Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCC(=O)N2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C2CCCN2)c1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of 5-(3-methoxyphenyl)-2-pyrrolidinone (7.0 g) in dry tetrahydrofuran (280 ml) was added 1M lithium aluminum hydride in tetrahydrofuran (55 ml), dropwise at ambient temperature, under nitrogen. Upon completion of the addition, the reaction mixture was warmed under reflux for 2 hrs, cooled to ambient temperature, and quenched with 10% aqueous tetrahydrofuran (60 ml) followed by 10% sodium hydroxide solution (50 ml). The suspension was filtered through a pad of celite, and the filter cake was washed with dichloromethane. The combined filtrates were dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated to give 6.3 g (96%) of 2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.[F:14][C:15]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:14][C:15]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:16][O:17][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccc(OCC(F)(F)C(F)(F)F)c1C#N
Temperature: 50 °C
Yield: 95.1 %

Procedure:
A reaction flask was loaded with 8.7 g of 3-nitrophthalonitrile, 9.0 g of 2,2,3,3,3-pentafluoropropanol, 13.8 g of anhydrous potassium carbonate, and 350 ml of dimethyl sulfoxide, and the temperature was raised to 50° C. with stirring under nitrogen flow. After stirring at 50° C. for 4 hours, the heating was stopped. The reaction liquid was cooled and added into 500 ml of water, and the precipitated crystal was collected and dried to yield 13.2 g of the intended compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([NH2:23])[CH2:21][CH3:22]>C1COCC1>[CH2:20]([NH:23][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH2:21][CH3:22]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNc1cc(OCCCN(CC)CC)ccc1[N+](=O)[O-]
Yield: 87.3 %

Procedure:
A solution of 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene (2 mmol; preparation described in Example 5) in THF (5 mL) is treated with propylamine (3 mmol) at rt. After completion of the reaction, the reaction mixture is concentrated in vacuo. The residue is redissolved in EtOAc (10 mL), washed with saturated sodium bicarbonate solution, water, and brine. The organic phase is then dried over sodium sulfate and the solvent is removed in vacuo to afford the product, 2-(propylamino)-4-(3-diethylamino-1-propoxy)nitrobenzene (540 mg) which was used for further transformation without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) and triethylamine (0.30 mL, 2.1 mmol) in THF (15 mL) at 5˜10° C., was added 3-chloro-4-methyl phenyl isocyanate (0.27 mL, 1.9 mmol). Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.58 min (99.1%); mp, 250-252° C.; 1HNMR (DMSO-d6)2.17-2.22 (m, 4H, CHH, ArCH3), 2.59-2.93 (m, 6H, CHCH2, CH3), 4.71 (d, J=6 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.64 (t, J=6 Hz, 1H, CH2NH), 7.06-7.78 (m, 6H, Ar), 8.88 (s, 1H, NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.69, 20.70, 23.31, 30.62, 42.31, 56.52, 116.24, 117.46, 117.81, 125.78, 126.28, 127.24, 130.98, 132.96, 133.99, 139.66, 141.30, 148.49, 154.76, 154.88, 161.02, 169.49, 172.65. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.2H2O: C, 58.59; H, 4.79; N, 14.85; Cl, 7.52. Found: C, 58.42; H, 4.55; N, 14.57; Cl, 7.83.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#[C:19][C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)=[CH:15][CH:16]=3)[C:11](=[O:27])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]4[CH:25]=[N:24][C:23]([CH3:26])=[N:22][CH:21]=4)=[CH:15][CH:16]=3)[C:11](=[O:27])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3cnc(C)nc3)cc2c1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(CCc3cnc(C)nc3)cc2c1=O
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Compound P (25 mg, 0.059 mmol, 1.0 eq) was dissolved in methanol (2 mL) and palladium on carbon (1 mg) was added. The reaction was pumped and purged with hydrogen and allowed to stir overnight. The reaction was filtered over Celite® and washed with 5% methanol in DCM. The organics were concentrated and purified using reverse phase chromatography to afford 16 mg (63%) of title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.41 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.74-7.71 (m, 2H), 7.55 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (t, J=8.8 Hz, 2H), 6.89 (d, J=8.7 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.04 (t, J=8.3 Hz, 2H), 2.89 (t, J=8.3 Hz, 2H), 2.53 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 432.3.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:30][S@:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[NH:33])=[O:32]>C1COCC1>[CH3:30][S:31](=[O:32])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N:33][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11][CH:12]=1
Reactant: C[S@](=N)(=O)c1ccccc1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=NC(=O)c1cncc(C#Cc2ccccc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 1.25 h
Yield: 56 %

Procedure:
To a slurry of 5-(2-phenyleth-1-ynyl)nicotinic acid (339 mg, 1.5 mmol) in 6.0 mL THF at room temperature was added 1,1′-carbonyldiimidazole (271 mg, 1.7 mmol). After stirring 1.25 hour, a solution of (S)-(+)-S-methyl-S-phenylsulfoximine (260 mg, 1.7 mmol) in 1.5 mL THF was added and the mixture heated at 50° C. for 22 hours. Then an additional 50 mg (0.32 mmol) (S)-(+)-S-methyl-S-phenylsulfoximine was added and heating continued at 60° C. for 3.5 hours. The reaction was quenched with NaHCO3 solution and then extracted into EtOAc. The EtOAc layer was washed with NaHCO3 solution, H2O, brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil obtained was chromatographed eluting with hexane/EtOAc to give N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-(phenylethynyl)nicotinamide as a white foam (303 mg, 55%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@H:10](O)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C:32]([F:47])([F:46])[C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:36](Cl)=[O:37].O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@:9]1([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C@H:10]([C:36](=[O:37])[C:35]1[CH:34]=[C:33]([C:32]([F:47])([F:46])[F:31])[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=1)[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CC[C@@H]2CC[C@@]1(c1ccc(F)cc1)N2Cc1ccccc1
Yield: 58 %

Procedure:
(1R*,2 R*,5R*)-8-Benzyl-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 15; 1.23 g, 3.95 mmol), and triethylamine (0.61 ml, 4.35 mmol) in dichloromethane were stirred with 4-dimethylaminopyridine (5 crystals) and 3,5-bis(trifluoromethyl)benzoyl chloride at room temperature for a weekend. The reaction mixture was poured into water and extracted with dichloromethane (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [10%-20% ethyl acetate in iso-hexane] to give the title compound as a yellow solid (1.27 g, 58%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[C:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1)#[N:2].Cl.[OH2:14]>>[C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[C:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1)(=[O:14])[NH2:2]
Reactant: O
Reactant: Cc1nccn2c(C#N)ccc12
Agent: Cl
Product: Cc1nccn2c(C(N)=O)ccc12
Temperature: 25 °C

Procedure:
To 2.0 g of 6-cyano-1-methylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 4 were added 10 ml of water and 5 ml of hydrochloric acid; and the reaction mixture was reacted at 80° C. for 2 hours, cooled to room temperature, extracted with ethyl acetate, and concentrated. The residue was chromatographed over silica gel to obtain 1.0 g of title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:5]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (5.36 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester was dissolved in 40 ml of anhydrous tetrahydrofuran. To this solution was added 0.923 g (5.9 mmol) of 2-(4-chloro-phenyl)-ethanol, 5.35 g (equivalent to 16.1 mmol PPh3) of triphenylphosphine derivatized polystyrene and 2.80 g (16.1 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5). Yield 1.6 g. LC-MS (ES+): m/e=325 (M)+
Reaction SMILES: C([O:5][C:6](=[O:23])[C@H:7]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[NH:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(N(CC)CC)C.Cl>CN(C)C=O>[C:11]1([CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:23])=[O:5])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NC(=O)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CC[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reaction time: 0.75 h

Procedure:
As shown in Scheme III (FIG. 3), phenylacetylglutamine 5 (25 mg) from Example 1 was dissolved in dimethylformamide (500 μl), and 2-ethyl 5-phenylisoxazolium-3'-sulfonate 8 (26 mg) was added. The pH of the reaction mixture was adjusted to 9 with triethylamine. After 45 minutes, aminomethylfluorescein hydrochloride 7 (38 mg) was added, and reaction mixture was stirred for an additional 12 hours. After evaporation to dryness, the residue was dissolved in methanol and purified by preparative thin layer chromatography using reversed silica gel and water-methanol-acetic acid (40:60:0.4) as an eluent. The result was 40 mg of the desired PAG/AMF conjugate 9. Mass spectrum (FAB): 608 M+.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][NH2:21].Cl>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N:20]1[CH:5]=[CH:4][CH:3]=[N:21]1
Reactant: COC(CC(OC)OC)OC
Reactant: NNc1cc(F)ccc1F
Agent: Cl
Solvent: CCO
Product: Fc1ccc(F)c(-n2cccn2)c1
Yield: 97.6 %

Procedure:
Add 1,1,3,3-tetramethoxypropane (8.2 g, 50 mmol) to a mixture of 2,5-difluorophenylhydrazine (9.022 g, 62.6 mmol) and hydrochloric acid (5M, 5 mL, 25 mmol) in ethanol (50 mL) and heat and stir under reflux under nitrogen for 17 hr. Cool the mixture, evaporate the ethanol in vacuo, suspend the residue in DCM (80 mL), filter the DCM solution and pass through an SCX-2 column. Collect the eluent and pass through a second SCX2 column and evaporate the eluent to give 1-(2,5-difluoro-phenyl)-1H-pyrazol as a liquid (8.79 g, 97%). MS (m/z): 181 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7](/[CH:8]=[CH:9]/[CH2:10]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7](/[CH:8]=[CH:9]/[C:10]2[S:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1S
Reactant: O=[N+]([O-])c1ccc(/C=C/CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(/C=C/c2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
trans-4-Nitrocinnamyl chloride 10 (1.77 g, 9.5 mmol, 1.2 eq.) in DMF (20 ml) was added dropwise to a solution of 2-aminothiophenol 9 (1.0 g, 8.0 mmol) in DMF(15 ml) at room temperature. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was poured into a solution of 10% sodium carbonate (100 ml). The participate was collected by filtration under reduced pressure. Recrystallization from methanol gave 1.92 g (85.1%) of the product 11.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[I:23]I.[OH-].[K+].[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:23])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: II
Reactant: Clc1cc2[nH]ncc2cc1-c1ccc(N2CCOCC2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cc1-c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 6-chloro-5-[4-(morpholin-4-yl)phenyl]-1H-indazole (72 mg, 0.23 mmol) and N,N-dimethylformamide (3 mL) was treated with iodine (91 mg, 0.36 mmol) and freshly ground potassium hydroxide (16 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for three hours, then treated with additional iodine (50 mg) and potassium hydroxide (20 mg) and heated to 40° C. for 20 minutes. The reaction mixture was poured into ethyl acetate and saturated aqueous ammonium chloride. The layers were separated and the organic phase was washed with 2N sodium thiosulfate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography utilizing heptanes/ethyl acetate (100:0 to 0:70) to give the title compound (86.7 mg). MS (ES−): 438.0 (M−H)−.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13]I.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([O:12][CH3:13])[CH3:11])[CH:5]=1
Reactant: CC(O)c1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
To a stirred and ice-cooled mixture of 1.09 g (27.4 mmol) NaH (60% in mineral oil) in 20 mL dry DMF was added a solution of 5.00 g (24.9 mmol) 1-(3-bromo-phenyl)-ethanol in 10 mL dry DMF under argon atmosphere. The mixture was stirred for 30 min at 0° C. 1.70 mL (27.4 mmol) methyl iodide was added and stirring was continued for 4 h at RT. The mixture was worked up by adding water, followed by extraction with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Cyc/EtOAc=9/1).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide (Intermediate 19, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35]N)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc4c(c3)OCCO4)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to example 43 gave the desired product. MS: M=451 (M+H)+
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1)#[CH:27].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12]([C:27]#[C:26][C:28]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CCCC1
Reactant: OC1(C#Cc2ncc(Br)cc2Cc2ccccc2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2cnc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)c2)CCCC1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
100 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol (Example 22-a), 55 mg of 1-ethynylcyclopentanol, 50 mg of tetrakis (triphenylphosphine)palladium(0), 10 mg of cuprous iodide and 1 ml of triethylamine were mixed in 5 ml of N,N-dimethylformamide, followed by stirring in an oil bath kept at 80° C. for one hour. An aqueous sodium carbonate solution was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 10% methanol/ethyl acetate, to give 93 mg of the target compound.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:40][C:39]([C:41]([NH:43][CH3:44])=[O:42])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[S:40][C:39]([C:41]([NH:43][CH3:44])=[O:42])=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CNC(=O)c1ccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)s1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)s1
Yield: 93 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 5-[4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl]-N-methyl-2-thiophenecarboxamide (1.39 g) and pyridine hydrochloride (484 mg), the colorless amorphous title compound (769 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]([C:15](=[C:18](OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]#[N:17])#[N:14].[H-].[Na+]>CN(C)C=O>[C:13]([C:15]1[C:16](=[NH:17])[N:1]2[C:2]([CH:3]=[CH:4][CH:5]=[CH:6]2)=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[N:14]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: COC(=C(C#N)C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c(C#N)c(=N)n2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of 2.50 g of ethyl 2-pyridylacetate and 2.79 g of 2-cyano-3-methoxy-3-phenylacrylonitrile was dissolved in 15 ml of dry N,N-dimethylformamide. To the solution was added 0.61 g of 60% sodium hydride and the reaction mixture was stirred for 1 hour at 60° C. The reaction mixture was poured into ice-water, and precipitated crystals were collected by filtration, washed with water and dried under vacuum to obtain 2.50 g of 3-cyano-1-ethoxycarbonyl-4-imino-2-phenyl-4H-quinolizine.