Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:18])[CH2:13][C@@H:12]1C.[CH3:20][C@H]1N[C@@H](C)CN(C2C=CC([N+]([O-])=O)=CC=2)C1>>[CH3:18][N:14]1[C@H:13]([CH3:20])[CH2:12][N:11]([C:3]2[CH:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][CH:4]=2)[CH2:16][C@@H:15]1[CH3:17]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1C
Yield: 106 %

Procedure:
Crude cis-1,2,6-trimethyl-4-(4-nitrophenyl)piperazine (5.55 g, 106% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine from cis-3,5-Dimethyl-1-(4-nitrophenyl)piperazine (4.91 g, 20.8 mmol). LCMS-ESI (m/z): calcd for C13H19N3O2, 249; [M+H]+ found, 250.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:13][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)[C:5]1=[O:24].Cl>CO.O1CCCC1>[SH:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:24])[N:4]([CH2:3][C:2]([F:25])([F:1])[F:26])[CH2:12]2
Reactant: CC(C)[Si](Sc1ccc2c(c1)CN(CC(F)(F)F)C2=O)(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C1c2ccc(S)cc2CN1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
2-(2,2,2-trifluoroethyl)-5-(triisopropylsilylthio)-isoindolin-1-one (1.39 g, 3.45 mmol) was dissolved in a solution of hydrochloric acid (6.7 ml, 1.25 M, 8.62 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to afford the desired compound as an off-white solid (0.783 g, 92% yield). 1H NMR (CDCl3, 400 MHz) 3.70 (1H, s), 4.22 (2H, q), 4.53 (2H, s), 7.35-7.39 (2H, m) and 7.76 (1H, d); MS (ES+) 248, (ES−) 246.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:18])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>O1CCOCC1.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>[Cl:18][C:11]1[CH:10]=[CH:9][C:8]([C:6]([C:5]2[CH:19]=[CH:20][C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:13][C:12]=1[S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccc(Br)cc2)ccc1Cl
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)cc2)ccc1Cl
Yield: 20.4 %

Procedure:
A mixture of 220 mg of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide (0.587 mmol, 1 equivalent), 196 mg of 3-nitrobenzene boronic acid (1.174 mmol, 2 equivalent), 556 mg of Ba(OH)2 (1.761 mmol, 3 equivalent), and 14 mg of Pd(PPh3)4 in degassed dioxane/water (30 mL/10 mL) is refluxed for 18 h. The reaction is quenched with 1 N HCl and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and concentrated in vacuo. After purification by flash chromatography, 50 mg of the title compound is obtained as white solid. 1H NMR (400 MHz, CDCl3): δ 5.2 (br, 2H), 6.18 (br, 1H), 7.02 (d, 2H, J=8 Hz), 7.12-7.45 (m, 5H), 7.6-7.8 (m, 3H), 7.90 (dd, 1H), 8.41 (s, 1H). MS (m/z): 387 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ncc(Br)cc1N
Temperature: 70 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 5-bromo-2-(2-methoxyphenyl)-3-nitropyridine (0.2618 g, 0.85 mmol) in EtOAc (10.0 mL) was added tin(II) chloride dihydrate (0.9667 g, 4.28 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the residue was identified as 5-bromo-2-(2-methoxyphenyl)pyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (1H, d, J=2.0 Hz), 7.46 (2H, m), 7.24 (1H, d, J=1.2 Hz), 7.14 (1H, m), 7.03 (1H, d, J=8.3 Hz), 3.84 (3H, s).
Reaction SMILES: C(O)C.[NH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH:14][OH:15])=[NH:8]
Reactant: N#Cc1cccnc1N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cccnc1N
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of ethanol (10 mL) and 2-amino-nicotinonitrile (590 mg) were added hydroxylamine hydrochloride (510 mg) and potassium carbonate (1.4 g) at room temperature, which was stirred for 7 hours and 30 minutes under reflux. After this, the reaction mixture was stirred for 13 hours and 30 minutes at room temperature, then water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the titled compound (520 mg) as a cis-trans mixture. The titled compound was used in the subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[C:15](=[O:16])[N:14](CC(O)=O)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[S:11]1.[N+](=[CH2:27])=[N-].[C:28]([O:31][CH2:32]C)(=[O:30])[CH3:29]>[H+].[B-](F)(F)(F)F.CCOCC>[CH3:32][O:31][C:28](=[O:30])[CH2:29][N:14]1[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[S:11][CH:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[O:1][CH3:27])[C:15]1=[O:16]
Reactant: COc1ccc(O)c(C2Sc3ccccc3N(CC(=O)O)C2=O)c1
Reactant: C=[N+]=[N-]
Reactant: CCOC(C)=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: COC(=O)CN1C(=O)C(c2cc(OC)ccc2OC)Sc2ccccc21
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of [3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-3-oxo-2H-1,4-benzothiazin-4-yl]acetic acid (compound No. 14, 2.5 g) in ethyl acetate (20 ml) containing one drop of fluoboric acid, diazomethane dissolved in ether is added and standed overnight. The mixture is concentrated in vacuo to give 1.9 g (70%) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](Br)=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH2:40])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](/[CH:38]=[CH:37]/[C:36](=[O:39])[NH2:40])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(N)=O
Reactant: Cc1cc(Br)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(/C=C/C(N)=O)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
50 mg (0.09 mmol) {1-[4-(8-Bromo-6-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 13.4 mg (0.19 mmol) acryl amide, 4.86 mg (0.016 mmol) tri-2-tolylphosphane, 2.1 mg (0.009 mmol) palladium(II) acetate and 0.02 mL (0.1 mmol) triethylamine in 0.7 mL degassed acetonitrile were heated in the microwave at 110° C. for 60′. Due to an incomplete reaction additional 13.3 mg acrylamide and 4.2 mg palladium(II) acetate were added, and heating in the microwave was continued for two hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase was once more extracted with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (76 mg) was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 24.2 mg (49.3%) of the desired compound.
Reaction SMILES: BrCC([N:5]1[C:14]2[N:10]([C:11]([CH3:15])=[N:12][N:13]=2)[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:6]1)=O.COC1[C:30]([NH2:35])=[CH:31][CH:32]=CC=1.[CH2:36]([OH:38])[CH3:37]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=3[N:10]3[C:14]([N:5]([CH2:37][C:36](=[O:38])[NH:35][CH2:30][CH2:31][CH3:32])[N:6]=2)=[N:13][N:12]=[C:11]3[CH3:15])=[CH:21][CH:22]=1
Reactant: CCO
Reactant: COc1ccccc1N
Reactant: Cc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NN2C(=O)CBr
Product: CCCNC(=O)CN1N=C(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Bromoacetyl-6-(4-chlorophenyl)-1-methyl-4H-2,3,4,5,10b-pentaazabenz[e]azulene (8 mg) obtained in Example 171 was suspended in ethanol and 2-anisidine (12.5 μl) was added. The mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (20 ml) was added to the residue and the mixture was extracted with ethyl acetate (20 ml). The organic layer was further washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative thin-layer chromatography to give 2.4 mg of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][O:5][CH3:6].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]([NH:7][C:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])[CH2:4][O:5][CH3:6])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl [(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate (30 g, 0.13 mol) in DCM (300 mL) at 0° C. was added triethylamine (19.0 g, 0.188 mol) and methanesulfonylchloride (21.6 g, 0.188 mol) and then the reaction mixture was allowed to warm to ambient temperature. After 16 hours, the reaction mixture was washed with brine, and the organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/petroleum ether) to give (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxypropyl methanesulfonate. MS ESI calc'd. for C13H20NO6S [M+H]+ 318. found 318. 1H NMR (400 MHz, CDCl3) δ 7.36-7.33 (m, 5H), 5.24 (d, J=8.0 Hz, 1H), 5.10 (s, 2H), 4.28 (d, J=5.6 Hz, 2H), 4.12-4.09 (m, 1H), 3.55-3.42 (m, 2H), 3.35 (s, 3H), 2.99 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:12][OH:13])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][NH:4]1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CO.O>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:1][CH2:2][C:3]2([CH2:12][OH:13])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][NH:4]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCC1(CO)NCC(O)C(O)C1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 27.1 %

Procedure:
5.4 g of 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine are dissolved in 50 ml of a methanol/water mixture (1:1), and 3.92 ml of triethylamine and, at -5° C., 5.44 g of 4-nitrobenzoyl chloride are added. The mixture is stirred for 24 hours and evaporated in vacuo, the residue is taken up in ether/water and the phases are separated. The aqueous phase is extracted once with ether and the product phase is then evaporated. The residue is dissolved in a little water and the solution is discharged onto a column 120 cm long and 4 cm wide which contains cellulose as the stationary phase and 99% pure acetone as the mobile phase. The column is eluted successively with 99% pure acetone, 95% pure acetone and finally 90% pure acetone. The individual fractions are examined by thin layer chromatography to determine their content of the required compound. The fractions containing the desired product are collected and evaporated. 2.6 g of 2-(4-nitrobenzoylaminomethyl)-2-hydroxymethyl-3,4,5 -trihydroxypiperidine are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.CCN(CC)CC>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:35]2[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=c1c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)cnn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
A mixture of the product from Example 8 (154 mg, 0.36 mmol), 4-(methylthio)benzeneboronic acid (67 mg, 0.4 mmol), Et3N (0.11 mmol; 0.8 mmol) and Pd(Ph3P)4 (30 mg, 0.025 mmol) in 15 mL of toluene was heated at reflux, about 100° C. for about 45 minutes. The mixture was concentrated in vacuo and the residue purified by column chromatography (hexanes-ethyl acetate 3:1) to provide the title compound (yield: 98 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 2.47 (s, 3H), 5.38 (s, 2H), 6.98 (m, 4H), 7.12 (m, 2H), 7.20 (m, 2H), 7.35 (m, 3H), 7.54 (m, 2H), 7.86 (s, 1H). MS (DCI/NH3) m/z 403 (M+H)+, 420 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([Cl:19])=[O:16])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cccc(CC(=O)O)c2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2cccc(CC(=O)Cl)c2c1

Procedure:
The (7-methoxynaphth-1-yl)acetic acid obtained above is dissolved by heating in 300 ml of chloroform. The mixture is heated under reflux, and then thionyl chloride is added dropwise. The mixture is refluxed for two hours and evaporated to dryness. An oil is obtained which crystallizes on cooling. The residue obtained is used as such in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][NH:36][CH2:37][CH:38]([OH:46])[C:39]1[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:36]([CH2:37][CH:38]([OH:46])[C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[CH3:35])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccc(O)cc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ccc(O)cc1
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.09 gm) from Preparation No. 35 in dry DMF (2 mL) containing diisopropylethylamine (0.07 mL) is treated with synephrine (0.05 gm). The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane (50 mL) and washed with water (2×10 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue is purified by flash column chromatography eluting with 3% to 6% methanol in dichloromethane and then by recrystallization from toluene to afford 0.09 gm of the title compound as a tan solid.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[CH:13]([CH2:30][S:31][C:32](=[O:34])[CH3:33])[CH2:14][CH2:15][CH2:16][NH:17]C(OCC1C=CC(OC)=CC=1)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C1(OC)C=CC=CC=1>[C:32]([S:31][CH2:30][CH:13]([CH2:14][CH2:15][CH2:16][NH2:17])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:36])=[O:5])=[O:35])(=[O:34])[CH3:33].[F:37][C:38]([F:43])([F:42])[C:39]([O-:41])=[O:40]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: COc1ccccc1
Product: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Product: O=C([O-])C(F)(F)F
Reaction time: 1 h

Procedure:
1-[2-Acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-proline tert-butyl ester (2 g) is dissolved in a mixture of trifluoroacetic acid (15 ml) and anisole (6 ml). The solution is stored at room temperature for one hour, the solvents are removed in vacuo and the residue is precipitated from ethyl acetate-ether to yield 1-(2-acetylthiomethyl-5-aminopentanoyl)-L-proline, trifluoroacetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: OB(O)c1cccnc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 160 °C

Procedure:
To propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0773, prepared as described in Example 1, 65.0 mg, 0.14 mmol) in acetonitrile (4.0 mL) was added pyridine-3-boronic acid (609, 25.0 mg, 0.20 mmol), tetrakis (triphenylphosphine)palladium(0) (11 mg, 1.0% mmol) and aqueous potassium carbonate (1.0 M, 2.0 mL). The reaction was heated to 160° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0088, 30 mg, 46.9%). MS (ESI) [M+H+]+=457.2.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][N:21]([CH3:3])[CH2:20][CH:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:19][CH2:18]2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CNCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A 37% aqueous solution of formaldehyde (5 ml; 67 mmol) and sodium cyanoborohydride (314 mg; 5.0 mmol) were added to a solution in acetonitrile (20 ml) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]amine (1.0 g; 2.4 mmol) synthesized by the above process, and the mixture was stirred at room temperature for 15 minutes. Acetic acid was then added to the solution to adjust the pH to about 5, and the mixture was stirred further for 48 hours at room temperature. The reaction mixture was brought to pH about 10 by addition of aqueous 2.5N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 989 mg (yield: 95%) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]-methylamine as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH2:30])=[C:28]([CH3:35])[CH:27]=1.C(=O)(O)[O-].[Na+]>C(OCCO)C.O>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:29]3[CH:31]=[C:32]([O:33][CH3:34])[C:26]([Cl:25])=[CH:27][C:28]=3[CH3:35])=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: O
Product: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c(C)cc1Cl
Temperature: 120 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
To a stirred suspension of 0.9 g (3.3 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile and pyridine hydrochloride (0.381 g, 3.3 mmol) in 2-ethoxyethanol (10 mL) under nitrogen, is added 0.634 g (3.69 mmol) of 4-chloro-5-methoxy-2-methylaniline (WO 8501939 A1). The reaction is stirred at 120° C. for 4 hours. The mixture is then cooled to room temperature and solid sodium bicarbonate is added until foaming subsided. Water is added to the reaction mixture (40 mL), which is subsequently extracted with 3×30 mL ethyl acetate. After combining the organic portions and drying with sodium sulfate, the solvents are removed in vacuo. The residue obtained is purified by flash chromatography, eluting with 99.5:0.5 methylene chloride/methanol. The solid obtained is recrystallized from hot ethyl acetate to afford 1.1 g of an orange crystalline solid, mp 217–219° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][CH2:14][CH2:13][O:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: COCCN
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.10 g, 8.02 mmol) in DMA (20 ml) was treated with 2-methoxyethylamine (2.07 ml, 24.1 mmol) and DIPEA (4.20 mL, 24.1 mmol), heated to 50° C. and stirred for 15 h. The reaction mixture was cooled to room temperature and concentrated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated and dried under vacuum to give the title compound as an off-white solid.