Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1>C1(C)C=CC=CC=1.C(O)C>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH:40][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 2 (2.69 g, 13.80 mmol) in toluene (16.5 mL) and ethanol (16.5 mL) was added a suspension of 31 (4.87 g, 11.50 mmol) in toluene (41 mL) and ethanol (41 mL). The mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent EtOAc/MeOH, 98/2) to afford intermediate 32 (5.31 g, 8.58 mmol, 74% yield) as a beige solid. MS (m/z): 619.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.47 (s, 1H), 11.83 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.2 Hz, H), 8.38 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.02 (dd, J=12.4, 1.6 Hz, 1H), 7.92 (dd, J=8.2, 1.8 Hz, 1H), 7.54-7.52 (m, 2H), 7.37 (dd, J=8.6, 5.8 Hz, 2H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (d, J=5.2 Hz, 1H), 5.66 (s, 1H), 4.18 (dd, J=10.6, 5.0 Hz, 2H), 3.97-3.94 (m, 2H), 3.82 (s, 2H), 2.10-1.98 (m, 1H), 1.47 (dd, J=14.0, 1.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
4-Fluoro-3-trifluoromethylbenzoic acid (100 g) was dissolved in N,N-dimethylformamide (400 ml), potassium carbonate (199 g) and benzyl bromide (84.0 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 20 min and further at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (144 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:8]([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:28])[C:26](Cl)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:29])([CH3:11])([CH3:10])[CH3:9].O>CC(N(C)C)=O>[C:8]([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:28])[C:26]([N:5]3[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]3)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC1CCNC1
Reactant: CC(C)(C)ON1C(=O)c2cccc3c(Cl)c(Cl)cc(c23)C1=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC1CCN(c2c(Cl)cc3c4c(cccc24)C(=O)N(OC(C)(C)C)C3=O)C1
Yield: 91 %

Procedure:
Following the procedure of Example Q2, 3-methoxypyrrolidine (0.2 g, 2.0 mmol) and 2-tert-butyloxy-5,6-dichloro-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.2 mmol, from Example V2) were reacted in DMA (1.0 mL) at 120° C. overnight followed by addition of water (10 mL). The precipitate that formed was filtered to give 0.44 g of the title compound.
Reaction SMILES: [N:1]([C@@H:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=3[CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.C(OCC)C.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:19][C:16]1([CH3:18])[C:17]2[C:12]([CH:11]=[C:10]3[C:9]=2[CH:8]=[N:7][N:6]3[CH2:5][C@@H:4]([NH2:1])[CH3:21])=[C:13]([CH3:20])[CH:14]=[CH:15]1
Reactant: CC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2C(C)(C)C=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Product: CC1=C2C=c3c(cnn3C[C@H](C)N)=C2C(C)(C)C=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
0.7 g (2.5 mmol) of (S)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous methanol was hydrogenated over 70 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 290 mg (2.5 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 4 hours and the white crystals were subsequently filtered off. 0.5 g (54%) of (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 158° was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]([C:34]([O:36][CH2:37][CH:38]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[C@H:25]([C:31](O)=[O:32])[CH2:26][O:27]C(C)=O.C1CCC([N:57]=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:34]([NH:24][C@H:25]([C:31]([NH2:57])=[O:32])[CH2:26][OH:27])([O:36][CH2:37][CH:38]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(=O)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 64.2 %

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene (1.5 g, 4.76 mmols), 2.1 g (5.7 mmols) of Fmoc-L-Ser(Ac), 1.2 g (5.7 mmols) of DCC and 0.87 g (5.7 mmols) of HOBt.H2O were dissolved in 30 ml of N,N-dimethylformamide, and the mixture was reacted at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate, then filtered and concentrated. The product was purified through silica-gel column chromatography (mixture of ethyl acetate and hexane at a ratio by volume of 1:2) to produce 1.96 g of the final product in a yield of 61.8%.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Yield: 41.1 %

Procedure:
To a solution of 3-acetylamino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (556 mg, 1.4 mmol) in ethanol/water (3:1, 20 ml) was added KOH (85% pellets, 480 mg, 7.2 mmol) and the mixture was heated at reflux temperature for 1 h. The mixture was cooled and concentrated, and the residue partitioned between water (50 ml) and diethyl ether (100 ml). The organic extract was washed with water (100 ml) and then brine (100 ml). After drying (MgSO4) and removal of solvent, the crude product was recrystallized from dichloromethane/hexane to afford 180 mg (41%) of the title compound as a yellow powder. m.p.: 212-213° C. 1H-NMR (CDCl3) δ: 9.90 (1H, br s), 8.29-8.15 (2H, m), 7.84-7.75 (2H, m), 7.70-7.52 (3H, m), 7.32-7.27 (1H, m), 7.12 (1H, dd, J=1.83, 9.16 Hz), 2.26 (3H, s). IR (KBr) ν: 3400, 1680, 1640, 1520, 1320 cm−1
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:11]([NH:27]C(OC(C)(C)C)=O)[C:10]1=[O:35])=[O:7].Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:12][CH:11]([NH2:27])[C:10]1=[O:35])=[O:7]
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccco1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccco1)C(=O)C(N)CN2C(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
1-(Furan-2-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was suspended in ethanol (10 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in etheyl acetate, successively washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, diethyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 373 mg of the titled compound.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:35])[CH2:23][C:24]=1[CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])[CH:20]([NH:36]C(OC(C)(C)C)=O)[C:19]2=[O:44])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].O>C(#N)C>[NH2:36][CH:20]1[C:19](=[O:44])[N:18]2[CH:21]1[S:22](=[O:35])[CH2:23][C:24]([CH:25]=[C:26]([S:28][C:29]1[S:33][C:32]([CH3:34])=[N:31][N:30]=1)[CH3:27])=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2S(=O)C1)Sc1nnc(C)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2S(=O)C1)Sc1nnc(C)s1
Temperature: 40 °C
Reaction time: 0.58 h
Yield: 93.7 %

Procedure:
A solution of the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (4.45 g) in acetonitrile (150 cc) is heated to 40° C. A solution of p-toluenesulphonic acid (monohydrate) (2.59 g) in acetonitrile (75 cc) is added dropwise in the course of 5 minutes. The mixture is stirred at 40° C. for 35 minutes and then poured into a saturated aqueous solution of sodium bicarbonate (200 cc). Distilled water (500 cc) is added and extraction is carried out with methylene chloride (500 cc). The organic phase is washed with distilled water (500 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of 7-amino-2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (3.53 g) in the form of a hard brown foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[SH:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:21][CH:22]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C(O)CCc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.74 g, 11.0 mmol) and 4-mercaptohydrocinnamic acid (2.00 g, 11.0 mmol) in DMF (30 mL) was added potassium carbonate (4.55 g, 32.9 mmol), and the resulting solution was stirred for 1 hour at 80° C. To the reaction solution were added water and concentrated hydrochloric acid, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 3.29 g of the title compound.
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[NH:43]1[CH2:48][CH2:47][S:46][CH2:45][CH2:44]1>CC(N(C)C)=O>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][S:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:41])/[C:20]/2=[CH:19]\[C:16]1[NH:15][C:14]([CH3:42])=[C:13]([C:11]([N:43]2[CH2:48][CH2:47][S:46][CH2:45][CH2:44]2)=[O:10])[C:17]=1[CH3:18])(=[O:30])=[O:31]
Reactant: C1CSCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCSCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added thiomorpholine (33 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as an orange solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Br.[Br:21][CH2:22][CH2:23][CH2:24][NH2:25]>CC#N>[Br:21][CH2:22][CH2:23][CH2:24][NH:25][C:8]1[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCBr
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Br
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Reaction time: 3 h
Yield: 41.7 %

Procedure:
A solution of TEA (0.18 mL, 1.33 mmol) in MeCN (5 mL) was added dropwise to a mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.20 g, 0.67 mmol) and (3-bromopropyl)amine hydrobromide (0.146 g, 0.67 mmol) in MeCN (3 mL). After 45 mins a solution of (3-bromopropyl)amine hydrobromide (0.073 g, 0.33 mmol) and TEA (0.093 mL, 0.66 mmol) in MeCN (5 mL) was added dropwise to the reaction mixture. After 3 h, (3-bromopropyl)amine hydrobromide (0.073 g, 0.33 mmol) and TEA (0.093 mL, 0.66 mmol) was added to the reaction mixture. After 17 h the solvent was evaporated and the residue was purified by silica gel column chromatography using 10-20% EtOAc in petroleum ether mixture as eluant, to yield the title compound (0.112 g, 42%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.69-7.50 (m, 2H), 7.50-7.44 (m, 3H), 5.32 (t, 1H), 3.18 (t, 3H), 3.10-3.04 (m, 2H), 1.90-1.78 (m, 2H), 1.76 (s, 9H); Mass Spectrum M+H+ 403.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15](Br)[CH:16]=3)[N:11]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:10]=2)[C:5]1=[O:25])(=O)C.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(#N)C.C([O-])(=O)C.[K+]>O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:15]2[CH:16]=[C:17]3[C:9]([N:6]4[CH2:7][CH2:8][NH:4][C:5]4=[O:25])=[N:10][N:11]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:12]3=[CH:13][N:14]=2)[CH:27]=1
Reactant: CC(=O)N1CCN(c2nn(C3CCCCO3)c3cnc(Br)cc23)C1=O
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: O=C1NCCN1c1nn(C2CCCCO2)c2cnc(-c3cccnc3)cc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution containing 1-acetyl-3-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-2-one (0.295 g, 0.722 mmol), 3-pyridineboronic acd pinacol ester (0.444 g, 2.17 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (0.0472 g, 0.0578 mmol) in Acetonitrile (5.47 mL, 105 mmol) was added 1.00 M of Potassium acetate in Water (1.44 mL) and 1.00 M of Sodium carbonate in Water (1.44 mL). The reaction was stirred at 100° C. for 3 h. The reaction is filtered thru celite. The crude product was diluted in EtOAc then washed with water and sat. NaCl. The organic layer was dried Na2SO4, filtered, and concentrated to give 1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-2-one. ESI MS m/z=365.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)=[O:29])[CH:9]=[N:8]1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=405.24.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:12][SH:13].Cl[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH2:18]>O>[CH3:12][S:13][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH2:18]
Reactant: CS
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(N)ccc1[N+](=O)[O-]

Procedure:
A mixture of dry dimethylformamide (150 ml) and potassium carbonate (12.0 g) is stirred and methyl mercaptan is introduced as a gas for 45 minutes. After stirring for another 45 minutes, 3-chloro-4-nitroaniline (10.0 g) is added. The mixture is stirred and heated at 120°-130° C. for 18 hours. It is then cooled and poured into water (1 liter), the precipitate is collected and recrystallized from methanol to afford 8 grams of 3-methylthio-4-nitroaniline, m.p. 178°-182° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].N[CH2:12][C:13]([NH:15][C:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:24]([F:27])([F:26])[F:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]>CO>[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[CH3:1][NH:2][CH2:12][C:13]([NH:15][C:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:24]([F:26])([F:27])[F:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: CN
Reactant: NCC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CNCC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.4 %

Procedure:
To a stirred solution of monomethylamine (50 ml, 1.13 mol) in 150 ml of methanol at 0° C. under nitrogen, was added 2-chloro-N-[(1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide (from Example 1) (10.2 g) followed by 100 ml of methanol to effect solution. The mixture was allowed to slowly warm to ambient temperature and stirred for 24 hours. The solvent was evaporated and the resulting semi-solid was dissolved in 150 ml of chloroform, 100 ml of water and 20 ml of 15% NaOH. The phases were separated, the aqueous phase extracted with chloroform (2×125 ml) and the combined organic phases washed with brine (150 ml), decolorized with charcoal, dried and evaporated to a yellow-orange oil, 9.8 g. This was dissolved in 150 ml of methanol, treated with 3.4 g of maleic acid and the solvent removed under vacuum to yield a solid which was recrystallized from methanol (150 ml) and ethyl acetate (150 ml), then from methanol (30 ml) and ethyl acetate (75 ml) and vacuum dried to give 4.88 g of 2-(methylamino)-N-[1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide maleate as a white solid, mp 179°-181° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]([CH2:15][CH:16]1[CH2:18][O:17]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:3][CH:2]([OH:1])[CH2:4][N:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:15][CH:16]([OH:17])[CH2:18]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Reactant: NCc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1

Procedure:
IMS (2.5 L, 10 vol) was added to the dichloromethane solution from step (iii) above. The solution was distilled until the internal temperature reached 70° C. Approximately 1250 mL of solvent was collected. More IMS (2.5 L, 10 vol) was added followed by benzylamine (120 mL, 0.7 eq.) in one portion (no exotherm seen), and the reaction was heated at reflux for 6 hours (no change from 2 hour sampling point). More benzylamine was added (15 mL) and the solution was heated for a further 2 hours. The IMS was distilled off (ca. 3.25 L) and toluene was added (2.5 L). More solvent was distilled (ca. 2.4 L) and then further toluene added (1 L). The head temperature was now 110° C. A further 250 mL of solvent was collected at 110° C. Theoretically, this left the product in ca. 2.4 L of toluene at 110° C. This solution was used in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([O:16][CH3:17])[CH:15]=1)=[O:5])C.Cl.C(O)(=O)C>O>[F:22][C:20]1[C:19]([F:23])=[CH:18][C:11]2=[N:12][C:13]3[N:14]([O:16][CH3:17])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:24])[C:8]=3[CH:9]=[C:10]2[CH:21]=1
Reactant: CCOC(=O)c1cn(OC)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine (2.78 g) in 17.5% strength hydrochloric acid (30 cc) and acetic acid (30 cc) is heated to a temperature in the region of 100° C. for 1 hour. After cooling to approximately 20° C., the reaction mixture is poured into water (100 cc). The precipitate formed is drained and washed with water (3×+cc) and ethanol (2×5cc). After 1 recrystallization in dimethylformamide (100 cc) containing ethanol (20%), 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (2.03 g) is obtained in the form of a yellow solid, m.p. 325°-327° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][NH:39][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:27]([F:28])([F:30])[F:29])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CNCCc2ccccc2)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and phenethylamine according to the procedure of Example 66. MS (ES) m/z 511.3.