Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([NH:13][CH3:14])[CH3:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:13]([CH2:11][CH3:12])[CH3:14])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CCNC
Product: CCN(C)C(=O)c1cnc(Cl)cn1
Yield: 81.4 %

Procedure:
The title compound (I-7a) was prepared by a method analogous to that described for the preparation of SM-1 using 5-chloropyrazine-2-carboxylic acid (2 g, 12.62 mmol) and ethyl-methyl-amine (0.846 g, 13.9 mmol) to afford the title compound 5-chloro-N-ethyl-N-methylpyrazine-2-carboxamide (SM-4: 2.05 g, 81%) as a clear oil
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:4].[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][C:30]3[CH:31]=[C:32]([CH2:40][OH:41])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:18])([F:17])[C:3]([NH:19][CH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([CH2:40][OH:41])[CH:31]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:4]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21)C(F)(F)F
Yield: 26.5 %

Procedure:
Pentafluorophenyl trifluoroacetate (28 mg, 0.1 mmol) was added to a solution of (3-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (30 mg, 0.093 mmol) and triethylamine (26 μL, 0.187) in DCM (1 mL). The reaction was stirred at rt for 24 h before aq. sat. NaHCO3 (2 mL) was added to the mixture and the whole was filtered over a phase separator. The organic filtrate was evaporated to dryness in a Genevac. The crude material was purified by prep. LCMS to afford LEBE27-031-2 the title compound (10.3 mg, 27.7%). MS (ESI): m/z [M−H]− 416.0
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1csc2cncn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1csc2cncn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 651 mg potion of 3-(1-hydroxyethyl)imidazo[5,1-b]thiazole was dissolved in 130 ml of dichloromethane, and 9.77 g of active manganese dioxide was then added, followed by stirring at room temperature for 4 hours. After the completion of the reaction, insolubles were removed therefrom by filtration, followed by washing with dichloromethane. The filtrate was concentrated to dryness under reduced pressure to obtain 550 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[N:13]([CH3:15])[CH3:14].C[O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20](OC)O1>CC(O)=O>[CH3:14][N:13]([CH3:15])[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([N:12]2[CH:20]=[CH:21][C:22]([CH:18]=[O:17])=[CH:23]2)[N:6]=1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CN(C)c1nc(N)nc2ccc(F)cc12
Solvent: CC(=O)O
Product: CN(C)c1nc(-n2ccc(C=O)c2)nc2ccc(F)cc12
Temperature: 90 °C
Yield: 50 %

Procedure:
A stirring mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine (20.0 mg, 0.10 mmol), 2,5-dimethyoxy-3-tetrahydrofurancarboxaldehyde (43 μL, 0.30 mmol), and AcOH (500 μL) was heated at 90° C. for 30 minutes. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 70% hexanes/30% EtOAc to obtain the desired aldehyde as a white solid (15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 285.1 retention time 3.23 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)CCNCc1ccccc1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(CCN(C)C)Cc3ccccc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with N'-benzyl-N,N-dimethyl-ethane-1,2-diamine to give 98 mg of {4-[benzyl-(2-dimethylamino-ethyl)-carbamoyl]-6,8-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C29H38H4O5+H 523.6; found 523.0.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1.[CH:15](=O)[C:16]([CH3:18])=[O:17]>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:13][N:14]=[CH:15][C:16](=[O:17])[CH3:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)C=O
Reactant: COc1cccc(NN)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(NN=CC(C)=O)c1
Reaction time: 48 h
Yield: 33.7 %

Procedure:
Acetic acid (1.7 mL) was added to a solution of 3-methoxyphenylhydrazine (3.0 g, 17 mmol) in water (35 mL). This mixture was then added dropwise to a solution of pyruvaldehyde (3.1 g, 2.8 mL, 17 mmol) in water (45 ml) over 15 minutes. The mixture was stirred for two days and solids were removed by filtration and washed with water to obtain 2-oxopropanal (3-methoxyphenyl)hydrazone as a black solid (1.1 g, 33%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[C:9]=2[F:37])=[O:6])[CH2:3][CH2:2]1.CO.C(Cl)Cl.[C:43](OC(=O)C)(=[O:45])[CH3:44]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:43](=[O:45])[CH3:44])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:36])[C:9]=2[F:37])[CH2:2][CH2:3]1
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A suspension of compound 25 (100 mg, 0.156 mmol, TFA salt) in acetic anhydride (1 mL) was stirred at RT for 2 days. The reaction mixture was quenched by addition of methanol and water. The fine suspension was collected by filtration, rinsed successively with water, 1N NaOH, water, and air-dried. The crude product was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV, then 10/90 over 5 CV) to afford the title compound 26 (34 mg, 0.06 mmol, 38% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.57-8.44 (m, 3H), 8.38 and 8.34 (2s, 1H), 8.30 and 8.24 (2d, J=8.2 Hz, 1H), 8.04 (bt, J=8.3 Hz, 1H), 7.82-7.75 (m, 1H), 7.32-7.25 (m, 1H), 6.87 (bd, J=2.7 Hz, 1H), 6.79-6.74 (m, 1H), 4.71 and 4.59 (2s, 2H), 3.54-3.40 (m, 4H), 3.24 and 3.21 (2s, 3H), 2.61-2.53 (m, 1H), 2.13 and 2.05 (2s, 3H), 0.73-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 568.6 (M+H).
Reaction SMILES: [CH:1]1([N:7]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1>[CH:1]1([N:7]([CH2:34][CH:35]2[CH2:36][CH2:37]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A solution of ethyl 4-({4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]phenyl}sulfonyl)butanoate (Example 131, 80 mg; 0.16 mmol) in THF (5 ml) was treated with 10% sodium hydroxide solution (20 ml). After stirring for 45 minutes the mixture was cooled to 0° C. and acidified with concentrated HCl. The mixture was extracted with EtOAc and the combined organic extracts washed with water, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with DCM containing increasing amounts of methanol to give the title compound as a white solid (65 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]([F:28])([F:27])[F:26])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Cl-].[OH:35][NH3+:36]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:25]([F:27])([F:26])[F:28])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[C:16]([CH:19]=2)/[C:17](=[N:36]/[OH:35])/[NH2:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [NH3+]O
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N/C(=N\O)c1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C

Procedure:
A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/water mixture (10 mL) was stirred at 70° C. for 8 h. The reaction was cooled to ambient temperature, and the ethanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off white solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:23]=[C:22]([C:24](=[S:26])[NH2:25])[N:21]=[N:20]1)(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([N:19]2[CH:23]=[C:22]([C:24](=[S:26])[NH2:25])[N:21]=[N:20]2)[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(N)=S)nn2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=S)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
1-(2,3,5-Tri-O-acetyl-β -D-ribofuranosyl)-1,2,3-triazole-4-thiocarboxamide (1.0 g) was added to sodium methoxide in methanol (60 mg of sodium in 30 ml of methanol) and the resulting solution was stirred at room temperature for 4 hr. After neutralization of the solution with Amberlite IRC 50, the solution was filtered, and the filtrate was evaporated to dryness. The product was crystallized from ethanol to give 0.55 g (82%) of 12: m.p. 152°-154°; [α]D25 -85.2° (c 1.00, water); nmr (DMSO-d6) δ 6.04 (d, 1, J1',2' 4.8 Hz, 1'--H), 8.90 (s, 1, 5--H).
Reaction SMILES: C1(C)C=CC=CC=1.O[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[CH2:11][CH2:10]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[C:12]12([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]1)[C:13]1[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:9]=[CH:10][CH2:11]2
Reactant: O=C1NC(=O)C2(CCC(O)c3ccccc32)N1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C2(CC=Cc3ccccc32)N1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a refluxing solution of 100 ml. of toluene containing 4.5 g. (0.019 mole) of 3',4'-dihydro-4'-hydroxyspiro [imidazolidine-4,1'(2'H)-naphthalene]2,-5-dione was added a trace of -toluenesulfonic acid and the refluxing continued for 2 hours. The reaction was cooled, stripped to dryness and the residue dissolved in 100 ml. of ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to dryness. The residue was triturated with diethyl ether, 2.7 g. (65% yield).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[C:9]2[C:13]=1[C:12](=[O:14])[C:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=1)(C(OC)=O)[CH2:10]2>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=2)=[C:9]2[C:13]=1[C:12](=[O:14])[CH:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)[CH2:10]2
Reactant: COC(=O)c1ccc(CC2(C(=O)OC)Cc3c(-c4cccc(C(F)(F)F)c4)ccc(OC)c3C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(C(F)(F)F)c2)c2c1C(=O)C(Cc1ccc(C(=O)O)cc1)C2
Temperature: 60 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
Aqueous lithium hydroxide (1 N, 1.0 mL, 1.0 mmol) was added to a solution of methyl 7-methoxy-2-(4-(methoxycarbonyl)benzyl)-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate (36 mg, 0.071 mmol) in THF (1.0 mL) in a scintillation vial. The vial was sealed under nitrogen and heated at 60° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were evaporated under a stream of nitrogen. The residue was diluted with water (5.0 mL), acidified with 1 N aqueous HCl (2.0 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude residue was purified by combiflash (4 g column, CH2Cl2→20% MeOH/CH2Cl2, gradient). All fractions containing the desired product were combined and the resulting crude product was further purified by preparative thin layer chromatography (1000 μM thickness, EtOAc), to afford 8 mg (26%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:23]([CH3:37])[C:24]([NH:26][CH2:27][C:28]2[NH:32][N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:29]=2)=[O:25])[CH:15]=[CH:16][C:17]=1[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([CH:23]([CH3:37])[C:24]([NH:26][CH2:27][C:28]2[N:32]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:31]=[C:30]([C:33]([F:36])([F:34])[F:35])[CH:29]=2)=[O:25])[CH:15]=[CH:16][C:17]=1[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C(=O)NCc1cc(C(F)(F)F)n[nH]1)c1ccc(CS(C)(=O)=O)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)c1ccc(CS(C)(=O)=O)c(F)c1
Reaction time: 8 h
Yield: 74.6 %

Procedure:
4-Fluorophenylboronic acid (41 mg, 0.295 mmol), 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)-N-((3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide (60 mg, 0.147 mmol) and copper(II)-acetate (0.021 mL, 0.221 mmol) were added to DCM (2.2 mL). At room temperature was added pyridine (0.238 mL, 2.946 mmol) and the mixture was stirred for overnight. The reaction mixture was concentrated in vacuo, the solid obtained was purified by CC (eluent: cyclohexane/ethyl acetate (1:2)) to afford 2-[3-fluoro-4-(methylsulfonyl-methyl)-phenyl]-N-[[2-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide (55 mg, 75%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(=O)N(C)C)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: CN(C)C(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzamide (A-20) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=404.3 (M+H)+
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10]Br>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10][N:3]1[CH2:4][CH:5]=[CH:6][N:2]1[OH:1]
Reactant: On1cccn1
Reactant: Fc1cccc(F)c1CBr
Solvent: ClC(Cl)Cl
Product: ON1C=CCN1Cc1c(F)cccc1F
Temperature: 80 °C
Yield: 68.9 %

Procedure:
1-Hydroxypyrazole (49.3 mg, 0.59 mmol, 1.0 eq) was mixed with 165.8 mg (0.80 mmol, 1.36 eq) of 2,6-difluorobenzyl bromide in ˜1-2 mL of anhydrous CHCl3 under argon. The mixture was heated at 80° C. for 18 b tinder inert atmosphere in a sealed flask without condenser. The residue was partitioned between 37 weight percent aqueous HCl and toluene. The aqueous layer was collected and the toluene fraction extracted again with 37 weight percent aqueous HCl. The combined aqueous HCL fractions were neutralized with 5N aqueous NaOH to pH˜11-12 and then back-extracted with 3×30 mL of CHCl3. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to yield 86.3 mg (70.1% yield) of 2-(2,6-difluorobenzyl)-1-hydroxy-1H-pyrazole as a tan brown solid. 1H NMR (CDC3 300 MHz) δ 7.37 (m, 1H), 7.18 (d, 1H), 6.95 (t, 2H), 6.85 (d, 1H), 6.11 (t, 1H), 5.43 (s, 2.00H) LC/MS (ES) M+1=211.2
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[SH:15])=O)(C)(C)C.[ClH:16]>C(O)(=O)C>[ClH:16].[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[SH:15]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1S
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cnccc1S
Temperature: 0 °C
Yield: 100 %

Procedure:
A 13.78 g (0.06 mol) sample of 3-(t-butyloxy-carbonyl)amino-4-mercapto pyridine was dissolved with acetic acid (250 mL) and added to an ice cold solution of ~3N HCl in acetic acid which had been made by bubbling HCl(g) through glacial acetic acid (100 mL). After about four hours the resulting solid was filtered, washed with diethylether and dried in vacuo to yield 10.4 g (~100%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[N:5]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[C:6]=[S:7]>O1CCCC1>[CH2:1]([NH:4][C:6](=[S:7])[NH:5][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3]
Reactant: COC(=O)c1ccsc1N=C=S
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNC(=S)Nc1sccc1C(=O)OC
Reaction time: 4 h
Yield: 597.2 %

Procedure:
In a sulfonation flask, 13.5 g (0.023 mol) of n-propylamine are added dropwise to 350 ml of tetrahydrofurane and 41.3 g (0.021 mol) of methyl 2-isothiocyanatothiophene-3-carboxylate, such that the internal temperature does not arise above 40° C. The reaction mixture is then stirred for 4 hours at reflux temperature and then the tetrahydrofurane is removed in a water-jet vacuum. The residue is taken up in ethyl acetate and extracted three times with water. The organic phase is then dried over sodium sulfate and the solvent is removed in the water-jet vacuum, giving the crude product, which is purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:3). 32.4 g of methyl 2-(3-propylthioureido)thiophene-3-carboxylate are obtained in the form of a beige powder having a melting point of 123-126° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].O.C([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:18][N:17]=[N:16]1)C=C>CN(C)C=O>[CH2:1]([N:16]1[N:17]=[N:18][C:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[N:15]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nnnc1-c1ccc(-c2ccc(OCOC)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1nnc(-c2ccc(-c3ccc(OCOC)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Allyl bromide (0.27 ml, 3.13 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to a solution of the obtained compound in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to give a mixture of 1-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-1H-tetrazole and 2-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-2H-tetrazole (504 mg, two-step total yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36].[Al]>C(NCC)C.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.[Cu]I>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1c(=O)cc(-c2cccc(I)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one (9.98 g, 20.0 mMol) was suspended in diethylamine (300 mL). To this solution was added 50 mL of anhydrous N,N-dimethylformamide (DMF), (trimethylsilyl)acetylene (8.5 mL) and bis(triphenylphosphine)-palladium(II) chloride (1.40 g, 2.00 mMol). The flask was covered with aluminum foil and then copper(I) iodide (780 mg, 4.09 mMol) was added causing the reaction mixture to exotherm. After stirring overnight under an atmosphere of dry N2 at ambient temperature, the reaction mixture was concentrated under vacuum and the residue was chromatographed on flash silica gel eluting with a gradient of DCM to MeOH/DCM (2:98) to give 8.55 g of the titled product as a solid.
Reaction SMILES: [F:1][C:2]([F:38])([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:39][CH:40]=O>>[CH2:39]([N:35]1[CH2:34][CH2:33][N:32]([C:2]([F:1])([F:38])[C:3]2[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:23]=[CH:22][N:21]=4)[CH:13]=3)=[O:10])=[CH:7][CH:8]=2)[CH2:37][CH2:36]1)[CH3:40]
Reactant: CC=O
Reactant: Cc1ccc(NC(=O)c2ccc(C(F)(F)N3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: CCN1CCN(C(F)(F)c2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1

Procedure:
The product from Example 14 was ethylated via reductive amination with CH3CHO/NaBHCN afforded the title compound. Mass: (M+1), 544.