Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([NH:5][CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=[O:4])=[O:3].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH3:28])[CH2:21][CH:20]2[C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:2]([NH:5][CH2:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=[O:4])=[O:3])=[CH:31][CH:30]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Reactant: CCOP(=O)(CCNS(=O)(=O)Cl)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOP(=O)(CCNS(=O)(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed diethyl 2-(chlorosulfonylamino)ethylphosphonate (intermediate 30.8) (670 mg, 2.40 mmol, 1.47 equiv), 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 30.7) (500 mg, 1.63 mmol, 1.00 equiv), N-ethyl-N-isopropylpropan-2-amine (400 mg, 3.10 mmol, 1.91 equiv) in acetonitrile (20 mL). The resulting solution was stirred for 3 h at 60° C. The resulting mixture was concentrated under vacuum and the residue was applied to a silica gel column and eluted with dichloromethane/methanol (20:1). This resulted in 150 mg (16%) of the title compound as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](I)[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O1C2C=CC=CC=2C[C:29](=O)[NH:28]1.[Cu]C#N>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:29]#[N:28])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: O=C1Cc2ccccc2ON1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (600 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (126 mg, 0.66 mmol), tetrakis(triphenyphosphine)palladium(0) (382 mg, 0.33 mmol) and copper(I) cyanide (800 mg, 8.8 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 440 mg of the title compound as a crude yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: c1cncc(-c2c[nH]cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Cn2cnc(-c3cccnc3)c2)cc1
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
To a solution of 34 (35 mg, 0.25 mmol) in THF (5 mL) under argon was added sodium hydride (12 mg, 0.29 mmol) in one portion and the resultant slurry was stirred for 20 min. Benzyl bromide (26 μL, 0.32 mmol) was added and the resultant solution was stirred for 10 min. The reaction was quenched by the slow addition of HCl(aq) (1 N, 2 mL), diluted with 13 mL of water and washed with ethyl acetate (3×15 ml). Dichloromethane was added (25 mL) and the aqueous fraction was adjusted to pH 9 with NaOH(aq) (10 N). The organic fraction was collected and the aqueous was extracted with dichloromethane (20 mL), the combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 2.5/97.5, Rf=0.26) to afford the title compound 60 (43 mg, 74% yield) as a white semisolid: 1H NMR (CDCl3) δ 8.95 (br s, 1H), 8.47 (br s, 1H), 8.10 (m, 1H) 7.64 (m, 1H) 7.42-7.17 (m, 7H) 5.17 (s, 2H); LRMS (ESI) m/z calcd for C15H14N3 [M+H]+ 236. found 236; HRMS (ESI) m/z calcd for C15H14N3 [M+H]+ 236.1188. found 236.1198; HPLC>99% (tR=10 min, 60 (A):40 (B): 0.02 (C); tR=6.12 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH3:3].[S:15]([NH2:25])(=[O:24])([C:17]1[CH:22]=[CH:21]C(N)=[CH:19][CH:18]=1)=[O:16]>Cl.C(O)C>[O:14]=[C:6]1[NH:7][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:13]2[C:5]1=[CH:4][NH:2][C:3]1[CH:21]=[CH:22][C:17]([S:15]([NH2:25])(=[O:24])=[O:16])=[CH:18][CH:19]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)C=C1C(=O)Nc2cnccc21
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3cnccc32)cc1
Reaction time: 3 h
Yield: 16.8 %

Procedure:
To a 25-ml round-bottom flask was added 0.12 g (0.47 mmol) of 3-dimethylaminomethylene-1,6-diazainden-2(3H)-one, 0.081 g (0.47 mmol) of sulfanilamide, 10 ml of ethanol and two drops of concentrated hydrochloric acid. The reaction mixture was refluxed using an oil bath with stirring for 3 hours, then cooled and filtered. The collected solid was dissolved in a minimum volume of hot methanol. Upon cooling, a dark material deposited. The methanol solution was decanted and diluted to twice its volume with ethyl acetate. A light brown solid deposited after standing for 48 hours. The solid was isolated by filtration, dried, and redissolved in hot methanol (30 mL). The solution was concentrated to 20 mL and diluted with an equal volume of ethyl acetate. On cooling, a tan solid formed. The solid was isolated by filtration and washed with methanol/ethyl acetate to give 25 mg (17%) of the title compound. 1H NMR (DMSO-d6): δ7.42 (s, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.28 (s, 1H), 8.11 (d, J=6.0 Hz, 1H), 8.38 (d, J=6.0 Hz, 1H), 9.35 (d, J=13.5 Hz, 1H), 11.53 (s, 1H), 11.60 (d, J=13.5 Hz, 1H), 14.6 (br s, 1H); C14H12N4O3S: APCI−MS m/z 315 (M−H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.C(#N)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:15]=[O:16]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(Br)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (6.87 g, 48 mmol), 3-bromo-4-fluorobenzaldehyde (8.12 g, 40 mmol), and potassium carbonate (6.63 g, 48 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12 mL) and acetonitrile (8 mL) was heated at 80° C. under N2 atmosphere for one day. Reaction mixture was cooled down to room temperature and poured onto water (150 mL). The mixture was extracted with methylene chloride. The organic layer was dried (MgSO4) and concentrated to give the title compound as an off-white solid (12.4 g, 96%); mp 63–64° C.; 1H NMR (300 MHz, CDCl3) δ 1.93 (t, J=5.7 Hz, 4H), 3.25 (t, J=5.4 Hz, 4H); 4.02 (s, 4H), 7.12 (d, J=4.2 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 2H), 8.06 (d, J=1.8 Hz, 1H), 9.84 (s, 1H); MS (ES) m/z: 325.7 (MH+); HRMS Calcd. for C14H16BrNO3 (MH+): 325.0314. Found: 325.0288.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:19].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:19])[CH2:2]1
Reactant: c1ccc(CO[C@H]2CCOC2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1CO[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
(S)-2-(Tetrahydrofuran-3-yloxymethyl)pyridine (110.33 g, 0.616 mol, 1 eq) was dissolved in 900 mL DCM and cooled in an ice bath. 3-Chloroperoxybenzoic acid (151.77 g, 0.677 mol, 1.1 eq) was added and the solution was warmed to room temperature and stirred overnight. K2CO3 (85.09 g, 0.616 mol, 1 eq) was added as a solid and stirred for 2 hours. The white precipitate was filtered off and the filter cake washed with dichloromethane. Another portion of K2CO3 (85.09 g, 0.616 mol, 1 eq) was added to the filtrate and stirred for 3 days. The white solid was filtered off and the filtrate evaporated to give the title compound (119.62 g, 99%) as a yellow oil; LC-MS Retention time 1.27 min; (M+H)+ 196.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:12][S:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1cncc(-c2nsnc2OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of cyclopropylcarbinol (360 mg, 5 mmol) and sodium hydride (110 mg, 5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 400 mg (69%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[O:27]=[C:28]=[N:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C>C1COCC1>[C:18]1([C:17]([NH:16][CH:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:15][N:14]([C:28]([NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:27])[CH2:13]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: COC(=O)CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 22 mg (0.19 mmol) of methyl N-(oxomethylidene)glycinate and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 76 mg (82% of theory)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([NH:17][C:18](=[O:29])[NH:19][C:20]2[S:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[N:6]=1.[H-].[Na+].[CH2:34]([O:41][CH2:42]Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:41][CH2:42][N:17]([C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:30])[F:31])[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=1)[C:18](=[O:29])[NH:19][C:20]1[S:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)Nc1ccc(C(F)(F)F)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)s1)N(COCc1ccccc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (1) (750 mg, 1.54 mmol) in anhydrous DMF (7.5 mL) at ambient temperature was added NaH (37 mg, 1.54 mmol, 60% dispersion in mineral oil). After stirring for 20 minutes a solution of benzyloxymethylchloride (241 mg, 1.54 mmol) in anhydrous DMF (0.75 mL) was added. After 2 h of stirring at room temperature the reaction was quenched with H2O (5 mL) and diluted with EtOAc. The organic layer was separated and washed with H2O (3×10 mL) and brine (10 mL). The organics were dried (Na2SO4), filtered and evaporated. The crude material was purified by silica gel chromatography (0 to 10% EtOAc in pet ether) to afford 3-(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea as an off white solid (550 mg, 59%), mp 101-104° C.; 1H NMR (400 MHz, Acetone-d6) δ 11.82 (s, 1H), 7.37-6.99 (m, 5H), 6.65 (d, J=4.0 Hz, 1H), 6.17 (s, 1H), 5.71 (s, 2H), 4.97 (q, J=8.5 Hz, 4H), 4.60 (s, 2H); ESIMS m/z 605 ([M+H]+). Also isolated was a by-product 1,3-bis(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (11) as a pale yellow gum (65 mg); 1H NMR (400 MHz, Aceton) δ 7.29-7.05 (m, 10H), 6.87 (d, J=4.0 Hz, 1H), 5.90 (s, 1H), 5.40 (s, 2H), 5.23 (s, 2H), 4.75 (q, J=8.7 Hz, 4H), 4.69 (s, 2H), 4.52 (s, 2H); ESIMS m/z 618 ([M−PhCH2O]+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Cl-:17].[Mn+2:18].[Cl-:19]>CO>[Cl:17][C:2]1([CH3:1])[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][N:3]1[Cl:19].[Mn+2:18]
Reactant: [Cl-]
Reactant: CC1CNCCNCCNCCNCCN1
Agent: [Mn+2]
Solvent: CO
Product: CC1(Cl)CNCCNCCNCCNCCN1Cl
Yield: 43 %

Procedure:
A solution of 2-methyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 2E (1.2 g, 5.3 mmole) and anhydrous manganese(II) chloride (0.67 g, 5.3 mmole) in anhydrous methanol (60 ml) was refluxed under a dry nitrogen atmosphere for 2 h. A small amount of suspended solid was removed by filtration and the solvent was removed in vacuo. The residue was recrystallized from ethanol-ethyl ether to give 0.81 g (43% yield) of the product as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 354 (M+, 3), 319/321 [(M-Cl)+, 100/31]; Anal. calcd. for C11H27C2MnN5 : C, 37.19; H, 7.66; Cl, 19.96; N, 19.72. Found: C, 36.73; H, 7.32; Cl, 19.85; N, 19.49.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:22][C:23](=[O:32])[NH:24][C:25](=[NH:31])[N:26]3[CH:30]=[CH:29][CH:28]=N3)[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2].NCCC[OH:38].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:22][C:23]([NH:24][C:25]([NH2:31])=[N:26][CH2:30][CH2:29][CH2:28][OH:38])=[O:32])[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(=N)n2cccn2)cc1
Reactant: NCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(N)=NCCCO)cc1
Yield: 29.4 %

Procedure:
To a slurry of ˜0.12 mmol ethyl benzamide from Step 5 in 2 mL CH2Cl2 was added 27 mg (0.36 mmol, 3 equiv.) 3-aminopropanol and 62 μL (0.36 mmol) diisopropylethylamine and the reaction was mixed overnight at room temperature. The reaction was concentrated and the residue was purified by preparative 6HPLC to afford 15.8 mg of the title compound [5LC-MS data (molecular ion and retention time): m/z 448 (M+H); 1.90 min] as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][CH:19]=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.Br[C:22]1[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=1[CH3:27]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([C:22]3[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=3[CH3:27])=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC=O)cc1
Reactant: Cc1nn(C)c(C)c1Br
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2c(C)nn(C)c2C)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-yl)-acetaldehyde 6b and 4-bromo-1,3,5-trimethyl-1H-pyrazole using the procedure of Method B described above. 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 2.38 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.78 (s, 3H), 4.43 (s, 2H), 7.04 (d, J=8.8 Hz, 1H), 7.22 (m, 3H), 7.57 (m, 3H). Mass spectrum (m/e) 373 (M+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][C:27](=[O:29])[CH3:28])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([NH:26][C:27](=[O:29])[CH3:28])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CC(=O)Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Product: CC(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 34 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and N-(cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-acetamide following a procedure analogous to that described in Example 1. Yield: 34% of theory; LC (method 1): tR=1.97 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.B(O)(O)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[N:15][CH:14]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:19][C:16]1[N:15]=[CH:14][C:13]([NH:1][C:2]2[CH:3]=[N:4][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:7]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(Nc2ccc(Br)nc2)cn1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-6-trifluoromethyl pyridine (0.25 g, 1.2 mmol, 2.0 equiv) and 2-bromopyridyl-5-boronic acid (0.10 g, 0.62 mmol, 1.0 equiv) in 5 Ml dichloromethane was added pyridine (0.10 Ml, 1.2 mmol, 2.0 equiv), copper (II) acetate (0.17 g, 0.93 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir vigorously open to air overnight. The reaction was then filtered through Celite, concentrated in vacuo, and purified by silica gel chromatography to afford the title compound: (M+H)+319.9.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].C(=O)(O)[O-].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([C:3]1[N:2]([NH:1][C:23](=[O:24])[O:25][CH2:26][CH3:27])[C:6]([CH3:7])=[CH:5][CH:4]=1)=[O:16]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(C(=O)c2ccccc2Cl)n1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1c(C)ccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred slurry containing 1-amino-2-(2-chlorobenzoyl)-5-methylpyrrole (27.1 g, 0.115 mol) and sodium bicarbonate (16.8 g, 0.20 mol) in 300 ml of dichloromethane was added ethyl chloroformate (21.7 g, 0.20 mol) over 5 minutes. The reaction mixture was stirred at room temperature overnight and thereafter quenched with 500 ml of H2O. The organic layer was washed with brine, dried (MgSO4), charcoaled, filtered, and evaporated to an oil. This oil crystallized in hexane, which was recrystallized from ether-hexane to give 31.9 g (90%) of powder, m.p. 82°-84°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH:38]O)=[NH:37])[CH:34]=2)[N:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:28]=1>CN(C=O)C>[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[N:37]=[C:5]([C:4]4[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([Cl:1])[CH:3]=4)[O:7][N:38]=3)[CH:34]=2)[N:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:28]=1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(O)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
3-Chloro-4-hydroxybenzoic acid (commercial) (240 mg, 1.40 mmol) in dry DMF (8 ml) was treated with EDC (292 mg, 1.52 mmol) and HOBt (208 mg, 1.52 mmol) and stirred for 5 minutes. Added ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (432 mg, 1.40 mmol) and stirred at RT for 30 minutes. The reaction mixture was heated at 80° C. for 7 hours. Added EtOAc (70 ml) and washed with water (70 ml), sat. aq, sodium hydrogen carbonate (70 ml) and water (70 ml). Dried over MgSO4 and evaporated off the solvent. The residue was subjected to chromatography using a biotage (EtOAc/hexane 1:2) to obtain the title compound as 200 mg of white solid. δH (400 MHz, d6-DMSO) 1.10 (3H, t), 2.91 (2H, t), 4.04 (2H, q), 4.50 (2H, t), 7.67-7.70 (2H, m), 7.75 (1H, s), 7.80-7.81 (2H, m), 7.94 (1H, dd), 8.22-8.25 (1H, m), 10.95 (1H, broad s). MS (ES) C21H1735Cl2N3O4 requires 445; found 446 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:18]=[CH:17][C:12]2[NH:13][CH2:14][CH2:15][S:16][C:11]=2[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[C:21]([CH2:25][C:26](OCC)=[O:27])(=[O:24])[CH2:22][CH3:23]>>[O:27]=[C:26]([SH:16]1[C:11]2[CH:10]=[C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:19])[F:20])[CH:18]=[CH:17][C:12]=2[NH:13][CH2:14][CH2:15]1)[CH2:25][C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CCOC(=O)CC(=O)CC
Reactant: OC(c1ccc2c(c1)SCCN2)(C(F)(F)F)C(F)(F)F
Product: CCC(=O)CC(=O)[SH]1CCNc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc21

Procedure:
A stirred mixture of 3,4-dihydro-7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2H-1,4-benzothiazine and ethyl propionylacetate can be heated in an oil bath to give 3,4-dihydro-1-(1,3-dioxopentyl)-7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2H-1,4-benzothiazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1.C(N(CC)CC)C>CC(O)C.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: Clc1ccncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1c(C(=O)NC2CCN(c3ccncn3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 41.9 %

Procedure:
A solution of the compound of Example 77 (200 mg, 0.42 mmol), 4-chloropyrimidine (58 mg, 0.51 mmol) and triethylamine (0.12 mL, 0.85 mmol) in 2-propanol (4.0 mL) was heated under reflux for 23 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with a mixed solvent of ethyl acetate-methanol. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=0/100-5/95) and recrystallized from THF to give the title compound (97 mg, 42%) as a white solid.