Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:34][CH:33]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[CH:36]=[CH:37][N:32]=[CH:33][N:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: NC1(c2ccncn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.07 g, 0.173 mmol, 1.0 eq) and 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.023 g, 0.173 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.087 g, 0.861 mmol, 5.0 eq) and BOP reagent (0.114 g, 0.257 mmol, 1.5 eq). The reaction mixture was stirred at r.t. overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 3% MeOH/CHCl3 as eluent and further purified by prep HPLC. Yield: 0.040 g (44.45%). 1H NMR (400 MHz, CD3OD): δ 9.03 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.8 Hz, 1H), 8.04-7.94 (m, 2H), 7.91-7.83 (m, 2H), 7.72-7.64 (m, 2H), 7.57-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.34-7.24 (m, 2H), 2.96 (s, 3H), 2.37 (s, 3H), 1.90-1.81 (m, 2H), 1.57-1.49 (m, 2H). 19F NMR (376.51 MHz, CD3OD): δ −78.35 (TFA), −113.31. LCMS: (ES+) m/z=521.2 (M+H)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[N:2]1.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([N:29]2[CH2:30][CH2:31][N:26]([C:24]3[S:23][N:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:25]=3)[CH2:27][CH2:28]2)=[O:14])=[N:2]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccon1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 18.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl isoxazol-3-ylcarbamate (192 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 49.5 mg (18.8%) of the desired product as a solid.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]1([C:11]2[CH:12]=[CH:13][C:14]3[C:20](=[O:21])[C:19]4[CH:22]=[CH:23][C:24]([N+:26]([O-])=O)=[CH:25][C:18]=4[CH2:17][O:16][C:15]=3[CH:29]=2)[CH:10]=[N:9][N:8]=[N:7]1>C(O)C>[NH2:26][C:24]1[CH:23]=[CH:22][C:19]2[C:20](=[O:21])[C:14]3[CH:13]=[CH:12][C:11]([N:6]4[CH:10]=[N:9][N:8]=[N:7]4)=[CH:29][C:15]=3[O:16][CH2:17][C:18]=2[CH:25]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(-n3cnnn3)ccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)COc1cc(-n3cnnn3)ccc1C2=O

Procedure:
In accordance with general method Y, 1.50 g (6.66 mmol) of tin(II) chloride dihydrate are dissolved in 10 ml of ethanol, and 0.50 g (1.54 mmol) of (20) is added.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Product: Cc1cccc(C(=O)Cl)c1C

Procedure:
As described for Reference Example 26, 3.0 g of 2,3-dimethylbenzoic acid is reacted with 40 ml of thionyl chloride to give 3.2 g of the product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[NH:4][C@@H:5]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][C:16]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](B4OC(C)(C)C(C)(C)O4)[CH:23]=3)[C:17]=2[N:18]=1)=[O:7].[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62](=[O:77])[NH:63][C:64]3[CH:69]=[C:68]([O:70][C:71]([F:74])([F:73])[F:72])[C:67](Br)=[CH:66][C:65]=3[Cl:76])=[CH:58][N:57]=2)[C@H:52]([CH3:78])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62](=[O:77])[NH:63][C:64]3[CH:69]=[C:68]([O:70][C:71]([F:74])([F:73])[F:72])[C:67]([C:22]4[CH:23]=[C:24]5[C:19](=[CH:20][CH:21]=4)[C:17]4[N:18]=[C:14]([C@@H:9]6[CH2:10][C@H:11]([CH3:13])[CH2:12][N:8]6[C:6](=[O:7])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:42])[CH:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)[NH:15][C:16]=4[CH:26]=[CH:25]5)=[CH:66][C:65]=3[Cl:76])=[CH:58][N:57]=2)[C@H:52]([CH3:78])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)[nH]1)C1CCOCC1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)OC(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)ccc32)[nH]1)C1CCOCC1
Temperature: 90 °C
Yield: 92.4 %

Procedure:
To a mixture of [(S)-2-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-naphth[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (80 mg, 0.10 mmol; Preparation 23) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (85 mg, 0.14 mmol) dissolved in toluene (0.92 mL) and water (0.34 mL) was added potassium carbonate (103 mg, 0.75 mmol). The reaction mixture was sparged under nitrogen and Pd(dppf)Cl2 CH2Cl2 (7.0 mg, 0.009 mmol) was added and the reaction mixture was heated to 90° C. overnight, cooled to RT, filtered through a combined pad of Celite® and silica gel and washed with EtOAc. The filtrate was washed with water and brine to produce a brownish colored solid, which was purified by silica chromatography (12 g column, 5-100% EtOAc/hexanes) to produce the title intermediate (89 mg, 60% yield) as a light colored solid. (m/z): [M+H]+ calcd for C48H54ClF3N8O8 963.37 found 963.5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)c1
Yield: 79.4 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2,4-dimethoxyphenylboronic acid (171 mg, 0.94 mmol) were reacted. After purification the title compound (136 mg, 80% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=4.8 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.68 (ad, J=7.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.66 (s, 1H), 6.59 (ad, J=8.3 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 3H), 2.96 (m, 1H), 0.70(m, 4H). MS APCI, m/z=365.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:24][C:18]=4[N:17]=3)=[N:9]2)=[CH:5][CH:4]=1>[Fe].O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[C:10]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[CH:24][C:18]=4[N:17]=3)=[N:9]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Agent: [Fe]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(N)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Yield: 93.7 %

Procedure:
To a mixture of 2-[1-(4-methoxy-benzyl)-4-nitro-1H-pyrazol-3-yl]-5-morpholin-4-ylmethyl-1H-benzimidazole (1.6 g, 3.57 mmol), Fe powder (2 g, 35 mmol) and FeSO4.7H2O (0.496 g, 1.78 mmol) was added 1,4-dioxane:water (5:1, 120 ml). The mixture was refluxed for 3 h, filtered through celite, washing with MeOH, and reduced in vacuo azeotroping with toluene. EtOAc (100 ml) was added and insoluble material removed via filtration. The filtrate was reduced in vacuo to give 1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a dark brown solid (1.4 g, 94%). (LC/MS: Rt 1.72, [M+H]+ 419).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][C:37]([C:40]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[O:41])=[CH:36][CH:35]=4)=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>CO.O1CCOCC1>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:19]=[C:18]3[NH:29][N:30]=[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]5[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]5)=[O:41])=[CH:38][CH:39]=4)[C:17]3=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH:21]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccc(C(=O)N4CCCCC4)cc2)nn3C2CCCCO2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1ccc(/C=C/c2n[nH]c3nc(-c4ccc(O)cc4)cc(C(=O)N4CCNCC4)c23)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
To a solution of 4-[4-[6-(4-Hydroxy-phenyl)-3-{(E)-2-[4-(piperidine-1-carbonyl)phenyl]-vinyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.25 g, 0.35 mmol) in methanol (5 ml) was added 4N HCl in dioxane (0.9 ml). The reaction mixture was stirred at room temperature for 18 hours, diethyl ether was then added, the resulting precipitated was filtered and washed once with diethyl ether to afford the hydrochloride salt of the title compound (0.175 g, 82%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:11][C:10]([CH:12]3OCC[O:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccc(C3OCCO3)o2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: O=Cc1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.4 %

Procedure:
To a methanol (45 mL) solution of 2-(5-(4-fluoro-benzyl)-furan-2-yl)-[1,3]dioxolane (4.51 g, 18.2 mmol) described in Manufacturing Example 208-1-1 was added a solution (45 mL) of citric acid (12.2 g, 63.7 mmol), which was vigorously stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated sodium hydrogencarbonate aqueous solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.51 g, 51%). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C[O:10][C:11](=[O:15])[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C=O)C.CO>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:13][CH2:12][C:11]([OH:15])=[O:10])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)CCn1cc([N+](=O)[O-])cn1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
4-Nitro-1H-pyrazole (0.50 g, 4.4 mmol) was dissolved in DMF (5 mL). After addition of methyl-3-bromopropionate (0.72 mL, 1.5 eq) and potassium carbonate (0.92 g, 1.5 eq), the reaction mixture was stirred at 50° C. for 3 h, then partitioned between water and DCM. The aqueous phase was extracted with DCM, the combined organic phases dried over sodium sulfate and evaporated. The residue was hydrolyzed at rt over 30 min with lithium hydroxide (3M, aqueous) (4.4 mL, 3 eq) in methanol (5 mL) and the reaction mixture evaporated to dryness to afford 3-(4-nitro-1H-pyrazol-1-yl)propanoic acid in a quantitative yield.
Reaction SMILES: C([O:8][C:9](=[O:43])[C@@H:10]([NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)(=[O:32])=[O:31])=[O:23])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:20][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]2[S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=2)(=[O:32])=[O:31])=[O:23])[C:9]([OH:43])=[O:8])=[CH:17][CH:16]=1)[CH3:19]
Reactant: CC(=O)c1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(O)c1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Yield: 100 %

Procedure:
To 0.15 g (0.24 mmol) of (S)-3-(4-acetyl-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid benzyl ester in 30 ml of methanol was added 0.030 g of 10% palladium on carbon. The resulting suspension was stirred under 50 psi of hydrogen for 2 hours, after which the suspension was filtered and the filtrate was concentrated to provide 0.12 g (0.24 mmol) of the title compound which was used without further purification. The 300 MHz 1H NMR was consistent with the structure. LCMS (M+Na): m/z 551, retention time 3.05 min.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9]C.B(Br)(Br)Br>ClCCl>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([OH:9])[CH:4]=1
Reactant: COc1cc(N)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.6 %

Procedure:
To a stirred solution of 4-fluoro-3-methoxyaniline (4.80 g, 34 mmol) in dichloromethane (50 mL), at −10° C., was added a 4.0 M solution of boron tribromide in dichloromethane (20 mL, 80 mmol). The reaction mixture was allowed to warm to rt and stirring was continued for a further 15 h. The reaction mixture was quenched via the addition of methanol. After concentration under reduced pressure, the residue was taken up in water, basified with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford 5-amino-2-fluorophenol (4.00 g, 93%) as a solid which was taken on without further purification. 1H NMR (400 MHz, CDCl3) δ 6.87 (dd, J=9.2, 9.2 Hz, 1H), 6.35 (m, 1H), 6.16 (m, 1H), 5.09 (brs, 1H), 3.56 (brs, 2H); LC-MS (ESI) m/z 128 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]2)=[O:8])[CH:2]=1.S(Cl)(Cl)=O.N1C=C[CH:29]=[CH:28][CH:27]=1>>[CH3:27][CH:28]([O:20][C:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:13]=1)=[O:21])[CH3:29]
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25 ml round bottomed flask fitted with a magnetic stirrer bar, reflux condensor, and nitrogen inlet was added 1,6-dihydro-l-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylicacid (0.20 g, 0.70 mmol) and thionyl chloride (5.0 ml). The mixture was heated at reflux for 2 hours, cooled to room temperature, and concentrated. The residue was suspended in 2-propanol (5.0 ml) and 4-dimethylaminopyridine (1 mg). Pyridine (0.17 ml, 2.1 mmol) was added with stirring at room temperature. After 16 hours, the reaction mixture was concentrated. Purification via flash column chromotography (silica gel, 5% methanol/dichloromethane) and repurification via medium pressure liquid chromotography (silica gel, 5% methanol/dichloromethane) gave the desired product, MP: 160°-161 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:23][C:22](=[O:24])[N:21]=[CH:20][CH:19]=3)=[CH:11][C:10]=2[F:25])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][N:21]([CH2:32][C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:25])=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: O=c1nccc(OCCc2cnc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]1
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCCc3cnc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(F)c3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 6-{[2-(6-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-fluoro-3-pyridinyl)ethyl]oxy}-2 (1H)-pyrimidinone and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 524 [M+H]+; 3.36 min (ret time).
Reaction SMILES: C(N[NH:5][C:6]1(C(OCC)=O)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[NH:8][C:7]1=[O:18])(=O)C.[ClH:24]>>[ClH:24].[NH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:16][CH3:17])[NH:8][C:7]1=[O:18]
Reactant: CCOC(=O)C1(NNC(C)=O)Cc2c(cccc2OC)NC1=O
Agent: Cl
Product: COc1cccc2c1CC(N)C(=O)N2

Procedure:
A mixture of 3-acetamidoamino-3-carboethoxy-5-methoxy-3,4-dihydrocarbostyril (5.7 g) and 6 M aqueous hydrochloric acid (75 mL) was refluxed for 6 h. This mixture was evaporated to a solid which was triturated with acetonitrile. Filtration provided 3-amino-5-methoxy-3,4-dihydrocarbostyril hydrochloride (3.8 g, mp 301–302° C. with decomp.) as gray crystals. The free base, 3-amino-5-methoxy-3,4-dihydrocarbostyril, was prepared by ion exchange on an SCX column (United Chemical Technologies, CLEAN-UP Extraction Column, sorbent CUBCX1HL, Synthesis 1997, 553–558) by loading in methanol and eluting with methanol, followed by 2 M methanolic ammonia. The ammonia containing eluant was evaporated to provide 3-amino-5-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29].C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:28]=[O:29])=[CH:14][CH:15]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(c1ccccc1)c1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
2,2-Diphenylpropane (3.93 g; 20.0 mmol) and hexamethylenetetramine (2.80 g; 20.0 mmol) were added to trifluoroacetic acid (35 ml), and the mixture was refluxed for 16 hours. The mixture was brought to room temperature, and poured into ice/water, followed by stirring for 1 hour. The pH of the mixture was adjusted to about 9 with potassium carbonate, followed by extraction with ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 3.61 g of the target compound (yield: 80.5%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.ON1C2C=CC=CC=2N=N1.[CH3:31][C:32]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])[CH3:33]>C(#N)C.O1CCCC1.O1CCCC1>[C:1]([NH:11][C@H:12]([C:17]([NH:38][CH2:37][C:36]([O:35][C:32]([CH3:34])([CH3:33])[CH3:31])=[O:39])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cold solution of 5.00 g of carbobenzoxy-L-leucine, 2.55 g of 1-hydroxybenzotriazole hydrate and 2.47 g of glycine 1,1-dimethylethyl ester in 100 ml of 1:1 acetonitrile/tetrahydrofuran is added dropwise a solution of 3.89 g of N,N-dicyclohexylcarbodiimide in 40 ml of tetrahydrofuran. The solution is stirred overnight allowing the ice bath to melt. The mixture is filtered and the solvent removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, a 0.1M citric acid solution, a saturated sodium bicarbonate solution and then a saturated brine solution. After drying over magnesium sulfate, the solvent is removed under reduced pressure. The residue is chromatographed on silica gel eluting with 7:3 chloroform/ethyl acetate giving 6.68 g of an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O.C(O)CCC>C(Cl)(Cl)Cl.CCCCCC>[C:10]1([CH3:14])[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)[CH:9]=1
Reactant: NNC=O
Reactant: Cc1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 6.0 g of 3-chloro-6-(m-tolyl)pyridazine and 3.52 g of formylhydrazine in 100 ml. of n-butanol is refluxed for 48 hrs. and worked up as in Example 35 to give 2.0 g. of white crystals (from CHCl3 -hexane), m.p. 164°-166° C.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([O-:23])=[O:22].[Na+]>C(O)C.CCOC(C)=O.O>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([O:23][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])=[O:22]
Reactant: O=C([O-])c1c(F)cccc1F
Reactant: CCOC(=O)C(Br)C(=O)c1ccc(OC)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(OC(=O)c1c(F)cccc1F)C(=O)c1ccc(OC)cc1
Yield: 96.7 %

Procedure:
A solution of ethyl 2-bromo-3-(4-methoxyphenyl)-3-oxopropanoate (0.090 g, 0.3 mmol) and sodium 2,6-difluorobenzoate (0.054 g, 0.30 mmol) in ethanol (2 mL) was heated at 120° C. in the microwave for 10 minutes. The reaction mixture was diluted with EtOAc (25 mL) and water (25 mL). The organic phase was washed with water and brine, dried over MgSO4 and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-40% EtOAc in hexanes to afford 3-ethoxy-1-(4-methoxyphenyl)-1,3-dioxopropan-2-yl 2,6-difluorobenzoate (0.108 g, 0.29 mmol, 96%) as a clear film. 1H NMR (CDCl3) δ 1.27 (3H, t), 3.89 (3H, s), 4.30 (2H, m), 6.47 (1H, s), 6.97 (4H, m), 7.46 (1H, m), 8.06 (2H, d). LCMS (1) Rt: 2.26 min; m/z (ES+) 379.