Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH3:9][O:10][C:11]([C:13]12[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][C:18](O)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH:17]1[CH2:16][N:15]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:14]2)=[O:12].[OH-].[Na+]>ClCCl>[CH2:36]([N:15]1[CH2:14][C:13]2([C:11]([O:10][CH3:9])=[O:12])[C:17](=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:19][CH2:20][CH:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccccc1C)CCC2c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C12CN(Cc3ccccc3)CC1=C(c1ccccc1C)CCC2c1ccccc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
A mixture of 3.2 cm3 of trifluoromethanesulphonic acid and of 3 cm3 of dichloromethane was added dropwise to a solution of 2.2 g of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(2-methylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate in 20 cm3 of dichloromethane maintained at a temperature in the region of 0° C. The reaction mixture was stirred for thirty minutes at a temperature in the region of 0° C. and twenty hours at a temperature in the region of 20° C. and then cooled to a temperature in the region of 0° C. The pH was then brought to 8 by addition of a normal aqueous sodium hydroxide solution. The aqueous phase was separated by settling and extracted with three times 50 cm3 of dichloromethane. The organic phases were combined, washed with three times 100 cm3 of distilled water and 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. 1.9 g of methyl(3aRS,4SR)-2-benzyl-7-(2-methylphenyl)-4-phenyl-1,3,3a,4,5,6-hexahydroisoindole-3a-carboxylate were thus obtained in the form of an oil, and used in the subsequent syntheses, the characteristics of which were as follows:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CN)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-(1-hydroxy-1-methyl-ethyl)-benzonitrile (20.9 g, 0.13 mol.) in dry tetrahydrofuran (300 mL) at 0° C. was added slowly dropwise 1.0M lithium aluminium hydride in tetrahydrofuran (388 mL, 0.39 mol.). The mixture was refluxed for 30 min. then cooled to 0° C. and quenched with methanol (50 mL) added slowly dropwise. The mixture was concentrated in vacuo to half volume and diluted with chloroform (1200 mL) then washed with water (300 mL). The resulting suspension was filtered through Celite and the filtrate layers seperated. The organic extract was dried (MgSO4) and concentrated to give 16.2 g as a light yellow solid mp 64-6° C. NMR (CDCl3): 7.45 (d, 2H), 7.26 (d, 2H), 3.83 (s, 2H), 1.57 (s, 6H). GC-MS (m/e, %): 164 (M+, 15), 150 (80), 132 (75), 106 (100).
Reaction SMILES: [CH2:1](I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[Mg]Br>C1COCC1>[CH2:1]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1cccs1
Reactant: ICc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.8 g (52 mmol) of NaI and 5 mL (43 mmol) of benzyl chloride in THF was heated at reflux for 2 h to form benzyl iodide in situ and then the reaction was cooled to rt. In a separate flask, 37 mg (0.87 mmol) of LiCl and 58 mg (0.43 mmol) of copper(II) chloride were dissolved in 5 mL of THF and stirred at rt for 5 min to form Li2CuCl4 in situ. The benzyl iodide reaction flask was fitted with an addition funnel and 3 mL (3 mmol) of a 1 M solution of 2-thienylmagnesium bromide in THF was added dropwise, followed by addition of the Li2CuCl4 solution, and then the remaining 2-thienylmagnesium bromide solution (49 mL, 49 mmol) was added at such a rate as to maintain the reaction temperature ≦40° C. and the reaction solution was stirred for 2 h at rt. The THF was removed in vacuo, and the residue was partitioned between 250 mL of Et2O and 150 mL of NH4Cl and separated. The organic layer was treated with 15 mL of piperidine and stirred for 18 h, then washed twice with 10% (w/v) aqueous HCl, filtered, concentrated and the dark red residue was purified by flash chromatography eluting with neat hexane to yield the title compound. GC-MS (M)+ 174.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:19]1[CH:20]=[C:21]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]2)[C:22]([O:25][CH3:26])=[N:23][CH:24]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:26][O:25][C:22]1[N:23]=[CH:24][C:19]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:20][C:21]=1[NH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ncc(-c2ccncc2)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 50.2 %

Procedure:
Pyridine-4-boronic acid (0.950 g, 7.77 mmol) and potassium phosphate (2 M, 70 mL) was added to a solution of (R)-tert-butyl 3-((5-bromo-2-methoxypyridin-3-yl)amino)piperidine-1-carboxylate (2.00 g, 5.18 mmol) in dioxane (70 mL). The mixture was degassed for 20 min and then Pd(dppf)Cl2 (1.28 g, 1.55 mmol) was added. The mixture was stirred at 80° C. for 6 h. The mixture was allowed to cool to room temperature and was filtered through celite and concentrated. The residue was purified by chromatography using 40-50% ethyl acetate in pet ether to give 1 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 8.55-8.65 (narrow m, 2H), 7.85 (s, 1H), 7.65-7.75 (narrow m, 2H), 7.10-7.30 (m, 1H), 5.03 (br s, 1H), 3.94 (s, 3H), 3.45-3.80 (m, 3H), 2.90-3.15 (m, 2H), 1.85-2.00 (m, 1H), 1.15-1.75 (m, 12H); MS (ES) m/z 385 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH:7]=1>CO.[Pd]>[NH2:21][C:20]1[CH:19]=[CH:18][C:4]([NH:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[CH:7]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C(Nc1cc(Nc2ccc([N+](=O)[O-])c(F)c2)ccn1)C1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Nc2ccnc(NC(=O)C3CC3)c2)cc1F
Yield: 95.9 %

Procedure:
Dissolve N-[4-(3-fluoro-4-nitro-anilino)-2-pyridyl]cyclopropanecarboxamide (160 mg, 0.51 mmol) in methanol (10 mL), add wet Pd/C (10%, 60 mg), flush with H2 and then stir the reaction under H2 atmosphere at room temperature for 6 hrs. Remove H2, filter the mixture. Concentrate the filtrate under reduced pressure to give the crude product (140 mg) which is used directly without further purification. MS: (M+1): 287.2.
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: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
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:1][CH:2]([C:12]([CH3:14])=[O:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[N+](=[CH2:17])=[N-]>C(Cl)Cl>[Cl:1]/[C:2](=[C:12](/[O:13][CH3:17])\[CH3:14])/[C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CC(=O)C(Cl)C(=O)Nc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: CO/C(C)=C(/Cl)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
52.9 g of α-chloroacetoacetanilide in 500 ml of methylene chloride was held at 0° C for 4 hours and then 725 ml of methylene chloride solution titrating 17.4 g/l of diazomethane were added. The mixture was stirred for 16 hours at 0° C and then 1 hour at 20° C and was concentrated to dryness under reduced pressure. The residue was added to isopropyl ether and the precipitate formed was recovered by vacuum filtration and was crystallized from isopropyl ether to obtain 12 g of 2-chloro-3-methoxy-crotonanilide melting at 100° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].Cl>CCOCC>[C:18]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:20])[CH3:19]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)N1CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
1,2,3,4-Tetrahydroquinoline (5 g, 0.038 mol) and triethylamine (4.55 g, 0.045 mol) were dissolved in 55 ml ether. Acetyl chloride (3.24 g, 0.041 mol) was added and the mixture stirred for 30 minutes, and poured into a mixture of 100 ml 1M HCl and 50 ml ether. The organic layer was separated, washed 1×100 ml 1M HCl and then 2×100 ml 5% NaHCO3, dried (K2CO3) and stripped to yield title product as an oil, 5.13 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)C.[NH4+].[Cl-]>[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(Cl)cc(N)c1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-nitrobenzoate (1 equiv.) in ethanol (2 mL per 1 mmol), was added NH4Cl solution (5.1 equiv., dissolved in water. Volume of water equivalent to volume of ethanol) followed by Fe powder (8 equiv.). The resulting reaction mixture was stirred at 90° C. for 1 h. On completion, reaction mixture was filtered and the filtrate concentrated until dryness. The resulting solid which was dissolved in saturated sodium bicarbonate solution and the aqueous layer extracted with ethyl acetate. Combined organic layers were dried over sodium sulfate and concentrated to afford solid methyl 3-amino-5-chloro-2-methylbenzoate in quantitative yield.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].[NH:26]1[CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I>[CH3:25][O:24][C:3]1[C:2]([N:26]2[CH2:31][CH2:30][CH2:29][NH:28][C:27]2=[O:32])=[N:7][C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=C1NCCCN1
Reactant: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCCNC1=O
Temperature: 110 °C
Yield: 15.2 %

Procedure:
A solution containing 1-(6-bromo-5-methoxy-2-pyridyl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (50 mg, 0.126 mmol), tetrahydro-2-pyrimidinone (40 mg, 0.38 mmol), Copper(I) iodide (126 mg, 0.126 mmol), Potassium carbonate (21 mg, 0.15 mmol) and N,N′-Dimethylethylenediamine (0.028 mL, 0.252 mmol) was stirred at 110° C. 18 h. The reaction was filtered through celite and concentrated. The crude product was submitted for reverse phase HPLC to give 251 (8 mg, 14%). MS (ESI) m/z: 417.1. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 6.74 (s, 1H), 3.86 (s, 3H), 3.35 (d, J=5.4 Hz, 2H), 2.63 (s, 3H), 2.16-2.08 (m, 2H).
Reaction SMILES: NC1N=NN=C(Cl)C=1N.[CH2:10]([NH2:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+].[N:25]1[C:32]([NH2:33])=[N:31][C:29](N)=[N:28][C:26]=1[NH2:27]>O>[CH2:10]([NH:22][C:29]1[N:31]=[C:32]([NH2:33])[N:25]=[C:26]([NH2:27])[N:28]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1nc(N)nc(N)n1
Reactant: CCCCCCCCCCCCN
Agent: Nc1nnnc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCNc1nc(N)nc(N)n1
Yield: 65 %

Procedure:
A mixture of 14.6 g (0.1 mol) of diaminochlorotriazine, 19.5 g (0.105 mol) of n-dodecylamine and 4.0 g (0.1 mol) of sodium hydroxide in 200 ml of water is refluxed for 5 hours. The solid formed is filtered off wich suction, washed until free of chloride and then treated with a mixture of methylene chloride/ether (1:1). The precipitate is filtered off and boiled in dimethylformamide. After filtration, the concentrated filtrate is poured into water with stirring. The precipitate formed is dried to constant weight. The yield is 65% of theory. The product contains 0.1 mol of hydrated water per mole of melamine and melts at 119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].Cl[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]>>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][CH:13]([C:14]([OH:16])=[O:15])[CH3:17])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(Cl)C(=O)O
Product: COc1cc(NC(C)C(=O)O)cc(OC)c1

Procedure:
The title compound was prepared according to the procedure described in U.S. Pat. No. 3,598,859 (or Example A above) using 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1O[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:10]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:24][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:10]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3c(Cl)cccc3Cl)on2)cc1
Agent: N
Product: O=[N+]([O-])c1ccc(-c2cc(-c3c(Cl)cccc3Cl)sn2)cc1

Procedure:
By the method of Tetrahedron, 1992, 48, 8127-8142 the substance 5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)isoxazole can be treated with diphosphorus pentasulfide followed by aqueous or ethanolic ammonia quench to produce 5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)isothiazole. The nitrophenyl group can be reduced to the corresponding aniline with tin (II) dichloride or iron powder and ammonium chloride. This aniline can then be treated with 2,2-dichloroacetyl chloride and triethylamine to yield 2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-3-isothiazolyl]phenyl]acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16]([OH:17])=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.I[CH2:26][C:27]([F:30])([F:29])[F:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: FC(F)(F)CI
Reactant: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ncn1CC(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-2A-1b: 1.20 g, 3.36 mmol), 2-iodo-1,1,1-trifluoroethane (705 mg, 3.36 mmol) and Cs2CO3 (2.19 g, 6.72 mmol) in DMF (20 ml) was heated at 100° C. for 17 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with saturated aqueous NaCl, dried, and concentrated in vacuo. The crude residue was purified via a Shimadzu HPLC system using a Waters XTERRA C18 50×50 mm column and a mixture of two solvent systems (0.1% NH4OH/CH3CN and H2O/0.1% NH4OH) to give the title compound 2A-1 (300 mg, 20%) as an amorphous solid: +ES MS (M+1) 439.1; 1H NMR (CDCl3) δ 7.87 (s, 1H), 7.54–7.30 (m, 8H), 4.7 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:18]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=1[O:11][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(Cl)c(O)c(C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(Cl)cc(C(C)=O)cc1C(C)(C)C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
1-(3-tert-Butyl-5-chloro-4-hydroxyphenyl)ethanone (1.65 g, 7.28 mmol) and methyl iodide (2.07 g, 14.56 mmol) were added to N,N-dimethylformamide (2.5 mL), followed by stirring on ice, and addition of potassium carbonate (1.51 g, 10.92 mmol). After 3 hours of stirring, toluene (30 mL) and water (20 mL) were added, and the solution was separated. The organic layer was washed with water (15 mL), dried, and then concentrated under reduced pressure (50° C.) to obtain 1.37 g of the subject compound as a yellowish oily substance (yield: 78.2%, HPLC purity: 99.4%)
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[C:8]([CH3:10])=[CH2:9].C(N(CC)CC)C>O>[C:13]([O:12][C:7](=[O:11])[CH:8]([CH3:10])[CH2:9][S:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: OCC(O)CS
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CSCC(O)CO)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
To thioglycerol (0.835 mI), t-butyl methacrylate (10 ml) and triethylamine (1 ml) were added, followed by stirring at 60° C. for 48 hours. After cooling and addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off, to yield the title compound (2.11 g, yield 84%) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([NH:13][C:14](=[O:24])[C@@H:15]([N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=[O:23])[CH3:16])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([NH:13][C:14](=[O:24])[C@@H:15]([N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=[O:23])[CH3:16])[C:9](=[O:12])[CH2:10][F:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)n1ccccc1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF)n1ccccc1=O
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
A stirred solution of 5-Fluoro-4-hydroxy-3-[(S)-2-(2-oxo-2H-pyridin-1-yl)-propionylamino]-pentanoic acid tert-butyl ester (135 mg, 0.38 mmol) in anhydrous DCM (5 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (193 mg, 0.46 mmol) at 0° C. The resulting mixture was kept at 0° C. for 1.5 h, diluted with ethyl acetate, then poured into a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulphate. The organic layer was removed and the aqueous layer re-extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (1% methanol in ethyl acetate) to afford the title compound as a colorless gum (125 mg, 93%): 1H NMR (400 MHz, CDCl3) δ 1.2-1.4 (9H, 2×s), 2.6-2.9 (2H, m), 4.7-4.9 (1H, m), 4.9-5.3 (2H, m), 5.6-5.7 (1H, m), 6.2-6.3 (1H, m), 6.5-6.6 (1H, m), 7.2-7.4 (1H, m), 7.5-7.6 (1H, m), 8.0-8.2 (1H, m); 13C NMR (100 MHz, CDCl3) δ 16.57, 16.87, 28.24, 28.29, 36.44, 36.60, 52.50, 52.62, 52.90, 53.09, 82.31, 82.44, 83.51, 83.72, 85.33, 85.55, 107.35, 107.44, 120.45, 120.49, 134.42, 134.67, 140.22, 140.36, 162.85, 162.98, 169.93, 169.99, 170.59, 170.63, 202.58, 202.64, 202.75, 202.80; 19F NMR (376 MHz, CDCl3) δ −231.94, −231.96, −232.48, −232.49.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:25]([O:27][CH2:28][CH2:29][NH2:30])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:25]([O:27][CH2:28][CH2:29][NH:30][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])[CH3:26]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C

Procedure:
1-Methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (33 mg) was prepared by following General Procedure F using 1-methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (36 mg), 2-ethoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 431; and 1H NMR (DMSO-d6, 400 MHz): δ 8.26 (t, 1H), 7.80 (s, 1H), 7.65 (t, 1H), 7.56 (br, 2H), 7.48 (d, 1H), 7.18 (m, 1H), 7.14 (d, 1H), 3.54 (s, 3H), 3.46 (q, 2H), 3.38 (m 2H), 3.24 (t, 2H), and 1.08 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([OH:13])[CH3:12]>>[CH2:11]([O:13][C:7]1[CH:2]=[C:3]([OH:9])[C:6]2[C:7](=[C:2]([Br:1])[C:3]([O:9][CH3:10])=[CH:4][CH:5]=2)[N:8]=1)[CH3:12]
Reactant: COc1cccc(N)c1Br
Reactant: CCO
Product: CCOc1cc(O)c2ccc(OC)c(Br)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-bromo-3-aminoanisole 2b4 (750 mg, 3.7 mmol, 1 eq) was added imidate 2g2 (0.73 g, 3.7 mmol, 1 eq) in ethanol (7 mL) under a N2 atmosphere. The mixture was stirred at RT. for 24 hrs at which point the reaction was concentrated and purified directly on a silica gel column (eluent: EtOAc/Hexanes (1:9)) to afford adduct 2o1 (1.12 g, 88%) as a pale yellow oil. MS: 344 (M+H)+ and 346 (MH+2)+.