Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([NH2:9])=[N:7][O:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[NH:30][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:28][CH:27]=3)=[CH:22][CH:21]=2)O1.C([O-])(O)=O.[Na+].O.CCOC(C)=O>COCCOC.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>[NH2:9][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[NH:30][C:29]([C@@H:31]5[CH2:35][CH2:34][CH2:33][N:32]5[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:28][CH:27]=4)=[CH:24][CH:25]=3)=[CH:3][C:4]=2[O:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: Nc1noc2cc(Br)ccc12
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(N)noc4c3)cc2)[nH]1
Temperature: 70 °C
Reaction time: 12 h
Yield: 26.8 %

Procedure:
A mixture of 6-bromobenzo[d]isoxazol-3-amine (1.78 g, 8.36 mmol), (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.95 g, 8.99 mmol), Pd(Ph3P)4 (0.42 g, 0.364 mmol) and NaHCO3 (1.93 g, 23.0 mmol) was suspended in DME (60 mL) and H2O (20 mL) and the solution was degassed by evacuating and back-filling with N2 (repeated 5 times). The mixture was then heated at 70° C. overnight. LCMS indicated the reaction to be incomplete. A further portion of Pd(Ph3P)4 (0.10 g, 0.087 mmol) was added and heating continued for a further 12 h. The cooled reaction mixture was poured into H2O/EtOAc and the layers separated. The aq layer was extracted with EtOAc (×2) and the combined org layers were washed (H2O, brine), then dried (Na2SO4) and concentrated. The residue was purified by BIOTAGE® (TLC 5:4.5:0.5 hexane:EtOAc:MeOH) solvent A was 1:1 hex:EtOAc and solvent B was 20% MeOH in EtOAc to afford a red-orange foam (1.0 g). This material was purified by prep HPLC (CH3CN—H2O—NH4OAc) giving a light yellow foam (404.4 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ 11.85-12.21 (m, 1H), 7.85 (app t, J=8.0, 8.6, 2H), 7.72-7.73 (m, 4H), 7.54-7.60 (m, 2H), 6.41 (s, 2H), 4.76-4.83 (m, 1H), 3.54 (s, br, 1H), 3.31-3.37 (m, 1H, partially obscured by H2O), 2.14-2.25 (m, 1H), 1.79-2.04 (m, 3H), 1.40, 1.15 (s, 9H, rotamers). LCMS: Anal, Calcd. for C25H27N5O3: 445; found: 446 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10]O.[Br:12][C:13]1[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:10][CH2:9][C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: OCCC#Cc1ccccn1
Product: O=c1ccc(Br)cn1CCC#Cc1ccccn1
Yield: 23.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 109(D), from 4-(pyridin-2-yl)but-3-yn-1-ol (700 mg, 4.76 mmol, Example 3(A)) and 5-bromo-1H-pyridin-2-one (870 mg, 5.00 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 334 mg (1.10 mmol, 23%) of 5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[I-].C[S+](C)(C)=O.O=C1C[CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]C1.O>COCCOC>[O:4]1[C:2]2([CH2:5][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:3]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Potassium t-butoxide (31 g) was added to a stirred suspension of trimethylsulfoxonium iodide (60.8 g) in 1,2-dimethoxyethane (250 ml) at 20° C. After 1 hour, the mixture was added portionwise over 30 minutes to a stirred solution of 4-oxo-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (50 g) in 1,2-dimethoxyethane (50 ml) at 0° C. After a further 2 hours, water (500 ml) was added and the mixture extracted with tert.-butyl methyl ether (2×500 ml). The organic extracts were washed separately with saturated sodium bicarbonate solution (250 ml), combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residual oil was co-evaoprated with toluene (100 ml) to give the sub-title compound (43.25 g, 81%) as a solid.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([C:24]([F:27])=[CH:25][CH:26]=1)/[CH:5]=[C:6]1/[C:7](=[O:23])[C:8]2[C:13]([CH2:14]/1)=[CH:12][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[C:10]([O:21][CH3:22])[CH:9]=2>CO.[Pd]>[F:27][C:24]1[CH:25]=[CH:26][CH:2]=[C:3]([F:28])[C:4]=1[CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=2)[C:7]1=[O:23]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1c(F)ccc(Br)c1F)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1c(F)cccc1F)C2=O
Reaction time: 6 h

Procedure:
The 41 (40 mg, 0.088 mmol) was dissolved in methanol 15 mL and added Pd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through elite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 42, which was purified by flash chromatography using 100-200 mesh silica gel. The compound 2-(2,6-difluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 42 was eluted as des-brominated compound at 26% ethyl acetate in hexane as half white coloured solid. 1HNMR (400 MHz, CDCl3) δ ppm 7.17 (m, 2H), 6.89 (m, 3H), 3.89 (m, 7H), 3.35 (m, 1H), 3.19 (m, 4H), 3.06 (m, 2H), 2.76 (m, 2H); MS (ESI) m/z 374.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15]/[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:13]\[CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COc1cccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OC/C=C(\C)CCC=C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-6-methoxybenzaldehyde (4.72 g, 30.43 mmol) in dry DMF (50 ml) was added geranyl bromide (7.5 g, 33.50 mmol) followed by solid potassium carbonate (5.5 g, 39.86 mmol). The mixture was stirred at room temperature for 48 h. The suspension was filtered through a layer of dry sodium sulfate (top) and silica gel (bottom), washed with 200 ml ethyl acetate and decanted into a separatory funnel. The mixture washed sequentially with aqueous ammonium chloride, water (twice), brine, and the organic phase was dried over Na2SO4. The solution was concentrated in vacuo on a rotovap. The brown gel material was then purified by chromatography via silica gel using 8:2 hexanes:ethyl acetate eluent to provide 2-((E)-3,7-dimethylocta-2,6-dienyloxy)-6-methoxybenzaldehyde as pale yellow oil.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].CCN(CC)CC.[C:27](Cl)(=[O:31])[CH2:28][CH2:29][CH3:30]>C1COCC1>[C:27]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:31])[CH2:28][CH2:29][CH3:30]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
To a suspension of (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (140 mg, 0.49 mmol) (Example 176c) in THF (3 mL) were added Et3N (143 μL, 1.03 mmol) and butyryl chloride (56 μL, 0.54 mmol). The reaction was stirred for 72 h at rt under N2. Upon completion, the reaction was filtered, and the filtrate was concentrated to provide (R)-2-((1-butyrylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile (127 mg, 82%) as a yellow syrup. MS 318 (MH+).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[NH:23][C:24]([NH:26][C:27]([O:29][CH3:30])=[O:28])=[S:25].[OH-].[Ca+2].[OH-].S(OC)(O[CH3:37])=O>CN(C)C=O.O>[NH:1]=[C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[NH:23][C:24](=[N:26][C:27]([O:29][CH3:30])=[O:28])[S:25][CH3:37]
Reactant: COC(=O)NC(=S)NC1C(=N)C=C(C(=O)c2ccccc2)C=C1Cc1ccccc1
Reactant: COS(=O)OC
Agent: [Ca+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N=C(NC1C(=N)C=C(C(=O)c2ccccc2)C=C1Cc1ccccc1)SC
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-5-benzoylbenzene (4.33 g.; 0.01 mol) in dimethylformamide (50 ml.) and water (5 ml.) there is added calcium hydroxide (0.74 g.; 0.01 mol). The mixture is stirred at 30° C. for 2 hours and to it there is added dimethyl sulfite (1.1 g.; 0.01 mol). The mixture is stirred at room temperature for 3 hours and the precipitate collected and dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-5-benzoylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9]([C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)CC(=O)CNC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)CC(C)C
Yield: 74.7 %

Procedure:
2.5 g of N-(4-chlorobenzoyl)isovalerylmethylamine, 0.5 g of 61% sodium hydride and 1.81 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(5). 2.5 g of ethyl 3-(4-chlorobenzoylamino)-3-isovalerylpropionate are thereby obtained. Yield: 74.4%.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[SH:21].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[S:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Sc1cc(Cl)ccc1Cl
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Yield: 300.3 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (10.0 g, 54.77 mmol) in THF (300 mL) was added 2,5-dichlorobenzenethiol (19.6 g, 12.108 mmol) and K2CO3 (37.8 g, 273.85 mmol). The reaction mixture was refluxed for 48 hrs. The solid was filtered and washed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated NaHCO3, H2O, and saturated NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The resulting solid was then triturated with DCM and hexanes, and filtered to yield compound 27 as a yellow solid (11.823 g, 91.0% HPLC purity, 66.4% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.82 (d, J=2 Hz, 1H), 8.00 (m, 3H), 7.80 (d, J=9 Hz, 1H), 7.75 (dd, J1=3 Hz, J2=9 Hz, 1H), 6.97 (d, J=9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([O:29]C)=[O:28])=[CH:18][C:17]=3[CH:31]=2)=[CH:9][CH:8]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:27]([OH:29])=[O:28])=[CH:18][C:17]=3[CH:31]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
In methanol (20 ml) and THF (20 ml) was dissolved methyl 7-[4-(2- ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.13 g). To the solution was added 1N sodium hydroxide solution (3 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.12 g) as pale yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=O)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.C(P(=O)(OCC)OCC)#N>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:22])[C:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:20])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Reactant: C1COCCN1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)N3CCOCC3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoic acid (Example 1, Step H, 180 mg, 0.46 mmol), morpholine (Wako Pure Chemical Industries, Ltd., 48 mg, 0.55 mmol), N,N′-diisopropylethylamine (71 mg, 0.55 mmol) in N,N′-dimethylformamide (3 mL) was added diethyl cyanophosphonate (Aldrich, 90 mg, 0.55 mmol) at room temperature. The mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4 as eluent) to afford the title compound (102 mg, 48%) as a white solid.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH3:9]>CO>[CH2:1]([NH:6][C:7]([NH2:9])=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN=C=S
Reactant: N
Solvent: CO
Product: CCCCCNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Pentylisothiocyanate (10 g, 0.08 mol) was added slowly (about 10 mins) to a mixture of ammonia (50 mL, 0.2 mol) in methanol (7 N) at 0° C. After being stirred at room temperature for 1 h, the solvent was stripped off and the product was obtained as a white solid (10 g, 88.4%), which was used for next step without further purification. LCMS calculated for C6H15N2S: (M+H) 147.1. Found 147.1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)(=[O:13])=[O:12])[CH:3]=1.[CH3:24][O:25][C:26]1[N:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(OCC)(=O)C.O>C(=O)([O-])[O-].[K+].[K+].O1CCCC1.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>[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]4)(=[O:13])=[O:12])[CH:3]=2)=[CH:28][N:27]=1
Reactant: COc1nccc(B(O)O)n1
Reactant: O=S(=O)(c1cccc2cccnc12)n1cc(Br)c2cccnc21
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: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2cn(S(=O)(=O)c3cccc4cccnc34)c3ncccc23)cn1
Temperature: 120 °C
Yield: 5.6 %

Procedure:
In a microwave reaction tube, 8-(3-bromo-pyrrolo[2,3-b]pyridine-1-sulfonyl)-quinoline (44, 68 mg, 0.18 mmol), 2-methoxy-pyrimidine-4-boronic acid (67.4 mg, 0.438 mmol), and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0088 mmol) were mixed in 1.0 M of potassium carbonate (0.52 mL) and tetrahydrofuran (0.84 mL). The resulting mixture was heated at 120° C. in a CEM Discover microwave unit for 10 minutes. Ethyl acetate and water were added and two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. The product was concentrated under reduced pressure and the resultant crude material was purified by column chromatography (80-90% ethyl acetate in hexane) to yield the desired product as a white solid (43, 0.005 g, 0.01 mmol). MS(ESI) [M+H+]+=417.8.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[S:11][CH:12]=1)(=O)=O.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:7][CH2:6][N:25]3[CH2:31][CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]4[N:9]=[C:10]([C:13]5[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=5)[S:11][CH:12]=4)[CH2:27][CH2:26]3)[N:9]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: COc1cc(-c2nc(CCOS(C)(=O)=O)cs2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2nc(CCN3CCCN(CCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(2-Methanesulfonyloxyethyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (250mg) and homopiperazine (30mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[C:21]1([NH:27][N:28]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A stirred mixture of 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine (33.0 g., 0.11 mol.), phenylhydrazine hydrochloride (34.2 g) and anhydrous sodium acetate in isopropanol was refluxed for 2 hours. The reaction was stirred overnight (about 16 hours) at ambient temperature. The reaction was filtered and the filter cake was washed with ether and then dispersed into water. The water insoluble solid was collected and dried to yield 21.3 g of the product, mp 209°-211° C. Concentration of the filtrate afforded an oil which on standing one week partially solidified. The resultant mixture was triturated with CH3CN and an additional 7.5 g of the product 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine phenylhydrazone was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:25])=[C:22]([OH:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:25])=[C:22]([CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 26.9 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), 5-amino-2-chlorophenol (422 mg, 2.93 mmol), potassium carbonate (843 mg, 6.1 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 91, the title compound (226 mg, 27%) was obtained as a brown solid.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[O:18][CH3:19].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>CO>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[O:18][CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Reactant: CC(C)(C)N
Solvent: CO
Product: COc1cc(C2=NNC(=O)CC2)ccc1OCC(O)CNC(C)(C)C
Yield: 95.8 %

Procedure:
A stirred mixture of 6-[4-(2,3-epoxypropoxy)-3-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (1.2g, 0.0043 mole), methanol (24 ml), and t-butylamine (2.76 ml, 0.026 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave a glassy residue (1.44g, 95%). The crude hemisulphate of 6-[4-(3-t-butylamino-2-hydroxypropoxy)-3-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (m.p. 266°-268.5° C) was recrystallised from methanol-ether to give the pure hemisulphate m.p. 270°-272° C decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[N:10]2[C:11](=[O:23])[C:12]3[NH:13][CH:14]=[N:15][C:16]=3[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9]2=[N:8][N:7]=1.[Br:27]N1C(=O)CCC1=O>O1CCCC1>[Br:27][C:14]1[NH:13][C:12]2[C:11](=[O:23])[N:10]3[C:6]([CH2:5][C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=4)=[N:7][N:8]=[C:9]3[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:16]=2[N:15]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3cccc(Br)c3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(Cc3cccc(Br)c3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To the solution of 3-(3-bromobenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (210 mg, 0.50 mol) in tetrahydrofuran (20 mL) was added N-bromosuccinimide (140 mg, 0.00076 mol). The mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative LCMS to yield the desired product (0.15 g, 60%). 1HNMR (300 MHz, d6-DMSO): δ 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67 (s, 2H), 1.79 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated for C18H19Br2N6O (M+H): 493. found: 493, 495 and 497.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]=1[C:13]1[CH:14]=[C:15]([N:19](S(CC)(=O)=O)[S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=1)#[N:2]>CN(C=O)C.CO.[OH-].[Na+].O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]=1[C:13]1[CH:14]=[C:15]([NH:19][S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:16]=[N:17][CH:18]=1)#[N:2]
Reactant: CCS(=O)(=O)N(c1cncc(-c2c(C#N)c3ccccc3n2C)c1)S(=O)(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)Nc1cncc(-c2c(C#N)c3ccccc3n2C)c1

Procedure:
A solution of ethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide in DMF (2 mL), methanol (10 mL) and 5 M NaOH in water (1 mL) is stirred at room temperature for 1 h. The mixture is purified on Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give ethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.24-3.32 (m, 2H), 3.80 (s, 3H), 7.32-7.38 (m, 1H), 7.43 (td, J=7.8, 1.1 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.90 (t, J=2.3 Hz, 1H), 8.58-8.62 (m, 2H), 10.42 (s, 1H). HRMS (ESI) m/z 341.1078 [(M+H)+ Calcd for C17H17N4O2S: 341.1072].