Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[C:21]([CH3:36])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.C(OC(=O)N(C1C=CC(C(OC)C2C3C(=NC=CC=3)NC=2)=C(C)N=1)CC1C=CC(C(F)(F)F)=CC=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:36][C:21]1[N:20]=[C:19]([NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=2)[CH:24]=[CH:23][C:22]=1[CH2:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1
Reactant: Cc1nc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1C(O)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: COC(c1ccc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)nc1C)c1c[nH]c2ncccc12
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The combined materials of {5-[Hydroxy-(1H-pyrrolo[2,3-b]-pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (37) and {5-[Methoxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl }-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (38) (194 mg, 0.378 mmol) were dissolved in acetonitrile (3 mL) and triethylsilane (0.30 mL, 1.9 mmol) and trifluoroacetic acid (0.17 mL, 2.3 mmol) were added. After stirring at 25° C. for overnight, TLC analysis indicated that the reaction was about 50% complete. To the reaction mixture was added triethylsilane (0.30 mL, 1.9 mmol), and trifluoroacetic acid (0.17 mL, 2.3 mmol). The mixture was allowed to stir for another 48 hours at 25° C. and the solvent, excess triethylsilane and trifluoroacetic acid were removed by evaporation. Ethyl acetate was added and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a brown oil. Purification of 80 mg of the crude material was carried out using preparatory chromatography (50% ethyl acetate in hexanes) to afford the compound as an off-white solid (P-0013, 10 mg, 0.025 mmol). MS(ESI) [M+H+]+=397.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10](=[N:20]OS(C2C=CC(C)=CC=2)(=O)=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:8]=[C:7]([CH3:32])[CH:6]=1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.Cl>CS(C)=O.O>[C:1]([N:4]1[C:5]2=[CH:6][C:7]([CH3:32])=[N:8][N:9]2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C)nn1C(=NOS(=O)(=O)c1ccc(C)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)n1nc(-c2cccc([N+](=O)[O-])c2)n2nc(C)cc12
Temperature: 25 °C
Yield: 90.1 %

Procedure:
800 mg (1.75 mmol) of 5-acetamido-3-methyl-1-(O-tosyl-3-nitro-benzohydroximoyl)-pyrazole are suspended in 10 ml of DMSO, treated with 0.8 ml DBU with stirring at room temperature, diluted with water and acidified with 2N hydrochloric acid. The precipitate obtained is filtered under suction, washed with water, a little methanol and a little ethyl acetate and recrystallised from methyl glycol. 450 mg (90%) of 1-acetyl-6-methyl-3-(3-nitro-phenyl)pyrazolo[5,1-c][1,2,4]triazole with a m. pt. of 207°-210° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[C:4](/[NH:22]C(OCC1C=CC=CC=1)=O)=[CH:5]/[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH3:20])=[CH:8][C:7]=1Br.C([O-])(=O)C.[Cs+].N>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:4]1[NH:22][C:7]2[C:6]([CH:5]=1)=[CH:11][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:9]([CH3:20])[CH:8]=2)=[O:33]
Reactant: COC(=O)/C(=C/c1cc(OCc2ccccc2)c(C)cc1Br)NC(=O)OCc1ccccc1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: N
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)c(C)cc2[nH]1
Temperature: 90 °C
Reaction time: 5 h
Yield: 63.1 %

Procedure:
To a solution of (Z)-3-(5-benzyloxy-2-bromo-4-methylphenyl)-2-benzyloxycarbonylaminoacrylic acid methyl ester (0.2 g) and copper (I) iodide (0.075 g) in dimethylsulfoxide (8 mL) was added cesium acetate (0.38 g) at room temperature and this mixture was stirred under argon atmosphere at 90° C. for 5 hours. To this reaction mixture was added aqueous ammonia solution (28%) and the precipitated solid was collected by filtration, and washed with water, dried under reduced pressure to give the title compound (0.073 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)([O-:3])=[O:2].Cl.Br[C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=1)[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][C:5]=1[C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=1)[C:30]([O:32][CH3:33])=[O:31])([O-:3])=[O:2]
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2[N+](=O)[O-])OC1(C)C
Reactant: COC(=O)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
Into a 250-mL 3-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed a solution of 1-(4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (4 g, 12.05 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (60 mL), methyl 2-bromoisonicotinate hydrochloride (2.6 g, 12.09 mmol, 1.02 equiv), a solution of sodium carbonate (6.4 g, 60.38 mmol, 5.01 equiv) in water (30 mL), and Pd(PPh3)4 (1.4 g, 1.21 mmol, 0.10 equiv). The resulting solution was stirred for 3 h at 95° C. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1). This resulted in 1.8 g (44%) of methyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinate as a red semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[I-:19].[Na+]>[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([I:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: [I-]
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Agent: [Cu]I
Agent: [Na+]
Product: O=c1c2cc(I)ccc2ccc2ncc(Cl)cc12
Reaction time: 24 h

Procedure:
A sealed tube was charged with 3-chloro-7-bromo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.0 g, 3.1 mmol), CuI (59 mg, 0.31 mmol), and sodium iodide (0.94 g, 6.2 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed dioxane (8 mL) was added. The tube was sealed, placed in an oil bath at 110° C., and stirred rapidly for 24 hours. Upon completion, the reaction mixture was cooled and quenched via the addition of 20 mL of a 30% aqueous ammonia solution, poured into 80 mL of water, and extracted three times with 150 mL dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 0-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 8.99 (d, 1H), 8.43 (d, 1H), 8.39 (d, 1H), 8.16 (dd, 1H), 7.60 (d, 1H), 7.42 (d, 1H), 7.32 (d, 1H). LRMS (APCI) calc'd for (C14H8ClINO) [M+H]+, 367.9; found 367.9.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH:9]2[NH:12][C:13]([NH:15]C2C=CC=CC=2)=[O:14])=[CH:5][CH:4]=1)#[N:2].[CH2:24](N=C=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH:9]2[NH:12][C:13]([NH:15][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)CC(NC(=O)Nc2ccccc2)c2cc(C#N)ccc21
Solvent: CCO
Product: CC1(C)CC(NC(=O)NCc2ccccc2)c2cc(C#N)ccc21
Yield: 126.7 %

Procedure:
A solution of 3-amino-5-cyano-1,1-dimethylindane (0.40 g, 2.15 mmol, prepared according to part F of Example 6) and benzyl isocyanate (0.29 g, 2.15 mmole) in ethanol (3.5 ml) under argon was heated at reflux for three hours. The solvent was recovered under vacuum to obtain 0.87 g of yellow gum. The crude product was chromatographed on silica eluting with 1:1 ethyl acetate/hexane to obtain an amorphous white solid (0.44 g). The chromatogrpahy isolate was further purified by crystallization from isopropyl ether to afford the title compound as a pure white solid (0.40 g), m.p. 130°-132° C. 1H NMR δ 7.71 (d, J=8.21 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J=7.63 Hz, 1H), 7.31 (m, 5H), 6.44 (m, 2H), 5.22 (m, 1H), 4.28 (d, J=5.86, 2H), 2.30 (dd, J=7.04, 12.90 Hz, 1H), 1.71 (dd, J=9.38, 12.31 Hz, 1H), 1.35 (s, 3H), 1.17 (s, 3H); 13C NMR δ 157.97, 156.88, 145.38, 140.75, 131.88, 128.19, 127.59, 126.98, 126.58, 123.50, 119.06, 109.33, 52.06, 48.74, 42.98, 42.00, 28.64, 28.21.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:29][CH2:30][O:31][CH2:32][CH2:33]6)=[N:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound, white solid (108 mg, 83%), MS (ISP) m/z=521.5 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 6-morpholin-4-yl-nicotinic acid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:19]=1[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCCl>[CH3:16][O:17][C:18]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)=[CH:27][C:19]=1[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CCc1ccc(OC)cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OC)cc2)c(OC)cc1OC
Temperature: 0 °C

Procedure:
52 g of aluminum trichloride are suspended in 200 ml of 1,2-dichloroethane and cooled to 0° C. Then, at this temperature, 66.5 g of 4-methoxybenzoyl chloride are added dropwise, followed by 94.7 g of ethyl 2,4-dimethoxyhydrocinnamate in 30 ml of 1,2-dichloroethane. The mixture is then heated at 50° C. with exclusion of moisture until the reaction is complete. The reaction mixture is then poured onto ice-water, and the organic phase is separated off, diluted with 200 ml of methylene chloride and then extracted with sodium bicarbonate solution and water. It is dried over magnesium sulfate and concentrated. A gray-brown solid remains and is immediately reacted further.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:13][O:12][CH:11]2[CH:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16][CH:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]=O>C(O)=O>[CH2:1]([N:8]([CH3:25])[CH:9]1[CH2:13][O:12][CH:11]2[CH:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16][CH:10]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNC2COC3C(OCc4ccccc4)COC23)cc1
Reactant: C=O
Solvent: O=CO
Product: CN(Cc1ccccc1)C1COC2C(OCc3ccccc3)COC21
Temperature: 110 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of N-benzyl-6-(benzyloxy)hexahydrofuro[3,2-b]furan-3-amine (9.88 g, 30.36 mmol) in HCOOH (19 mL) was added formalin (2.96 g, 36.43 mmol). After addition, the reaction mixture was stirred at 110° C. overnight and concentrated in vacuo. The residue was adjusted to pH=8 with a saturated Na2CO3 solution and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water (100 mL×3) followed by brine (100 mL), then dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (4.77 g, 46.4%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[CH:33][C:32]([F:50])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25]>>[C:24]([O:27][CH2:28][C:29]1[C:30]([C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:31][C:32]([F:50])=[CH:33][C:34]=1[N:35]1[CH2:46][CH2:45][N:44]2[C:37](=[CH:38][C:39]3[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=32)[C:36]1=[O:49])(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCN(C)CC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 81 %

Procedure:
Following Example 150b, 282c and (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 230a were reacted to give 294a in 81% yield. LCMS: (M+H)+ 667
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CC=C(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CC=C(c4ccc(F)cc4)CC3)cnc12
Yield: 40.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (45 mg, 0.09 mmol) obtained in step 2 and ethanesulfonamide (49 mg, 0.47 mmol), the title compound (21 mg, 39%) was obtained.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]([C:18]2[C:26]3[C:21](=[C:22]([CH2:27][S:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:8]2C(=O)O[C:11](C)([CH3:15])[O:10][C:9]2=[O:17])=[CH:5][N:6]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Br:1][C:2]1[S:3][C:4]([CH:7]([C:18]2[C:26]3[C:21](=[C:22]([CH2:27][S:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:8][C:9]([O:10][CH2:11][CH3:15])=[O:17])=[CH:5][N:6]=1
Reactant: CSCc1cccc2c(C(c3cnc(Br)s3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1cnc(Br)s1)c1c[nH]c2c(CSC)cccc12

Procedure:
19 mg (0.29 mmol) of copper powder were added to 3.57 g (81% purity, 5.87 mmol) of the compound from Example 24A in 15 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux for 5 h and then the copper was filtered off through kieselguhr. The filtrate was concentrated, the residue was stirred with diethyl ether/dichloromethane, and the precipitated solid was filtered off. The filtrate was concentrated and purified by preparative HPLC (acetonitrile/water gradient). 1.24 g (46% of theory) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:22][CH2:19][CH2:20][N:21]2[C:15](=[O:17])[C:11]2[N:10]([CH:14]=[CH:13][CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: O=C(Cn1cccc1C(=O)O)c1ccc(Br)cc1
Reactant: NCCN
Product: O=C1c2cccn2CC2(c3ccc(Br)cc3)NCCN12
Yield: 91.1 %

Procedure:
To a suspension of crude 1-[2-(4-bromophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (1.1 g, 0.714 mmol) suspended in xylenes (50 mL) was added ethane-1,2-diamine (0.5 mL, 7.5 mmol). The orange reaction mixture was heated at reflux for 1 h. The reaction mixture was concentrated in vacuo to give a dark orange oil that was purified using flash chromatography (Biotage SP4, 40 g cartridge, 0-10% MeOH gradient in EtOAc) to give 10a-(4-bromophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a pale yellow solid (216 mg, 90% yield). 1H NMR (400 MHz, d6-acetone): δ 2.71-2.84 (m, 1H), 3.30-3.38 (m, 1H), 3.42 (ddd, 1H, J 11.0, 7.7, 3.2 Hz), 3.70 (dt, 1H, J 10.8, 7.8 Hz), 4.36 (d, 1H, J 12.3 Hz), 4.65 (d, 1H, J 12.3 Hz), 6.03 (dd, 1H, J 3.7, 2.6 Hz), 6.66 (m, 2H), 7.29-7.33 (m, 2H), 7.45-7.49 (m, 2H).
Reaction SMILES: CN(C)C1C=CC(C=[CH:8][CH:9]=[O:10])=CC=1.CN(C)C1C=CC(C=O)=CC=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH:29]=O>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH:29]=[CH:8][CH:9]=[O:10]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CN(C)c1ccc(C=CC=O)cc1
Agent: CN(C)c1ccc(C=O)cc1
Product: COc1ccc(OC)c(C=CC=O)c1

Procedure:
Using the procedure described by Konig et al., supra, for the preparation of 4-dimethylaminocinnamaldehyde but replacing the 4-dimethylaminobenzaldehyde employed as starting material by 2,5-dimethoxybenzaldehyde, there was obtained 2,5-dimethoxycinnamaldehyde.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[BH4-].[Na+]>CO>[OH:8][CH:5]1[CH2:4][N:3]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C@H:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: C[C@@H]1CCC(=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CCC(O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl (2R)-2-methyl-5-oxopiperidine-1-carboxylate (365 mg, 1.47 mmol) in methanol (2.9 mL) at 0° C. was added sodium borohydride (84 mg, 2.21 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then stirred for 16 hours at room temperature. The mixture was quenched with saturated aqueous ammonium chloride and concentrated. The resulting residue was extracted with DCM (3×) and the combined extracts were dried over sodium sulfate, filtered, and concentrated to afford benzyl (2R)-5-hydroxy-2-methylpiperidine-1-carboxylate. MS ESI calc'd. for C14H19NO3 [M+H]+ 250. found 250.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([N:11]1[C:15]([C:16]([O:18][CH2:19]C)=[O:17])=[C:14]([C:21]([O:23][CH2:24]C)=[O:22])[N:13]=[C:12]1[CH2:26]Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO>[CH2:4]([N:11]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([C:21]([O:23][CH3:24])=[O:22])[N:13]=[C:12]1[CH2:26][O:2][CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccccc1
Reaction time: 13 h

Procedure:
492 mg of a 28% w/v solution of sodium methoxide in methanol were added to a solution of 655 mg of diethyl 1-benzyl-2-bromomethylimidazole-4,5-dicarboxylate [prepared as described in step (ii) above] in 7 ml of methanol, and the mixture was allowed to stand at room temperature for 13 hours. At the end of this time, 2.5 ml of 1N aqueous hydrochloric acid were added to the reaction solution, and the methanol was removed by distillation under reduced pressure. The concentrate was mixed with ethyl acetate and water and then shaken. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 391 mg of the title compound as a syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:28])[C:13]([CH3:18])=[C:12]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1[nH]c2ccc(OCc3ccccc3)cc2c1-c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(Cl)c2)c2cc(OCc3ccccc3)ccc2n1C
Reaction time: 8 h

Procedure:
An amount of 3.21 g (9.25 m mole) of 5-benzyloxy-3-(3-chloro-phenyl)-2-methyl-1H-indole was dissolved in 50 ml of absolute dimethylformamide, and the solution was mixed with 406 mg (9.3 m mole) of 55% sodium hydride in paraffin oil. After one hour 1.45 g (10.2 m mole) of methyliodide were added, and the mixture was stirred overnight. After evaporation, the reaction mixture was mixed with water and extracted with chloroform. The extracts, which were dried over sodium sulfate, were evaporated, and the residue obtained was purified by chromatography on silicagel by using toluene as solvent.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.CO>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])([O-:14])=[O:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ncnc2ccc([N+](=O)[O-])cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccc([N+](=O)[O-])cc12)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 60.1 %

Procedure:
A mixture of 4-amino-6-nitroquinazoline (57.0 g) and diethyl ethoxymethylenepropanedioate (130 g) in anhydrous N,N-dimethylformamide (570 ml) was cooled at 5° C. To the reaction mixture was added sodium hydride (65.5% in mineral oil) (13.2 g) in the course of 30 minutes and the mixture was stirred for 1 hour and 40 minutes under ice-cooling. After ammonium chloride (47.2 g) was added to the reaction mixture and stirred for 20 minutes, ice-water (1 liter) was added to the resultant mixture with stirring and allowed to stand to give crystals, which were separated by filtration, washed with water and dried overnight at ambient temperature. The resultant crude crystals were dissolved in chloroform (1.5 liters) under heating. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure to give crystals, which were dissolved in methanol (300 ml) under heating and allowed to stand at ambient temperature. The resultant crystals were separated by filtration, washed with methanol and dried under reduced pressure to give yellowish crystalline diethyl [(6-nitro-4-quinazolinylamino)methylene]propanedioate (64.9 g).