Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:19][S:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20](=[O:22])(=[O:21])[NH:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:24]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.215 g, 3.1 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCO3 solution (2.7 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acryloyl chloride (16d) (0.23 g) in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate affording the title compound (0.054 g, 24%). M.p. 180° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.45 (1H, d, J=16.0 Hz); 7.14 (1H, dd, J=7.0 and 1.4 Hz); 7.31-8.14 (11H, m); 9.09 (1H, br s); 10.27 (1H, s); 10.76 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 4% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.3 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C19H16N2O4S, %: C, 61.94; H, 4.38; N, 7.60. Found, %: C, 61.18; H, 4.32; N, 7.54.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:9]=12)=[NH:4].[S:28]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=O)(=[O:31])(=[O:30])[NH2:29]>>[F:17][C:14]([F:15])([F:16])[C:13]1[N:8]2[N:7]=[CH:6][C:5]([C:3]3[N:4]=[C:35]([C:34]4[CH:33]=[C:32]([S:28]([NH2:29])(=[O:31])=[O:30])[CH:40]=[CH:39][CH:38]=4)[O:1][N:2]=3)=[C:9]2[N:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:12]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: N=C(NO)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2nc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)no2)c1

Procedure:
The title compound was prepared from N-hydroxy-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamidine (example B.1) (195 mg, 0.5 mmol) and commercially available 3-sulfamoyl-benzoic acid (101 mg, 0.5 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (144 mg, 52%). MS (ISN) 553.3 [(M−H)−]; mp 285° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:47][NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][S:58]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)(=[O:60])=[O:59].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:13])[N:48]([CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][S:58]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)(=[O:60])=[O:59])[CH3:47])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNCCc1ccccc1NS(=O)(=O)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (517 mg, 1.57 mmol) and 1-hydroxy-7-azabenzotriazole (214 mg, 1.57 mmol) were dissolved in dichloromethane (6 ml) and N,N-dimethylformamide (6 ml). The mixture was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (301 mg, 1.57 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of N-[2-(2-(methylamino)ethyl)phenyl]benzenesulfonamide (457 mg, 1.57 mmol) in dichloromethane (6 ml) and ethyldiisopropylamine (0.27 ml, 1.57 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a 10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (25 g), using ethyl acetate/heptane 1:1 as eluent, to give 785 mg of N-((1R)-1-{N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=O)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:24])=O.O.[OH-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:19]#[N:21])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([Cl:24])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2nc(C#N)c(N)nc2Cl)ccc1=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (29.1 g) was dissolved in DMF (290 ml). The solution was cooled to −30° C. To the cooled solution was added phosphoryl chloride (46.3 g) dropwise at −30˜−40° C. After addition of phosphoryl chloride, the temperature of the reaction mixture was raised to 40-45° C. The mixture was stirred at 40-45° C. for 1 hour. To the reaction mixture was added water (1160 ml). The suspension was stirred at 30-35° C. for 15 hours. The pH of the suspension was adjusted to 7 with 12% aq. NaOH (400 ml). The suspension was cooled to 0-5° C. and stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with water, and dried in vacuo at 40-50° C., to give 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile (17.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:9]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:39])[F:40])([C:34]([F:35])([F:36])[F:37])[OH:33])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.6 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (350.0 mg, 0.58 mmol) prepared in Example 291 and trifluoroacetic acid (444.0 uL, 5.79 mmol) were added at 0° C. to dichloromethane (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 400.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:12](=O)([O:18]N1C(=O)CCC1=O)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CO>O.[OH-].[K+]>[C:14]([O:13][C:12]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To the solution of 575 mg of lysine monohydrochloride in 2 ml of water, 6.2 ml of 1N methanolic potassium hydroxide was added and then 645 mg of t-butyl succinimidyl carbonate in 3 portions was mixed in over 20 minutes while stirring at room temperature. Stirring was continued for another 2 hours, then the reaction mixture was acidified to pH 5, methanol evaporated and the white precipitate collected by filtration giving 779 mg (quantitative yield) of the crude title compound. This was twice recrystallized from warm water to give 529.7 mg (68%) of pure compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:43])[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:41][N:40]([CH3:42])[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[F:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:43])=[O:39]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(CC(=O)N(C)C)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(=O)N(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide (Step 119.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 551.1 [M+H]+; tR=3.81 min (System 1); TLC: Rf=0.36 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(N(CC)CC)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 53 %

Procedure:
In the manner given in Example 15, 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine is reacted with 4-methoxyphenylsulfonyl chloride, in the presence of triethylamine to give 1-[(4-methoxyphenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 221°-223° C. in a 53% yield.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[N:20]=[C:21]([CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:22][C:23]=1[CH3:24])[CH:13]([CH3:33])[CH2:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5]>CO.[Pd]>[F:6][C:4]([F:5])([F:7])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[N:20]=[C:21]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:22][C:23]=1[CH3:24])[CH:13]([CH3:33])[CH2:12]2)([OH:8])[C:2]([F:35])([F:34])[F:1]
Reactant: Cc1oc(C=Cc2ccccc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Agent: [Pd]
Solvent: CO
Product: Cc1oc(CCc2ccccc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
A solution of 30 mg (0.06 mmol) of 1,1,1,3,3,3-hexafluoro-2-[2-methyl-1-(5-methyl-2-styryl-oxazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-propan-2-ol (example 136) in 1 ml of methanol was treated with 15 mg of Pd/C (10%) and stirred under H2 at atmospheric pressure for 6 hours. Filtration and evaporation of the solvent gave 24 mg (77%) of 1,1,1,3,3,3-hexafluoro-2-[2-methyl-1-(5-methyl-2-phenethyl-oxazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-propan-2-ol, light yellow oil, MS: 499 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[NH:12][CH2:13][CH2:14][NH:15]3)=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[NH:12][CH2:13][CH2:14][N:15]2[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of (3-chlorophenyl)(1,2,3,4-tetrahydroquinoxalin-5-yl)methanone (50 g, 183 mmol) in DCM (200 mL) at 0° C. was added pyridine (17.79 mL, 220 mmol). Then CBZ—Cl (26.2 mL, 183 mmol) in DCM (1.0 mL) was added dropwise. The reaction mixture was warmed up to room temperature and stirred at room temperature for 3 h. The reaction mixture was washed with H2O, saturated NaHCO3, and brine, dried over Na2SO4, filtered, concentrated to give crude material. This crude material was purified via BIOTAGE®, eluted with 10% EtOAC/hexane to afford benzyl 5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1D (60 g, 147 mmol, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.5 (1H, bs), 7.6 (1H, s), 7.45 (2H, m), 7.4 (7H, m), 7.25 (1H, m), 6.5 (1H, m), 5.2 (2H, m), 3.9 (2H, m), 3.6 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:15])[O:9][N:8]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>ClCCl>[NH:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:14](=[O:15])[CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CCc2nc(-c3ccccn3)no2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCNCC1
Yield: 63.3 %

Procedure:
tert-Butyl 4-({3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl}amino)-1-piperidinecarboxylate (0.40 g) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) was added. After 2 hours water, 2N sodium hydroxide and dichloromethane were added and the phases were separated. The organic phase was dried, filtered and evaporated to give the subtitle compound (0.19 g).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:31])[C:16]([CH2:29][CH3:30])=[C:17]([C:27]#[N:28])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1)=[O:13])[CH3:10].O>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:31])[C:16]([CH2:29][CH3:30])=[C:17]([C:27]#[N:28])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:21][CH:20]=1)=[O:13])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(C=O)cc2)c(C#N)c(CC)n1C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(O)c3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Add phenyl magnesium bromide (192 uL, 0.58 mmol) to 4-cyano-5-ethyl-3-(4-formyl-phenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester [(0.020 g, 0.64 mmol, prepared in example E-152] in THF with stirring at −78° C. After 30 minutes, gradually allow the reaction mixture to warm to ambient temperature. After 2 hours, pour the reaction mixture into water and extract with EtOAc. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 406.1 (M+18).
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[H-].[Na+].Cl[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[C:34]1([CH2:33][N:12]2[C:13](=[O:19])[C@H:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[N:9]([C:7](=[O:8])[CH2:6][N:5]3[C:4](=[O:24])[C:3]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]4[C:1]3=[O:29])[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]2=3)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)[C@@H]2CCC[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2cccc3ccccc23)C(=O)[C@H]2CCC[C@H]21
Temperature: 28 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
To a suspension of (3aR*,10aS*)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (391 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% liquid paraffin dispersion, 44 mg, 1.1 mmol). The mixture was stirred for 10 minutes at 28° C., to which was added 1-(chloromethyl) naphthalene(213 mg, 1.2 mmol), followed by stirring for 20 minutes at the same temperature. To the reaction mixture was added water (5 mL), and the mixture was subjected to extraction twice with chloroform. The organic layers were combined and washed with water, dried over magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was crystallized from ethanol to give 177 mg (yield 33%) of the titled compound, m.p. 266°-270° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 5.0 g (29.4 mmol) of 2-fluoro-4-methoxybenzoic acid in methanol (50 mL) at room temperature are added 2.13 mL (29.4 mmol) of thionyl chloride. The reaction is stirred at room temperature for 16 h and the solvent is removed under reduced pressure. The residue is dissolved in DCM and washed with brine. The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to give 5.04 g (27.1 mmol) of 2-fluoro-4-methoxybenzoic acid methyl ester. Yield: 92%, ES-MS: m/z 185 [M+H].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:26]=[CH:25][C:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[N:9](C(OC(C)(C)C)=O)[CH2:10][C:5]=2[CH:4]=1.[ClH:29].O1CCOCC1>>[ClH:29].[F:27][C:2]([F:1])([F:28])[C:3]1[N:26]=[CH:25][C:6]2[CH2:7][NH:8][NH:9][CH2:10][C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C(F)(F)F)cc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1cc2c(cn1)CNNC2
Yield: 110.6 %

Procedure:
A solution of the product from Step C (4.53 g, 11.24 mmol) in 4N HCl/Dioxane (55 ML, 225 mmol) was stirred overnight. The solvent was evaporated to yield the 7-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[3,4-d]pyridazine HCl salt (2.98 g, 100%). 1H-NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 7.78 (s, 1H), 4.80 (s, 2H), 4.48 (s, 2H). ESI-MS calc. For C8H8F3N3: 203.07; Found: 204 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[CH2:9][CH2:10][CH:11]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]2)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:17][C:14]1([CH3:18])[CH2:13][O:12][CH:11]([CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])[O:16][CH2:15]1
Reactant: CC1(C)COC(CCC(O)c2ccc(F)cc2)OC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)COC(CCC(=O)c2ccc(F)cc2)OC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of α-(4-fluorophenyl)-5,5-dimethyl-1,3-dioxane-2-propanol (Step 3) (2.6 g, 10.7 mmol) in methylene chloride (100 ml), pyridinium chlorochromate (3.5 g, 16.05 mmol) was added. After stirring at room temperature for 3 hr, the reaction mixture was diluted with ether and filtered through a short silica gel column. The column was eluted with ether and the fractions containing 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one were combined and concentrated (2.2 g, 85%): mp (DSC) 65° C. Anal Calc'd. for C15H19FO3: C, 67.65; H, 7.19. Found: C, 67.21; H, 7.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12](O)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.CN1CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:12]=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C2(C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Under an argon atmosphere, a solution of 1-(4-methoxyphenyl)cyclopropane carboxylic acid (2.00 g, 10.4 mmol) in tetrahydrofuran (20 mL) was added with lithium aluminum hydride (513 mg, 13.5 mmol) at 0° C., and the resultant was stirred at room temperature for 2 hours. The resultant was added sequentially with water and hydrochloric acid at 0° C., stirred at room temperature for 30 min and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was dissolved in dichloromethane (15 mL). The resultant was sequentially added with molecular sieves 4β (1.80 g), N-methylmorpholine (1.83 g, 15.6 mmol) and tetrapropylammonium perruthenate (1.83 mg, 0.520 mmol) at 0° C., and stirred at room temperature for 1.5 hours. The reaction solution was filtered using celite, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane:ethyl acetate=4:1), and 1-(4-methoxyphenyl)cyclopropane carboaldehyde (1.54 g, 84.0%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>>[NH:21]1[CH:22]=[CH:23][C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[N:20]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cc[nH]n1
Product: FC(F)(F)c1cc(Nc2cc[nH]n2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (75 mg, 0.289 mmol) and 3-amino pyrazole (31 mg, 0.373 mmol) similar to Example 166 and was isolated as a white solid (mp 230° C. decompose, 31 mg, 0.101 mmol, 35%). 1H NMR (DMSO-d6) 9.62 (d, J=1.2 Hz, 1H), 8.77 (m, 3H), 7.71 (s, 1H), 7.62 (dd, J=4.5, 7.5 Hz, 1H), 6.09 (d, J=3 Hz, 1H), 5.89 (s, 1H).