Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH3:31])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH3:31])[S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)-methyl)biphenyl-3-yl)cyclopropane carboxamide (30 mg, 0.070 mmol), methanesulfonyl chloride (7.8 μL, 0.14 mmol) and Et3N (30 μL, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) and allowed to stir at 25° C. for 16 hours. The crude reaction was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((N-methylmethylsulfonamido)methyl)biphenyl-3-yl)cyclopropanecarboxamide (22 mg, 64%). ESI-MS m/z calc. 492.2, found 493.3 (M+1)+; retention time 3.45 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].Cl[CH2:12][C:13]([OH:15])=[O:14]>>[C:13]([CH2:12][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])([OH:15])=[O:14]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cn1cc(Cl)cnc1=O
Yield: 47 %

Procedure:
A solution made from 5-chloropyrimid-2-one (0.015 mol), aqueous 0.78 M KOH (45 ml) and chloroacetic acid (0.018 mol) was heated under reflux until the pH had fallen to below 8. The solution was then concentrated to a small volume at reduced pressure. Addition of 1 N HCl (15 ml) caused the product to crystallize; yield 47%, m.p. 186°-188° C. (acetone). (Found: C, 38.35; H, 2.69. Calc. for C6H5ClN2O3 : C, 38.23; H, 2.67).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([N:34]3[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35]3)=[C:17]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[C:18]([CH3:22])=[N:19][C:20]=2[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CCO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([N:34]3[CH2:35][CH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][CH2:39]3)=[C:17]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[C:18]([CH3:22])=[N:19][C:20]=2[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccccc2)cc1
Yield: 85 %

Procedure:
A mixture of (S)-ethyl 2-(5-(4-(benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0224 g, 0.040 mmol) and LiOH (9.60 mg, 0.401 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(5-(4-(benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid (0.018 g, 0.034 mmol, 85% yield) as white solid. 1H NMR (400 MHz, CDCl3) δ 7.32-7.49 (m, 5H), 7.12-7.16 (m, 1H), 6.97-7.08 (m, 3H), 5.65 (br. s., 1H), 5.09-5.18 (m, 2H), 2.81 (s, 3H), 2.29 (s, 3H), 1.23-1.38 (m, 4H), 1.20 (s, 9H), 0.77 (br. s., 6H). 4H of piperidine were not resolved. LCMS (M+H)=531.4.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc2c1C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CC(C)c1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 73 %

Procedure:
The title compound was prepared from 4-isopropyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 73% yield: 1H NMR (DMSO-d6): δ 1.30 (d, J=6.7 Hz, 6H), 3.82 (septet, J=6.7 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H 7.24 (s, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 11.10 (s, 1H), 13.05 (s, 1H); APCI−MS m/z 357 (M−1)−. Anal. Calcd for C17H18N4O3S: C, 56.97, H. 5.06; N, 15.63; S. 8.95. Found C, 56.88, H, 5.12; N, 15.73; S, 8.91.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[C:26]([F:34])[CH:27]=[CH:28][C:29]=2[NH2:33])[N:24]=1>>[NH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[C:26]([F:34])[CH:27]=[CH:28][C:29]=2[NH:33][CH:11]2[C:5]3[C:4](=[C:3]([O:20][CH3:21])[C:2]([Cl:1])=[CH:7][CH:6]=3)[C:8]([CH3:18])([CH3:19])[CH2:9][C:10]2([OH:17])[C:13]([F:14])([F:16])[F:15])[N:24]=1
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1ccc2c(N)ccc(F)c2n1
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(N)ccc12

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 137 mg of 2,5-diamino-8-fluoroquinoline. The title compound is obtained analogously to Example 3 by reaction of the imine that is formed with 1.0 ml of titanium tetrachloride solution (1 M in dichloromethane).
Reaction SMILES: [Na].CO[C:4](=[O:37])[CH2:5][C:6]1=[N:7][N:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:9](=[O:29])/[C:10]/1=[C:11](/[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)\[CH2:12][C:13]1[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=1.Cl.C[CH:40]([OH:42])C>>[CH2:22]([N:21]1[C:4](=[O:37])[CH:5]=[C:6]2[NH:7][N:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:9](=[O:29])[C:10]2=[C:11]1[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:42][CH3:40])[CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)O
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(\Cc1ccc(OC)cc1)NCc1ccccc1
Agent: Cl
Agent: [Na]
Product: COc1cccc(Cc2c3c(=O)n(-c4ccccc4Cl)[nH]c3cc(=O)n2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.017 g, 0.75 mmol, 2 equiv.) in i-PrOH (2 ml), was treated with methyl[(4E)-4-[1-(benzylamino)-2-(4-methoxyphenyl)ethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (170 mg, 0.36 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 0.5 h, then cooled and neutralized to pH 6 by addition 1M HCl solution. i-PrOH were removed in vacuo and the crude was purified by flash chromatography to yield 24 mg of pure product 5-benzyl-2-(2-chlorophenyl)-4-(3-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione. Yield 14%. 1HNMR (500 MHz, DMSO-d6): 3.69 (s, 3H); 4.40-4.60 (m, 2H); 5.08-5.24 (m, 2H), 5.72 (s, 1H); 6.71-6.73 (m, 2H), 6.80-6.82 (m, 1H); 7.02-7.03 (m, 2H); 7.21-7.25 (m, 3H); 7.28-7.31 (m, 3H); 7.47-7.49 (m, 2H); 7.62-7.66 (m, 2H). MS (ESI+): 472.9; MS (ESI−): 470.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.C1C(=O)N([I:23])C(=O)C1.CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[I:23])[CH:13]=[CH:12][O:11]3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3occn3c2I)cc1
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of 6-(4-fluorophenyl)imidazo[2,1-b]oxazole (4.92 g, 24.3 mmol; prepared according to WO2004110990A2, Example 1, Steps 1-3), NIS (5.75 g, 25.6 mmol), and DMF (100 mL) was stirred at ambient temperature. After about 3 h, the reaction was poured into water (300 mL) and the resulting precipitate was filtered, washing with additional water, and dried in a vacuum oven at about 55-65° C. to give the title compound (7.21 g, 89%): LC/MS (Table 1, Method b) Rt, =2.09 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[I-:28].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[I:28][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2
Reactant: [I-]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Yield: 128.9 %

Procedure:
(S)-tert-Butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (1 g, 2.31 mmol) was dissolved in 25 mL anhydrous dioxane in a Schlenk vessel. Sodium iodide (1.38 g, 3.9 mmol), copper(I) iodide (0.13 g, 0.68 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.2 g, 1.41 mmol) were added under argon conditions and the mixture was further submitted to three vacuum-argon cycles. The reaction vessel was sealed and the mixture was heated at 120° C. for 7 h. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The organic phase was washed with 1N hydrochloric acid, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain 1.43 g (88% yield) of the title compound as a oil. Purity 68%.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:21]([C:22]([O:24]C)=[O:23])=[CH:20][N:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].O>C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:32]([F:33])([F:34])[F:35])[CH2:17][CH2:16][N:15]([C:18]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=3)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:8]=1
Reactant: COC(=O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.1 %

Procedure:
Methyl 6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoro-methyl)nicotinate (1.21 g), sodium hydroxide (0.26 g) and water (5 ml) were added to ethanol (40 ml) and stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, diluted hydrochloric acid and t-butyl methyl ether were added and then extracted. The target compound (1.11 g) was obtained by concentration under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:5]=NO.Cl.C=[O:18].O>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:5]=[O:18]
Reactant: C=O
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C=O
Temperature: 25 °C

Procedure:
7.1 g of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime (23 mmol) are stirred at 65° C. in a mixture of 17 g of 5% strength hydrochloric acid, 2 g of 37% strength formaldehyde solution, 15 ml of water and 30 ml of tetrahydrofuran for 32 hours. During this time, a further 3.5 g of 37% strength formaldehyde solution are added in portions of 0.5 g. The mixture is then cooled to room temperature and the product is filtered off with suction.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH2:10]1CCN2C(=NCCC2)C[CH2:11]1.C[Si](Cl)(C)C>ClC(Cl)C.CN(C=O)C>[CH3:4][C:3]1([CH3:5])[S:6][CH2:11][CH2:10][NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)SCCN[C@H]1C(=O)O

Procedure:
To a 0° suspension of 14.92 g (0.10 mmol) of D-penicillamine in 300 mL of dichloroethane and 2.0 mL of DMF was added 22.4 mL of DBU followed by 19.0 mL of trimethylsilyl chloride. The ice bath was removed and the reaction was stirred for 3h, after which an additional 29.9 mL of DBU was added. The reaction was stirred overnight at room temperature and then 10 mL of methanol was added and the reaction was stirred for 1h. The resulting white precipitate was filtered off, washed with 10 mL of methanol and dried in vacuo to provide 16 g of (3 S)-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[C:10]#[N:11].O>C(O)(=O)C>[Br:1][C:7]1[CH:6]=[C:5]([C:10]#[N:11])[N:4]([CH3:3])[C:8]=1[CH3:9]
Reactant: BrBr
Reactant: Cc1ccc(C#N)n1C
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)cc(C#N)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of bromine (6.58 mL, 0.13 mol) in acetic acid (60 mL) is added dropwise, with the aid of a dropping funnel, to a solution of 1,5-dimethyl-1H-pyrrole-2-carbonitrile (15.0 g, 0.12 mol) in acetic acid (300 mL). The batch is stirred at ambient temperature for 24 hours. The reaction mixture is then poured into a beaker containing 300 mL of water. The solid formed is filtered off and rinsed with water. It is then dissolved in dichloromethane (300 mL) and the organic phase is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the expected product in the form of a solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O.N1C2C=CC=CC=2N=N1>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1coc(-c2ccc(CO)cc2)n1)N1CCCC1
Agent: c1ccc2[nH]nnc2c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1coc(-c2ccc(CCl)cc2)n1)N1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
A solution of 2-[4-(hydroxymethyl)phenyl]-4-(pyrrolidin-1-ylcarbonyl)-1,3-oxazole (0.467 g, 1.89 mmol) in CH2Cl2 was treated with a solution of thionyl chloride (0.281 g, 2.36 mmol) and benzotriazole (0.281 g, 2.36 mmol) in CH2Cl2, stirred for 6 hours at room temperature, diluted with CHCl3, filtered over Celite and concentrated under vacuum, The resultant residue was purified by flash chromatography (silica, MeOH:CH2Cl2 5%) to give the title product in 82% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 291 (MH+) mp 126-128° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[CH3:25][CH:26]1[NH:27][CH:28]([CH3:32])[CH2:29][N:30]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:8]2(=[O:24])=[O:23])[CH2:31]1
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Reactant: CC1CNCC(C)N1
Product: CC1CN(CCOCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC(C)N1
Yield: 86.7 %

Procedure:
In an analogous manner as described in general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.18 mmol) was treated with 2,6-Dimethyl-piperazine (0.06 g, 0.54 mmol) to provide 0.07 g (92%) of 1-{2-[2-(3,5-dimethylpiperazin-1-yl)ethoxy]ethyl}-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[C:6]([CH:8]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9](OCC)=[O:10])#[N:7]>C(O)C>[NH2:7][C:6]1[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:9]([OH:10])[C:8]=1[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1
Reactant: NNCCO
Reactant: CCOC(=O)C(C#N)c1ccc(C)cc1
Solvent: CCO
Product: Cc1ccc(-c2c(O)nn(CCO)c2N)cc1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
2-Hydroxyethylhydrazine (5.87 g) was added dropwise over 5 minutes to a stirred solution of ethyl cyano-(4-methylphenyl)acetate (Synthesis, 1985, 5, 506) (10.14 g) in absolute ethanol (200 ml) and the resulting mixture was then heated under reflux overnight. The reaction mixture was cooled to room temperature and the ethanol was evaporated under reduced pressure. The resulting yellow/orange oil was triturated with methanol and the solid was isolated by filtration to give the title compound as a white solid (3.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.OS(O)(=O)=O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 130 °C
Yield: 98 %

Procedure:
To a hot solution of 2-amino-5-nitropyridine (1.4 g, 10 mmol) in acetic anhydride (5 mL) at 100° C. was added conc. H2SO4 (0.1 mL). The resulting mixture was heated at 130° C. for 2 h, cooled and partitioned between EtOAc (200 mL) and water (100 mL). The layers were separated and the aqueous layer was washed once with EtOAc (100 mL). The combined organic layers were washed with water (100 mL), saturated aqueous NaHCO3 (100 mL) and then brine (50 mL); dried over anhydrous MgSO4 and concentrated under reduced pressure to afford N-(5-nitropyridin-2-yl)acetamide (1.8 g, 98%), which was used without further purification. 1H-NMR (CDCl3): δ 9.14 (1H, d), 8.50 (1H, dd), 8.40 (1H, d), 8.23 (1H, br s), 2.29 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=2)[N:3]=1.Cl.[CH:31]1([C:34]2([F:38])[CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH:31]1([C:34]2([F:38])[CH2:37][N:36]([C:2]3[CH:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:5]=[C:4]([S:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=4)[N:3]=3)[CH2:35]2)[CH2:33][CH2:32]1
Reactant: FC1(C2CC2)CNC1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ccccn3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Nc3ccccn3)cc(N3CC(F)(C4CC4)C3)n2)cc1
Temperature: 140 °C
Yield: 3.9 %

Procedure:
N-(4-(4-chloro-6-(pyridin-2-ylamino)pyrimidin-2-ylthio)phenyl)-3,3,3-trifluoropropanamide (2b, 620 mg, 1.4 mmol) and 3-cyclopropyl-3-fluoroazetidine hydrochloride (598 mg, 3.94 mmol, 2.8 eq.) were dissolved in 1,4-dioxane and transferred to a microwave vial. DiPEA (437 mg, 3.38 mmol, 2.4 eq.) was added. The mixture was flushed with N2 for 10 minutes while stirring and heated at 140° C. for 30 minutes in the microwave. HPLC-MS analysis showed 27-40% product in the mixture. The mixture was concentrated and purified by preparative HPLC and lyophilized, yielding 28 mg (3.8%) of a light-yellow solid with a purity of 98+% (HPLC method B: Rf=5.855 minutes).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[S:16])[CH:6]=[CH:7][C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].[CH3:23][C:24]1[CH:25]=[C:26](N)[CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([CH3:39])=[N:36][C:35]=2[CH:40]=1.C(O)(=O)C>C(OC(C)C)(=O)C>[OH:20][CH2:19][C:18]([NH:17][C:15]([NH:14][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[N:9]=[CH:10][N:11]=[C:1]2[NH:2][C:26]1[CH:27]=[CH:28][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([CH3:39])=[N:36][C:35]=3[CH:40]=2)=[C:24]([CH3:23])[CH:25]=1)=[S:16])([CH3:21])[CH3:22]
Reactant: CN(C)C=Nc1ccc(NC(=S)NC(C)(C)CO)cc1C#N
Reactant: Cc1nc2cc(Oc3ccc(N)cc3C)ccc2o1
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Product: Cc1nc2cc(Oc3ccc(Nc4ncnc5ccc(NC(=S)NC(C)(C)CO)cc45)cc3C)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (275 mg, 0.861 mmol) and 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine (241 mg, 0.947 mmol) in isopropyl acetate (2 mL) was added acetic acid (0.2 mL, 3.44 mmol). After stirring at room temperature for 16 hours, hexanes was added and stirred with the mixture for 30 minutes. The mixture was filtered to provide the crude product (281 mg, 62%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.FC(F)(F)C(F)(F)C(F)(F)C([O:18][C:19](=O)[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:8][C:19](=[O:18])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])=[N:6][CH:7]=1
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Product: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)F

Procedure:
5-Chloro-3-nitro-2-aminopyridine is reacted with heptafluorobutyric anhydride to obtain 5-chloro-3-nitro-2-(heptafluorobutyramido)pyridine which when hydrogenated yields 6-chloro-1-hydroxy-2-(heptafluoro-n-propyl)-1H-imidazo(4,5-b)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:33]([OH:34])[C@@H:14]2[O:15][Si:16]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:17][Si:18]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:19][CH2:20][C@H:13]2[CH2:12]1.[CH:35]1[CH:40]=[CH:39][C:38]([O:41][C:42](Cl)=[S:43])=[CH:37][CH:36]=1>C(Cl)Cl>[C:42](=[S:43])([O:41][C:38]1[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=1)[O:34][C@@H:33]1[C@@H:14]2[O:15][Si:16]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[O:17][Si:18]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:22])[CH3:23])[O:19][CH2:20][C@H:13]2[CH2:12][C@H:11]1[N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)[C@H](OC(=S)Oc3ccccc3)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of (6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-ol (0.762 g, 1.44 mmol) and N,N-dimethylaminopyridine (0.529 g, 4.34 mmol) in DCM (20 mL) was added phenyl chlorothionocarbonate (0.440 mL, 3.2 mmol) and the solution was stirred for 1 h. The reaction mixture was concentrated and the residue purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.851 g, 88%).