c(-c2cc3cc(N)ccc3o2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-dimethyl-4-methoxymethoxy-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one (100 mg) in dioxane (20 ml) and EtOH (20 ml) there was added 5% Pd/C (5 mg), and after displacing the reaction vessel atmosphere with hydrogen, the mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated, and then purified by silica gel thin-layer chromatography (n-hexane/AcOEt=1/1) to obtain 6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one and 3,5-dimethyl-6-(5-(ethylamino)benzofuran-2-yl)-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:30])[CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:43][N:42]=[N:41][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:29])[CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-isopropyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Mg].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].[S:14](Cl)(Cl)=[O:15].[OH2:18]>C1COCC1>[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:14]([C:7]2[CH:12]=[CH:11][C:10]([O:18][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:9][CH:8]=2)=[O:15])=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(Cl)cc1
Reactant: O
Reactant: O=S(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(S(=O)c2ccc(OC(C)(C)C)cc2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A Grignard reagent which was conventionally prepared using 24.3 g (1 mol) of magnesium, 203.2 g (1.1 mol) of 4-tert-butoxyphenyl chloride, and 280 g of THF was diluted with 500 g of THF and cooled to lower than -60° C. in a dry ice/methanol bath. Then 47.5 g (0.4 mol) of thionyl chloride diluted with 70 g of THF was added dropwise over 1 hour at less 0° C. After ripening for 1 hour in an ice bath, 36 g of water was added to decompose the excess of Grignard reagent. Separation was carried out by adding 1,000 g of methylene chloride and further 400 g of saturated ammonium chloride aqueous solution and 300 g of water. The organic layer was washed twice with 700 g of pure water. The organic layer was dried over magnesium sulfate and filtered and then evaporated. The resulting oily residue was recrystallized, isolating bis(4-tert-butoxyphenyl) sulfoxide in a yield of 60%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].[CH3:17][NH:18]CCC.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([NH:18][CH3:17])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCNC
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(CO)cc(C(=O)NC)c1
Yield: 47.7 %

Procedure:
Stir a solution of 5-hydroxymethyl-isophthalic acid monoethyl ester (1.9 g, 8.4 mmol), N-methylpropylamine (947 μl, 9.2 mmol), 1-hydroxybenzotriazole (1.24 g, 9.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g, 9.2 mmol) in a mixture of dichloromethane (12 mL) and DMF (12 mL) at room temperature for 1.5 h. Concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (950 mg, 40% yield).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.C(O)C.C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>O>[Br:1][C:2]1[C:10]2[C:9]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1ncnc2scc(Br)c12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Brc1csc2ncnc(NCc3ccccn3)c12
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A stirred mixture of 5-bromo-4-chlorothieno[2,3-d]pyrimidine (3.8 g, 15.2 mmol), ethanol (250 ml), triethylamine (2.32 ml, 16.7 mmol) and 2-aminomethylpyridine (1.72 ml, 16.7 mmol) was heated under reflux for 2.5 hours. The solution was then cooled to ambient temperature, poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:1) gave (5-bromothieno[2,3-d]pyrimidin-4-yl)pyridin-2-ylmethylamine as a yellow solid (3.12 g), m.pt. 127°-129° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[C:35]1([NH2:42])[C:36]([NH2:41])=[CH:37][CH:38]=[CH:39][CH:40]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[NH:42][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:41]=2)[N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1N
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 1, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 1,2-benzenediamine, the title compound was obtained in 91% purity by HPLC. MS(ESI+): m/z=425.
Reaction SMILES: Br[CH2:2][O:3][CH3:4].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.[H-].[Na+]>O>[CH3:4][O:3][CH2:2][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromomethyl-methylether (0.87 ml) was added dropwise to a stirred suspension of p-hydroxyacetophenone (1 g) and sodium hydride (0.44 g) at 0° C. under nitrogen. The mixture was stirred for 1 h at room temperature. Then water was added and the mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulphate and concentrated in vacuo to leave p-methoxymethoxyacetophenone (1.4 g) as yellow solid which was processed without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:24]1([NH:27][CH3:28])[CH2:26][CH2:25]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:27]([CH:24]2[CH2:26][CH2:25]2)[CH3:28])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNC1CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F)C1CC1

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (3.40 g, 10 mmol) and cyclopropyl-methyl-amine hydrochloride (3.22 g, 30 mmol) and Et3N (6.97 mL, 50 mmol) in DMSO (50 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (3.74 g).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of dec-9-en-1-ol (1.22 g, 7.82 mmol) in DMF (18 mL) was added triphenylphosphine (2.30 g, 8.77 mmol). The solution was cooled to 0° C. and NBS (1.52 g, 8.54 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.8 mL). The solution was diluted with ether (80 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 10-bromo-dec-1-ene (1.38 g, 81%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.80 (1H, m), 4.94 (2H, m), 3.38 (2H, t, J=6.9 Hz), 2.02 (2H, m), 1.83 (2H, m), 1.20–1.55 (10H, m); 13C NMR (75 MHz, CDCl3) δ 139.17, 114.30, 34.29, 34.02, 33.06, 29.53, 29.25, 29.12, 28.96, 28.40.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].Cl>N1C=CC=CC=1.CC(C)=O.O>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114 %

Procedure:
2-Amino-5-chlorobenzophenone (2.92 g, 12.60 mmol) was dissolved in 60 mL of pyridine and 4-cyanobenzenesulfonyl chloride (2.66 g, 13.2 mmol) in 10 mL pyridine was then added. The mixture was stirred overnight at room temperature under N2, then poured in a steady stream into 350 mL vigorously stirring chilled 6M HCl which resulted in the precipitation of a yellow solid which was collected by vacuum filtration, washed well with H2O, then dissolved in 50 mL EtOAc and the solvents removed under vacuum to get a reddish powder which was dissolved in 75 mL boiling acetone. 150 mL of H2O was added in a slow stream to the hot, stirring acetone solution. A yellow precipitate formed upon cooling which was collected by vacuum filtration and dried overnight under vacuum to get 5.7 g product as a reddish powder (quant). 1H NMR (DMSO) δ 10.28 (s, 1H) 7.92 (dd, J=1.6, 8.8, 2H) 7.70 (d, 2H) 7.64(t, 1H) 7.58–7.52 (m, 3H) 7.50–7.46 (m, 2H) 7.42 (d, J=2.8 Hz, 1H) 7.03 (d, 8.8 Hz, 1H). MS: m/z=397.0 (M++1).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH:10]([CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][N:8]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:25]([O:24][C:22]([N:8]1[CH2:9][CH:10]([CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:7]1[C:6]([OH:29])=[O:5])=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: COC(=O)[C@@H]1CC(CCNC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.1 %

Procedure:
Lithium hydroxide monohydrate (7 mg) was added to a solution of N-tert-butoxycarbonyl-4-[2-(tert-butoxycarbonylamino)ethyl]-L-proline methyl ester (E, 50 mg) in tetrahydrofuran (0.5 mL)-methanol (0.5 mL)-water (0.5 mL). After stirring at room temperature for 4 hr, the reaction mixture was acidified with 10% citric acid and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the title compound (52 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: COCC(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (39.0 mg, 0.075 mmol) in DCM (754 μL) at 0° C. was added triethylamine (31.5 μL, 0.226 mmol) and 2-methoxyacetyl chloride (13.8 μL, 0.151 mmol). The reaction was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure and was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (14.0 mg, 31.5%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.30 (m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.75 (t, J=5.7 Hz, 0.7H), 2.83 (t, J=5.7 Hz, 1.3H), 3.08 (m, 2H), 3.44 (m, 5H), 3.77 (t, J=5.8 Hz, 1.3H), 3.88 (t, J=5.9 Hz, 0.7H), 4.14 (m, 1H), 4.24 (s, 0.7H), 4.28 (s, 1.3H), 4.49 (td, J=7.1, 3.5 Hz, 1H), 4.56 (s, 0.7H), 4.63 (s, 1.3H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 476.5.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=[O:7].[CH3:11][N:12]1[CH:16]=[C:15]([NH:17][C:18]([CH2:28]C)=[C:19]([C:24](OC)=O)[C:20]([O:22][CH3:23])=[O:21])[CH:14]=[N:13]1.C[N+](C)=CCl.[Cl-]>ClC(Cl)C>[CH3:11][N:12]1[C:16]2[C:15](=[N:17][C:18]([C:28]([O:4][CH3:3])=[O:7])=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:24]=2)[CH:14]=[N:13]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(Nc1cnn(C)c1)=C(C(=O)OC)C(=O)OC
Reactant: CN(C)C=O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc2c(cnn2C)nc1C(=O)OC
Temperature: -5 °C
Yield: 71.4 %

Procedure:
Dimethylformamide (7.4 mL, 0.096 mol) is dissolved in 125 mL dichloroethane and the mixture cooled -5° C. in an acetone/ice bath. Phosphorous oxychloride (8.9 mL, 0.095 mol) is added in one portion and the clear colorless solution is allowed to warm slowly to room temperature, gradually turning yellow. The unpurified dimethyl [(1-methylpyrazol-4-yl)amino]butenedicarboxylate is dissolved in 75 mL of dichloroethane and added chilled Viismeier reagent dropwise keeping the reaction temperature below 5° C. The mixture is allowed to warm slowly to room temperature over four hours, and then is heated to reflux for one hour. The mixture is concentrated to a solid which is chromatographed using 3:1 hexanes/ethyl acetate. The fractions containing the desired product are combined and concentrated to give the product as a white solid (16.93 g, 71.4%), melting point 148°-149° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[CH2:33]([NH2:35])[CH3:34]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:33]([NH:35][C:28]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:8]([F:7])([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:15])[CH3:16])(=[O:13])=[O:12])=[CH:23][CH:22]=2)=[CH:32][CH:31]=1)=[O:30])[CH3:34]
Reactant: CCN
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringe wise to 4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoic acid (140 mg, 0.37 mmol, prepared in example 4) in CH2Cl2 (10 mL) while stirring under nitrogen at room temperature. Immediately, 1 drop of DMF was added by pipette initiating a foaming of the mixture. The reaction was stirred one hour at this temperature and then concentrated under reduced vacuum to yield a white semi-solid. This material was placed into THF (10 mL) and added dropwise to a stirring solution of 2.0 M ethylamine in THF (0.5 mL) at room temperature and the mixture was stirred overnight. In the morning, the solution was concentrated under reduced vacuum and the resulting oil was taken into CH2Cl2 and the organic layer was washed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 151 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 2000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 1:1 to yield the title compound (127 mg, 85%) as a viscous oil. Ion spray M.S. 407.4 (M*+1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.575 g, 0.76 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.227 g, 0.85 mmol), tetrakis(triphenyl-phosphine)palladium (0.051 g, 0.038 mmol) in toluene (5 mL) was heated under reflux conditions for 4 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), placed in freezer for 30 min, added heptane (total volume: 25 mL), filtered the precipitate off, washed with toluene/heptane (ca. 1:1, 3×10 mL), dried in HV to give the title compound as an off-white solid (305 mg, 70%). MS (ISP) 576.3 [(M+H)+]; mp 236° C.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[I:8][C:7]1[C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Clc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Ic1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 80 °C

Procedure:
To a 250-mL round-bottomed flask was added 2-chloro-3-iodopyridine (5.32 g, 22.22 mmol), 4-(pyridin-2-ylamino)phenol (4.96 g, 26.6 mmol) and cesium carbonate (11.27 g, 34.6 mmol) in DMSO (100 mL) and the reaction was heated at 80° C. overnight. The reaction was cooled to rt and poured into water (400 mL). The solution was extracted with EtOAc (4×100 mL) and the combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered, evaporated onto silica gel and purified by flash chromatography (Isco, (330 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:19). The material was dissolved in MeOH, evaporated onto silica gel and further purified by flash chromatography (Isco (330 gram)) eluting with EtOAc:hexanes (0:1→3:1) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 389.9. IC50 (uM)=0.2284.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.CCO.C(OCC)(=O)C>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1nccs1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)Nc2nccs2)cc1
Reaction time: 72 h

Procedure:
4-Nitro-N-thiazol-2-yl-benzamide (28 mmol) was suspended in abs. EtOH (400 mL) and ethyl acetate (200 mL) and glacial acetic acid (50 mL) was added followed by 10% Pd/C (0.5 g). The mixture was hydrogenated for 72 h at 3 bar H2. The hydrogenation mixture was filtered, and the solvent was removed under reduced pressure. The crude product was added NaHCO3 (sat.) and ethyl acetate, the remaining solid fraction was removed by filtration and dried in vacuo. The liquid phases were separated, the organics were washed with brine, dried over MgSO4, filtered and evaporated to yield a solid. The solid fractions were combined.