Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10]>N1C=CC=CC=1>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][NH:7][S:11]([CH:9]([CH3:10])[CH3:8])(=[O:13])=[O:12]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1ccco1
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)NCc1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a stirred solution of furfurylamine (1.040 g, 10.7 mmol) in pyridine (10 mL) at 0° C. was slowly added 2-propanesulfonyl chloride (1.0 mL, 8.9 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the product (0.84 g, 46%) as a yellowish thick oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, 1H, J=1.8, 0.9 Hz), 6.35 (dd, 1H, J=3.3, 1.8 Hz), 6.29 (d, 1H, J=3.3 Hz), 4.42 (br s, 1H), 4.33 (d, 2H, J=5.7 Hz), 3.08 (m, 1H), 1.35 (d, 6H, J=6.9 Hz).
Reaction SMILES: Cl.[N:2]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:7][CH2:6][CH:5]([N:8]2[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32].C1(C)C=CC=CC=1>CC(C)=O.ClCCl.O>[O:17]=[C:9]1[N:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH:18]3[CH2:23][CH2:22][N:21]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:20][CH2:19]3)[CH2:7][CH2:6]2)[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10]1
Reactant: CC(C)OC(=O)Cl
Reactant: O=C1N[C@@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of cis-(+/−)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one hydrochloride salt from step B (70 mg, 0.18 mmol) in 5 ml acetone was added potassium carbonate (49 mg, 0.36 mmol) followed by 1M isopropyl chloroformate in toluene (0.36 mL, 0.36 mmol) and the mixture was stirred at room temperature for 3 h. Removal of solvent gave a residue, which was dissolved in dichloromethane, and then water was added. The mixture was passed through VARIAN CHEM ELUT™ cartridges. The cartridge was rinsed with dichloromethane (2×20 mL). The dichloromethane solution was concentrated in vacuo and the crude product was purified by high pH prep-LCMS H to afford the title compound (40 mg, 56%). 1H NMR (400 MHz, CDCl3): δ ppm 1.14-1.21 (m, 1H), 1.23 (d, J=6.25 Hz, 6H), 1.33-1.48 (m, 3H), 1.48-1.67 (m, 6H), 1.66-1.95 (m, 8H), 2.43 (t, J=10.94 Hz, 1H), 2.71 (t, J=12.21 Hz, 2H), 2.95 (dd, J=21.09, 10.35 Hz, 2H), 3.52-3.63 (m, 2H), 3.68 (t, J=12.01 Hz, 1H), 4.02 (s, 1H), 4.20 (s, 2H), 4.80-4.98 (m, 1H). MS (M+1): 393.3
Reaction SMILES: O.[C:2]12([CH3:12])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:11].C[C@H]1C[C@@H:18]([OH:20])[C@H:17](C(C)C)CC1>C(O)C>[C:2]12([CH3:12])[C:8]([CH3:9])([CH3:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2([CH2:17][CH2:18][OH:20])[OH:11]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: O
Solvent: CCO
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2

Procedure:
7 l of distilled water is added to 350 g of the genus Gelatin and the aqueous mixture is heated to produce a Gelatin solution. And 205 g of Borneol, 50 g of p-oxybenzoic methylester, 30 g of p-oxybenzoic propylester, and 0.5 l of l-menthol are solved with 3.5 l of ethanol to produce a Borneol-ethanol solution.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cu]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.25 h

Procedure:
2-Bromonitrobenzene (Beilstein, Vol. 5, p.247; 58g) and 2,5-dibromonitrobenzene (Beilstein, vol. 5 p.250; 81g) in nitrobenzene (250 ml.) were heated at 170°-180° C. while copper powder (70 g.) was added over 15 minutes. The reaction mixture was stirred at 180° C. for 15 minutes, cooled and filtered, and the filtrate evaporated under reduced pressure. The residue was extracted into chloroform, the extract dried and evaporated, and the solid recrystallised several times from methanol to give 4-bromo-2,2'-dinitrobiphenyl, m.p. 145°-147° C. (Found: Br, 24.6 C12H7BrN2O4 requires Br, 24.8%).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[C:8]1([CH3:20])[CH:13]=[CH:12][C:11]([S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:8]1([CH3:20])[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:19])(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: c1ccccc1
Product: CC(=O)C(C(C)=O)C(=O)NS(=O)(=O)c1ccc(C)cc1

Procedure:
Reaction of equimolar amounts of 2,4-pentanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 3-(N-p-TOLUENESULFONYLCARBAMOYL)-2,4-PENTANEDIONE, m.p. 137°-139.5° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>>[NH:17]1[C:16]([NH:15][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[O:10])=[N:20][N:19]=[N:18]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cccc(Cl)n1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1cccc(Cl)n1
Yield: 25.9 %

Procedure:
0.46 g of 6-chloro-2-pyridinecarboxylic acid, 15 ml of thionyl chloride and 0.29 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.17 g of N-(5-tetrazolyl)-6-chloro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(OCC3COC(C)(C)O3)ccc2F)c(Cl)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(OCC(O)CO)ccc2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 320 (31 mg, 0.07 mmol) was dissolved in TFA:H2O (3:1, 10 mL) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography using DCM/MeOH (v:v=99.5:0.5 to 98.5:1.5) as the eluent, affording the title compound as oil. 13C NMR (CDCl3) δ 190.5, 155.4 (d), 154.6 (d), 148.9, 136.7, 134.9, 134.3, 133.3, 131.2, 130.4, 128.5, 128.2 (d), 127.1, 125.1, 120.2 (d), 117.1 (d), 115.7, 115.2 (d), 112.5, 70.3, 69.9, 63.5, 17.9
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1
Reactant: BrCc1ccccc1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate, using benzyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:31])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2].BrCC1C2SC=CC=2C(OCCC2N=C(C3C=CC=CC=3)OC=2C)=CC=1.C(OC(=O)CN=C(C1C=CC=CC=1)C1C=CC=CC=1)C.[C:79]([CH2:87][C:88](=O)[CH3:89])(=[O:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:31]/[C:88](/[CH3:89])=[CH:87]\[C:79](=[O:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)N/C(C)=C\C(=O)c1ccccc1
Yield: 85.2 %

Procedure:
0.334 g (0.75 mmol) [rac]-2-Amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester (prepared from 4-[2-(7-bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole [PCT Int. Appl. (2001) WO01/79202] and N-(diphenylmethylene)glycine ethyl ester in analogy to the sequence described in examples 15 a] and 15 b]) and 0.161 g (0.97 mmol) benzoylacetone were dissolved in 25 ml of toluene. Then, 0.21 ml (1.5 mmol) triethylamine and 0.026 g (0.15 mmol) 4-toluene sulfonic acid were added and the reaction mixture was heated at reflux for 2 hours. After removing the solvent under reduced pressure, the residue was diluted in water/sodium hydrogen carbonate solution and the reaction mixture was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. Purification of the residue by flash-chromatography (silica gel, eluent: gradient of hexane and ethyl acetate) gave 0.38 g (85%) [rac]-2-[1-methyl-3-oxo-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester as light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24]([CH:25]=O)=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[C:1]1([C:7]2[O:8][C:9]([CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 3-[{4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), ethyl diethylphosphonoacetate (0.27 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) under ice-cooling. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoate as colorless crystals (0.51 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][CH2:13][C:14]1[N:19]=[C:18]([NH:20]CC2C=CC=CC=2)[C:17]2[NH:28][C:29](=[O:38])[N:30]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:16]=2[CH:15]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.O.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[NH2:20][C:18]1[C:17]2[NH:28][C:29](=[O:38])[N:30]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:16]=2[CH:15]=[C:14]([CH2:13][CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])[N:19]=1
Reactant: COCCN(CCc1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COCCNCCc1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Yield: 10.3 %

Procedure:
[2-(1-Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)-ethyl]-(2-methoxy-ethyl)-carbamic acid tert-butyl ester (64 mg, 0.12 mmol) was stirred in concentrated sulphuric acid (2 ml) for 30 minutes. Water (5 ml) was added and the mixture added drop-wise to a stirred solution of saturated NaHCO3 to achieve a basic pH. The aqueous was extracted with 2×EtOAc and the combined organics dried and concentrated to afford a yellow solid. The mixture of isomers was separated by column chromatography on silica, eluting with DCM:MeOH, 98:2 with increasing gradient to DCM:MeOH:NH3 90:10:1 to afford the title compound as a yellow solid, (4.2 mg, 11%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:24][CH2:25][CH2:26][N:27]=1>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:27]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:13]
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: C1CCOC1
Product: O=C(c1ccc2ccccc2n1)N1CCN=C1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.9 %

Procedure:
2.85 g (16.5 millimoles) of quinoline-2-carboxylic acid are dissolved in 200 ml of absolute tetrahydrofuran, 2.7 g (16.5 millimoles) of N,N'-carbonyl-diimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 3.75 g (16.5 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 75 ml of absolute tetrahydrofuran is then added dropwise and the batch is stirred overnight. Thereafter, the reaction solution is freed from solvent on a rotary evaporator and the oily residue is introduced into 200 ml of an 0.5% strength sodium bicarbonate solution. The crystalline crude product (5.2 g) is filtered off and recrystallized from N,N-dimethylacetamide/isopropanol, and the crystals are washed with cold isopropanol. 3.3 g of 1-(quinolin-2-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained, melting point 197°-198° C.
Reaction SMILES: Br[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C1(C)C=CC=CC=1.CCO>[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: OB(O)c1ccc(C2OCCO2)c(C(F)(F)F)c1
Reactant: Cc1c(Br)cccc1C(N)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 3-bromo-2-methylbenzamide (Ex IV-2) and 4-(1,3-dioxolan-2-yl)-3-(trifluoromethyl)phenylboronic acid (I-IX-8) according to the procedure described in Example IX-10, using PhMe/EtOH (4:1) as organic cosolvent. LC/MS (method A) 2.36 min; m/z 351 (M+H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH:46]=O)=[C:35]3[C:39]([O:41][C:42](C)(C)[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.Cl.[NH2:52][OH:53]>N1C=CC=CC=1.CCOCC.C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH:46]=[N:52][OH:53])=[C:35]3[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(C=O)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C=NO)SCC2C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.83 h

Procedure:
Under an inert atmosphere, 142 mg of (1,1-dimethyl)ethyl 7-[2-(2-tritylamino-thiazol-4-yl)-2-methoxyimino-acetamido]-3-formyl-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate, (prepared in Step A of Example 52) and 42 mg of hydroxylamine hydrochloride were dissolved in 0.4 ml of pyridine and the solution was stirred for 50 minutes and diluted with ether and with ethyl acetate. The mixture was washed with 6 ml of N hydrochloric acid and after extracting the aqueous phase with ethyl acetate, the organic phases were dried and concentrated to dryness. The residue was chromatographed under pressure on silica and eluted with a mixture of ethyl acetate and methylene chloride (25-75) to obtain 91 mg of 1,1-dimethy]-ethyl 7-[2-(2-tritylamino-thiazol-4-yl)-2-methoxyimino-acetamido]-3-hydroxyiminomethyl-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O)=[O:19].C([O-])(O)=O.[Na+].COCCOC.O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCCCC1.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[C:21]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[CH:6]=2)[CH:22]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)c2)cc1
Reactant: COc1ccc(C=O)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)c(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)c1
Temperature: 100 °C
Reaction time: 0.2 h
Yield: 72.8 %

Procedure:
4-Bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole (100 mg, 0.326 mmol), 2-formyl-5-methoxyphenylboronic acid (73 mg, 0.41 mmol), bis(triphenylphosphine)palladium dichloride (2 mg, 0.003 mmol), NaHCO3 (49 mg, 0.59 mmol) and 1:1 DME/H2O (8:8 mL) were combined and added to a microwave vessel. The reaction mixture was heated in the microwave with stirring at 100° C. for 12 min. The microwave took 5 min to reach 100° C., then maintained at 100° C. for 12 min, and then cooled. TLC (1:1 EtOAc:cyclohexane) showed the presence of starting materials, thus the sample was heated to 100° C. for another 8 min. Upon cooling a precipitate formed; this was filtered and washed with H2O to give a grey solid (86 mg): ESIMS m/z 363.0 (M+H).
Reaction SMILES: NC1C=C([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)C=CC=1>N.CCO>[NH2:8][C:9]1[CH:24]=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11](=[O:25])[N:10]=1)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)CCn1c-2cc(N)nc1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
To a suspension of 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (6) (919 mg, 3.5 mmol) in NH3/EtOH (7 mL) was stirred in an autoclave at 120° C. overnight. After cooling, the precipitate was filtered and washed with MeOH to give the title compound (898.3 mg, quant.). 1H-NMR (400 MHz, d6-DMSO) δ 7.99 (b, 1H), 7.71 (d, 1H), 7.44 (b, 1H), 7.01 (dd, 1H), 7.00 (s, 1H), 6.22 (s, 1H), 3.95 (t, 2H), 3.85 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 243.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(n3)c(-c3cccnc3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccc4c(n3)c(-c3cccnc3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 45 °C
Yield: 50.2 %

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (6 mg, 0.01 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2N NaOH (100 μL). The reaction mixture was heated at 45° C. overnight. The reaction mixture was concentrated, the residue was dissolved in DMF and MeOH, filtered and purified by reverse phase HPLC (10-100% ACN/H2O+0.1% TFA) to give the product (3 mg). 1H NMR (400 MHz, CD3OD) δ 9.70 (bs, 1H), 8.97 (d, J=3.8 Hz, 1H), 8.60 (bs, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.84-7.56 (m, 6H), 5.24 (s, 1H), 4.13 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H). LCMS-ESI+: calc'd for C32H28ClN5O3S: 598.2 (M+H+); Found: 598.2 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc(OCc2ccccc2)nc1
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cnn(Cc3ccc(OCc4ccccc4)nc3)c2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To an N,N-dimethylformamide (5.00 mL) solution of 3-(1H-pyrazol-4-yl)-pyridine-2,6-diamine (30.0 mg, 0.171 mmol) described in Manufacturing Example 36-1-2 was added sodium hydride (7.52 mg, 0.188 mmol, 60% in oil) on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. Thereafter, 2-benzyloxy-5-chloromethyl-pyridine (59.9 mg, 0.257 mmol) described in Manufacturing Example 191-1-2 was added to the mixture, which was stirred for 30 minutes at room temperature. The reaction mixture was partitioned into ethyl acetate and water. The organic layer was washed with water and a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (27.4 mg, 43.0%).