Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]([NH2:20])=[S:19].C(O)C>CN(C)C=O>[C:1]1([C:7]2[N:17]=[C:18]([SH:19])[NH:20][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCO
Product: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1

Procedure:
21.2 g (0.10 mol) of benzoin were dissolved in DMF (dimethylformamide) with 10.8 g (0.15 mol) of thiourea with warming and the mixture was heated under reflux for 15 hours. After cooling, the DMF was stripped off and the residue was treated with ethanol. The precipitate resulting in the course of this was filtered off with suction, washed with cold ethanol, dried and reused without further purification. The yield was 18.4 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[CH:14])([CH3:4])([CH3:3])[CH3:2].[Cl:15]C1CC(=O)NC1=O>CC(C)=O.C([O-])(=O)C.[Ag+]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[C:14][Cl:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCOc1ccccc1C(C)(C)C
Reactant: O=C1CC(Cl)C(=O)N1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccccc1OCC#CCl

Procedure:
To a solution of Example 5A (18.86 g, 100 mmol) in acetone (400 mL) was added N chlorosuccinimide (16.02 g, 120 mmol) and silver acetate (1.67 g, 10 mmol) and the mixture was heated at reflux for 4 hours. After cooling, the silver salts were removed by filtration and the filtrate evaporated under reduced pressure. The residue was taken up in diethyl ether, washed with water and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered, and the solvent was removed under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H), 4.73 (s, 2H), 6.91-6.97 (m, 2H), 7.19 (td, J=7.71, 1.86 Hz, 1H), 7.30 (dd, J=7.97, 1.53 Hz, 1H). MS (DCI) m/z 223 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1.Cl.[C:19]([C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)#[N:20]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:24]2[CH2:25][CH2:26][C:21]([C:19]#[N:20])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23]2)=[S:17])=[CH:11][CH:10]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1(c2ccccc2)CCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.4 mL, 10 mmol) was added to a suspension of 4-chlorophenyl isothiocyanate (1.69 g, 10 mmol) and 4-cyano-4-phenylpiperidine hydrochloride (2.22 g, 10 mmol) in dichloromethane (100 mL), and the reaction was then stirred at room temperature for 20 minutes. The mixture was washed with 2N hydrochloric acid, then brine, it was dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a white solid, 3.62 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:21][C:22]=1[F:27]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2C)cc1F

Procedure:
In analogy to example 221, step 6, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with methyl 4-bromobutyrate in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=500.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Product: CCCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21

Procedure:
1-Butyl-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine, melting at 94°-96° C. is prepared by reacting the compound of Example 1 with butyl bromide similarly in Example 9, and recrystallizing from petroleum ether.
Reaction SMILES: [CH:1]([C:4]1[C:9](C[C@@H](C2C=CC=CC2(O)C)OS(O)(=O)=O)=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:7]([CH2:32][CH2:33][CH3:34])=[C:6]([CH:35]([CH3:37])[CH3:36])[N:5]=1)([CH3:3])[CH3:2].[CH2:38]([OH:40])[CH3:39]>[Ni]>[CH:1]([C:4]1[C:9]([CH:38]([OH:40])[CH3:39])=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:7]([CH2:32][CH2:33][CH3:34])=[C:6]([CH:35]([CH3:36])[CH3:37])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CCCc1c(C(C)C)nc(C(C)C)c(C[C@H](OS(=O)(=O)O)C2C=CC=CC2(C)O)c1-c1ccc(F)cc1
Agent: [Ni]
Product: CCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A suspension of Raney nickel (40 g, washed with 3×100 mL ethanol) in ethanol (80 mL) was stirred under hydrogen atmosphere for 1.5 hours. The suspension was treated with a solution of the intermediate obtained in Step B (4.1 g, 8.5 mmol) in ethanol (180 mL) at room temperature and stirred vigorously for 5 hours. The suspension was carefully filtered through celite and concentrated. Filtration through silica gel (CH2Cl2) afforded the title compound (99% e.e.) as a white solid (2.74 g, 8 mmol, 94%). 1H NMR (300 MHz, CDCl3): δ 7.11 (m, 3H), 7.04 (m, 1H), 4.64 (dq, J=3.7, 6.6 Hz, 1H), 3.73 (sept, J=6.6 Hz, 1H), 3.18 (sept,. J=6.6 Hz, 1H), 2.15 (m, 2H), 1.56 (d, J=3.7 Hz, 1H), 1.39 (d, J=6.6 Hz, 3H), 1.28 (m, 14H), 0.73.(t, J=7.35 Hz, 3H). FAB-MS calculated for (C22H31FNO, M+H) 344, found 344. Anal. Calcd for C22H30FNO: C, 76.93; H, 8.80; N, 4.08; F, 5.53; Found: C, 77.20; H, 8.97; N, 4.01; F, 5.60. [a]D=+39.4° (CH2Cl2). mp 104-106° C. Rf=0.4 (CH2Cl2).
Reaction SMILES: Cl.CCOC(C)=O.[C:8]([O:12][C:13](=[O:47])[CH2:14][CH:15]([OH:46])[CH2:16][CH:17]([OH:45])[CH:18]=[CH:19][C:20]1[N:21]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[N:22]=[C:23]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]=1[CH:25]([CH3:27])[CH3:26])([CH3:11])([CH3:10])[CH3:9]>CO.[Pd]>[C:8]([O:12][C:13](=[O:47])[CH2:14][C@H:15]([OH:46])[CH2:16][C@H:17]([OH:45])[CH2:18][CH2:19][C:20]1[N:21]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[N:22]=[C:23]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:24]=1[CH:25]([CH3:27])[CH3:26])([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C=CC(O)CC(O)CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1CC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a solution of (6-{2-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester (0.360 g, 0.61 mmol) in MeOH (20 mL) was added 1N HCl (2 mL) and the solution was stirred for 3 hrs at 25° C. Subsequently, the reaction solvent was removed under reduced pressure and ethyl acetate (50 mL) and saturated NaHCO3 (10 mL) were added. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated to afford, after silica gel chromatography (35% EtOAc/Hex), 7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid tert-butyl ester (0.231 g, 69%). Subsequently, to a solution of 7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid tert-butyl ester (0.241 g, 0.437 mmol) in MeOH (20 mL) was added 10% Pd-C (50 mg; commercially available from Sigma Aldrich), and the reaction vessel was evacuated and filled with hydrogen gas (via balloon) for 3 hours. The reaction mixture was then filtered through a pad of celite and to the filtrate was added The crude product was purified by silica gel chromatography (30-50% EtOAc/Hex) to provide (3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester (0.143 g, 59%): MS(APCI+): m/z554.3 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34](O)[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:30][CH:29]=1>C(Cl)Cl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([I:25])[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:30][CH:29]=1
Reactant: COC(=O)CCC(O)c1ccc(F)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCC(I)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (419 mg, 1.6 mmol) in anhydrous 20 mL DCM was added imidazole (224 mg, 3.3 mmol) and iodine (406 mg, 1.6 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then methyl 4-(4-fluorophenyl)-4-hydroxybutanoate (212 mg, 1 mmol) in 10 mL DCM was added to the mixture. The resulting mixture was stirred at 0° C. for 2 h and the temperature was slowly raised to room temp over a period of 3 h. Evaporation of solvent left the crude product as an oil from which the product was isolated by Flash column chromatography eluting with 0% to 10% ethyl acetate/hexane to give the title compound, 161 mg, as a light yellow oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10]C(=O)C)=[O:3].Cl.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][C@@H:46]([NH2:53])[C:47]3[O:51][N:50]=[C:49]([CH3:52])[N:48]=3)=[CH:41][CH:40]=2)=[CH:35][C:34]=1[F:54])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][C@@H:46]([NH:53][C:2]([C:4]3[CH:5]=[C:6]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=4)[CH:7]=[CH:8][C:9]=3[OH:10])=[O:3])[C:47]3[O:51][N:50]=[C:49]([CH3:52])[N:48]=3)=[CH:41][CH:40]=2)=[CH:35][C:34]=1[F:54])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(OCc4ccccc4)c(F)c3)cc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(OCc4ccccc4)c(F)c3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2O)n1

Procedure:
4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (58 mg) was prepared from acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (1.96 mL, 0.1 M CH2Cl2), 2-(4′-benzyloxy-3′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride (90 mg, 0.178 mmol) and DIEA (95 μL, 0.55 mmol) analogous to procedure M. The crude reaction mixture was concentrated and redissolved in THF (3 mL) and MeOH (1 mL). 1N NaHCO3 (200 μL) and 1 N Na2CO3 (50 μL) were added and the hydrolysis was followed by TLC and LCMS. Once complete, the reaction was diluted with EtOAc and the layers were separated. After extraction and drying the combined organics over MgSO4, the crude mixture was concentrated onto silica gel and purified by chromatography using 15% EtOAc in hexanes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:30])=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[CH2:32][CH2:33][CH3:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]([CH2:20][C:21]([CH3:23])([CH3:24])[CH3:22])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2c(=O)n1CC(C)(C)C
Reactant: CCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC(C)(C)C)c(=O)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A solution of 5-benzyloxy-2-(ethoxycarbonyl)benzoic acid (21.86 g, 120 mmol), ethyl 2-(neopentylamino)acetate (20.79 g, 120 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.76 g, 150 mmol) and 1-hydroxybenzotriazole (22.97 g, 150 mmol) in N,N-dimethylformamide (200 ml) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (300 ml), and potassium carbonate (33.17 g, 240 mmol) and benzyl bromide (35.7 ml, 300 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (50 ml) and 20% sodium ethoxide ethanol solution (34.04 g, 100 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (150 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 7-benzyloxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate as an oil. To a solution of the obtained ethyl 7-benzyloxy-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.26 g, 8 mmol), 1-butanol (1.1 ml, 12 mmol) and tributylphosphine (4.0 ml, 16 mmol) in tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (4.04 g, 16 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 7-benzyloxy-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.61 g, 97.0%) as an oil.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[NH3:14]>CCO>[NH2:14][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCO
Product: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A 500 mL pressure flask was charged with 2,6-dichloro-3-nitrobenzonitrile (30.0 g, 138 mmol) and a 5.1 M solution of ammonia in EtOH (170 mL). The flask was sealed and heated in an oil bath at 80° C. with stirring for 1.5 h. The cooled solution was filtered, the crystals washed with water and dried to yield 2-amino-6-chloro-3-nitrobenzonitrile (18.4 g, 68%), mp 181-184° C.; MS (ES−) 196, 198 (M−H−).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=O.[CH3:23][NH2:24]>CO>[CH3:23][NH:24][C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:2]
Reactant: COC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Reactant: CN
Solvent: CO
Product: CNC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Yield: 88 %

Procedure:
A solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35b; 0.050 g, 0.15 mmol) in 4 mL of a 2 M solution of methylamine in methanol was stirred for 6 d, then concentrated to a white solid. Column chromatography (0→45% EtOAc/hexanes) afforded of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid methylamide (35d; 0.044 g; 88%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:37]=[N:38][CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:44]1([S:41]([NH:40][C:36]2[CH:35]=[C:34]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]5[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]5)[C:10]=4[N:11]=3)[CH:39]=[N:38][CH:37]=2)(=[O:43])=[O:42])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)nc23)CC1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.3 g, 0.822 mmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene-sulfonamide (Intermediate 2) (0.355 g, 0.987 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.067 g, 0.082 mmol) and 1N aq. sodium bicarbonate (1.64 ml, 1.64 mmol) in dioxane (4.11 ml) was subjected to microwave irradiation for 30 min at 120° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was diluted water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give tert-butyl 4-(6-(5-(phenylsulfonamido)-pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.15 g, 32%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.95-2.05 (2H, m), 2.14-2.18 (2H, m), 3.36-3.43 (2H, m), 3.89-3.95 (2H, m), 5.63-5.37 (1H, m), 7.46-7.52 (2H, m), 7.56-7.60 (1H, m), 7.85 (1H, d, J=7.2 Hz), 8.21 (1H, d, J=8.8 Hz), 8.34 (1H, s), 8.37 (1H, d, J=2.4 Hz), 8.41 (1H, d, J=2.0 Hz), 8.83 (1H, s), 9.14 (1H, d, J=1.6 Hz).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(Cl)Cl>[C:1]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1nc[nH]n1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)n1cncn1
Temperature: 25 °C

Procedure:
Palmitoyl chloride is dissolved in methylene chloride and added dropwise to a solution of 2 equivalents of 1,2,4-triazole in methylene chloride, the mixture is stirred for some hours at room temperature and filtered, and the filtrate is used directly in the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[N:11]([O-])=O.[Na+]>O.Cl>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][NH2:11]
Reactant: O=N[O-]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1c(Cl)cc(F)cc1Cl
Reaction time: 1 h
Yield: 70.8 %

Procedure:
9.0 g (0.05 mol) of 2,6-dichloro-4-fluoroaniline was added to 50 ml of concentrated hydrochloric acid, and a solution of 3.8 g (0.055 mol) of sodium nitrite in 25 ml of water was dropwise added thereto at a temperature of from 0° to 5° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 1 hour. Insolubles were removed by filtration, and the filtrate was dropwise added at a temperature of from 0° to 10° C. to a solution of 33.8 g (0.15 mol) of stannous chloride dihydrate in 50 ml of concentrated hydrochloric acid. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 2 hours. The precipitated hydrochloride was collected by filtration, and 50 ml of water was added thereto. The mixture was made alkaline with an addition of 20% sodium hydroxide, and the precipitated solid was extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue thereby obtained was washed with cold n-hexane to obtain 6.9 g (yield: 70.4%) of the desired compound as white feather-like crystals. Melting point: 117°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:7]=1.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:19][CH2:18]2)[N:7]=1
Reactant: O=c1c2ccccc2c(Cc2ccc(Cl)c(Cl)c2)nn1C1CCCNCC1
Reactant: ClCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1c2ccccc2c(Cc2ccc(Cl)c(Cl)c2)nn1C1CCCN(Cc2ccccc2)CC1

Procedure:
A solution of 3.28 grams (8.15 mmoles) of 4-(3,4-dichlorobenzyl)-2-(hexahydro-1H-azepin-4-yl)-1-(2H)-phthalazinone, 3.4 ml (29.5 mmol) of benzyl chloride and 9 ml (64.6 mmol) of triethylamine in 20 ml of dioxane were heated for 12 hours at 200° C.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=O.[NH2:24][OH:25].Cl>>[CH:1](=[N:24][OH:25])[C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: NO
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Agent: Cl
Product: ON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Yield: 76.1 %

Procedure:
was synthesized as described in Example 22 using (62) (150 mg, 0.50 mmol) instead of (55) and NH2OH.HCl (100 mg, 1.5 mmol). The reaction gave (63) (120 mg, 76%).Mp. 220-221° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][NH:5][CH:6]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([N:5]2[CH:6]=[C:2]([Br:1])[C:3]([C:7]#[N:8])=[N:4]2)=[CH:15][CH:14]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: N#Cc1n[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(Br)c(C#N)n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A suspension of 4-bromo-1H-pyrazole-3-carbonitrile (0.52 g), 4-fluoro-benzoic acid ethyl ester (0.56 g) and cesium carbonate (1.5 g) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 2 hours. After cooling to ambient temperature, this reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The organic layer was through an aminopropyl silica gel, and this filtrate was concentrated under reduced pressure. This obtained residue was washed with a mixed solvent of n-hexane/diethyl ether=5/1 to give the title compound (0.25 g).