Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:67])(=O)=O)CCCCCCCCCCCCCCC>>[I:67][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)Oc1ccon1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)Oc1ccon1

Procedure:
3-(3-Chloropropylsulfonylamino)-2-(3-isoxazolyloxy)-1-octadecylcarbamoyloxypropane IIIj2 is allowed to react and worked up by the same procedure as described in (5). m.p. 69°-71.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:35])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][C:30](C=O)=[CH:31][CH:32]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8].[CH3:40][NH:41][CH2:42][CH2:43][OH:44].[BH4-].[Na+].[CH3:47]CO>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:35])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][C:30]([CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH3:47])=[CH:31][CH:32]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8]
Reactant: CCO
Reactant: CNCCO
Reactant: O=Cc1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cn1
Agent: [BH4-]
Agent: [Na+]
Product: CN(CCO)Cc1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A suspension of N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)-7-(6-formylpyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (step 1) (100 mg, 0.189 mmol), 2-(methylamino)ethanol (70.9 mg, 0.944 mmol) and molecular sieves in EtOH (2 ml) was heated at 70° C. overnight. The mixture was cooled to 0° C. and treated with sodium borohydride (7.15 mg, 0.189 mmol). The mixture was allowed to warm to RT and was stirred overnight. The resulting suspension was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic portion was separated, washed with NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification of the residue by preparative chromatography eluting with 25-50% 0.1% TFA acetonitrile/water afforded fractions that were combined and diluted with NaHCO3 and 5% trifluoroethanol/DCM. The organics were separated, dried and concentrated in vacuo to afford a white solid. The solid was triturated with EtOH/Ether to afford the title compound as a white solid;
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:36][N:35]([CH3:37])[C:34](=[O:38])[CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:36][N:35]([CH3:37])[C:34](=[O:38])[CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: CN1CC(c2cccnc2F)CC1=O
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1=O
Temperature: 140 °C
Yield: 60.7 %

Procedure:
To a mixture of cesium carbonate (563 mg, 1.73 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.381 g, 1.60 mmol), and 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.131 g, 0.675 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 140° C. for 11 h. The mixture was cooled to room temperature and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) gave 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one (0.169 g, 0.410 mmol, 61% yield) as an off-white solid. MS m/z: 413.1 (M+1). The mixture of enantiomers was separated by preparatory SFC (Chiralcel OJH (21×250 mm), 25% EtOH/0.2% diethylamine) to afford the individual enantiomers (R)-4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one and (S)-4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one. MS (ESI, pos. ion) m/z: 413.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [H-].[Na+].[C:3]1([C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6])[OH:4].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][C:17]=1Cl>O1CCOCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]2[O:4][C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[O:6][C:16]=2[CH:17]=1
Reactant: Oc1ccccc1O
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1cc2c(nn1)Oc1ccccc1O2
Yield: 69.7 %

Procedure:
In 1,4-dioxane (30 mL) was suspended 3.49 g (80.0 mmol) of 55% sodium hydride, and to the suspension were added a 1,4-dioxane (30 mL) solution containing 4.40 g (40 mmol) of pyrocatechol, then a 1,4-dioxane (30 mL) solution containing 7.30 g (39.9 mmol) of 3,4,6-trichloropyridazine {described in The Journal of Organic Chemistry, 1963, vol. 28, pp. 218 to 221}, and the mixture was refluxed for 2 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L sodium hydroxide and water, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was recrystallized from methyl isobutyl ketone to obtain 6.15 g (27.8 mmol, Yield: 69.7%) of 3-chloro[1,4]benzodioxino[2,3-c]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[NH:33][C:34]([NH:36][C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[F:44])=[O:35])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[O:18])[CH:13]=2)[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][NH:19][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:30]=[CH:31][C:32]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl (2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate (300 mg, 0.49 mmol) in 10 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as beige solid. Yield: 200 mg, 80%.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.[OH:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.Cl[C:24]1[N:29]=[C:28]([NH:30][C@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=2)[CH3:32])[C:27]([C:40]([OH:42])=O)=[CH:26][N:25]=1.N>CN(C=O)C.O1CCOCC1>[N:14]1([O:13][C:24]2[N:29]=[C:28]([NH:30][C@H:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)[CH3:32])[C:27]([C:40]([NH2:3])=[O:42])=[CH:26][N:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1
Reactant: C[C@H](Nc1nc(Cl)ncc1C(=O)O)c1ccc(F)cn1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(On2nnc3ccccc32)ncc1C(N)=O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (177 mg, 0.92 mmol) and 1-hydroxybenzotriazole (125 mg, 0.93 mmol) were added to a solution of (S)-2-chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidine-5-carboxylic acid (Preparation 5b, 210 mg, 0.62 mmol) in N,N′-dimethylformamide (5 mL) and the mixture was stirred for 30 min at ambient temperature. 0.5M Ammonia solution in 1,4-dioxane (3 mL) was then added and the reaction mixture was stirred overnight at ambient temperature. The solvents were evaporated and the resulting residue was taken up in diethyl ether. The organic solution was washed with water and brine, dried (Na2SO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to yield the title compound (30 mg, 12%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24]([N:26]2[CH:30]=[C:29]([CH:31]=O)[CH:28]=[N:27]2)[N:23]=[CH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:51]CCCl>>[ClH:51].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:31][C:29]4[CH:28]=[N:27][N:26]([C:24]5[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=5)[CH:30]=4)[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cn1cnc(-n2cc(C=O)cn2)c1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: Cn1cnc(-n2cc(CN3CCN(c4nccnc4-c4ccc(F)cc4)CC3)cn2)c1
Yield: 71 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.053 g, 0.204 mmol) in DCE (2.1 mL). Add 1-(1-methyl-1H-imidazol-4-yl)-1H-pyrazole-4-carbaldehyde (0.036 g, 0.204 mmol) and stir at ambient temperature for 1 hr. Add sodium triacetoxyborohydride (0.065 g, 0.306 mmol) and acetic acid (19 μL) and stir at room temperature for 72 hr. Purify via SCX chromatography, followed by silica gel chromatography (50:50 to 0:100 hexanes:ethyl acetate then 10:90 to 20:80 methanol:ethyl acetate) to give the free base of the title compound (61 mg, 71%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25](C=O)[CH2:24][CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:38])=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:25][CH2:24][CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:38])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 70.4 %

Procedure:
To a solution of (−)-8-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (2.92 g) in methanol (75 ml) was added 3N hydrochloric acid (29.1 ml), after which the mixture was stirred at 80° C. for 7 hours. After diluting with water at 0° C., the product was neutralized with potassium carbonate. After extracting with ethyl acetate, the reaction product was washed with aqueous saturated solution of sodium bicarbonate and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified with a basic silica gel column chromatography (methanol:ethyl acetate=1:67) to give (−)-8-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (1.97 g) (Compound 30) as a yellow amorphous material.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.Br[CH2:16][C:17]#[C:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1)[C:17]#[C:18][CH3:19]
Reactant: CCCc1cc(OC)c(OC)cc1O
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1cc(OC)c(OC)cc1CCC

Procedure:
Following the same procedure as in Example 7a) and 7b), 3.92 g (0.02 moles) of 1-hydroxy-6-propyl-3,4-dimethoxybenzene were reacted with 2.66 g (0.02 moles) of 1-bromo-2-butyne and 2.8 g (0.02 moles) of anhydrous potassium carbonate in 20 ml of acetone.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22](F)[N:21]=2)=[CH:15][CH:14]=1>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[N:4]3)[N:21]=2)=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Fc1cccc(Nc2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(Nc2cccc(-n3ncc4ccccc43)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
Sodium hydride (325 mg, 8.12 mmol) was added to a solution of indazole (800 mg, 6.77 mmol) in N,N-dimethylformamide (10 mL) and stirred for 30 minutes. (4-Chloro-phenyl)-(6-fluoro-pyridin-2-yl)-amine (1.55 g, 6.77 mmol) was added and the reaction mixture was stirred at 80° C. overnight. The mixture was poured into a stirred ice-water solution and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtrated and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate-heptane as eluent to give (4-chloro-phenyl)-(6-indazol-1-yl-pyridin-2-yl)-amine (230 mg, 11%) as an yellow solid. LC-ESI-HRMS of [M+H]+ shows 321.0901 Da. Calc. 321.090699 Da, dev. −1.9 ppm
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([NH2:14])=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.CS(O)(=O)=O.[N:20](OCCC(C)C)=O>C(O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:6]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=3[N:14]=[N:20]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(NCC2CC2)c(N)c1
Reactant: CC(C)CCON=O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)nnn2CC1CC1
Reaction time: 0.25 h

Procedure:
N1-(Cyclopropylmethyl)-4-methoxybenzene-1,2-diamine (10.8 g, 56.2 mmol) was dissolved in ethanol (80 mL) and treated with methanesulfonic acid (3.65 ml, 56.2 mmol) followed by isoamyl nitrite (7.56 ml, 56.2 mmol). The mixture was stirred for 15 minutes, diluted with ethyl acetate (1500 mL) and washed with aqueous saturated bicarbonate solution (500 mL×2). The organic extracts were concentrated in vacuo and the residue was purified by silica gel gradient chromatography (5-50% ethyl acetate in heptanes), providing the titled compound as a tan solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:17](C)[C:18](=O)C(F)(F)F)[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+]>CO.C(Cl)Cl.[Cl-].[Na+].O>[CH3:18][NH:17][C:9]1[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: COC(=O)c1ncc(-c2ccccc2)nc1N(C)C(=O)C(F)(F)F
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(-c2ccccc2)cnc1C(=O)OC
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
Methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate. A solution of methyl 3-amino-5-phenylpyrazine-2-carboxylate (360 mg, 1570 μmol) in DCM (10 mL) was treated with DIPEA (547 μl, 3141 μmol) and trifluoroacetic anhydride (275 μl, 1963 μmol). The reaction stirred under nitrogen at 23° C. After 14 hours, the reaction was diluted with DCM (50 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo affording methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate as an orange solid, which was carried forward to the next reaction. A suspension of methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate (511 mg, 1571 μmol) and potassium carbonate (651 mg, 4713 μmol) in DMF (10 mL) was treated with iodomethane (196 μl, 3142 μmol). The reaction flask was capped with a septum and heated to 65° C. After 4 hours, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 5-25% EtOAc/hexane), affording 221 mg (41%, 2 steps) of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate as an yellow solid. A solution of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate (253 mg, 746 μmol) in MeOH (2 mL) and DCM (2 mL) was treated with sodium methoxide (0.5M solution in MeOH (2983 μl, 1491 μmol)). The reaction was stirred under nitrogen at 23° C. After 90 minutes, the reaction was diluted with brine (25 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated, affording 179 mg (99%) of methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate as a yellow solid. Mass: Calculated: 243.261. Observed: 244.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (1H, s), 8.07-8.17 (2H, m), 7.95 (1H, br. s.), 7.46-7.55 (3H, m), 4.00 (3H, s), 3.18 (3H, d, J=4.7 Hz).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)C>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([OH:33])=[O:42])=[CH:40][CH:39]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 4-amino-benzoic acid ethyl ester according to the procedure of Example 66. MS m/z 527; MS m/z 525.
Reaction SMILES: Br[C:2]1[S:25][C:5]2[CH2:6][CH2:7][C:8]3[CH:9]=[N:10][C:11]([NH:14][C:15]4[CH:16]=[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=4)=[N:12][C:13]=3[C:4]=2[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:26]1([C:2]2[S:25][C:5]3[CH2:6][CH2:7][C:8]4[CH:9]=[N:10][C:11]([NH:14][C:15]5[CH:16]=[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=5)=[N:12][C:13]=4[C:4]=3[CH:3]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)-c2cc(Br)sc2CC3)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)-c2cc(-c4ccccc4)sc2CC3)c1

Procedure:
To the 3-(8-Bromo-5,6-dihydro-thieno[2,3-h]quinazolin-2-ylamino)-benzenesulfonamide (200 mg, 0.46 mmol) in a 10 mL microwave reaction tube was added Phenyl boronic acid (56 mg, 0.46 mmol), 2M Na2CO3(aq) (920 μL, 1.84 mmol), Pd(PPh3)4 (5.3 mg, 0.0046 mmol), 3:4 EtOH/H2O (1.5 mL) and DME (2.5 mL).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[OH:13][C:14]1[CH:23]=[CH:22][C:17]2[NH:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([O:13][C:14]2[CH:23]=[C:22]([CH3:24])[C:17]3[NH:18][C:19](=[O:21])[O:20][C:16]=3[CH:15]=2)[CH:7]=1
Reactant: O=c1[nH]c2ccc(O)cc2o1
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)nc(C(F)(F)F)n2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.40 g (1.86 mmol) 4,6-dichloro-2-trifluoromethylpyrimidine, 0.31 g (1.88 mmol) 6-hydroxy-2-benzoxazolinone and 0.28.g (2.03 mmol) potassium carbonate in 2.0 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water and stirred for 1 h at RT. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:25]3[NH:24][CH:28]=[CH:27][N:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ncc[nH]3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 12.6 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.10 g, 0.32 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-imidazolecarbaldehyde (0.03 g, 0.31 mmol) was added followed by oxone (0.13 g, 0.21 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.10 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (15 mg, 12.1% yield) as light brown crystals.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-chloro-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.