Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:10]2=[N:11][CH:12]=1.[NH3:40]>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]4[C:23]([CH3:29])([CH3:28])[C:24](=[O:26])[NH:40][C:20]=4[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[F:39])[C:10]2=[N:11][CH:12]=1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3c(F)ccc(F)c3F)c3ncc(F)cc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4c(F)ccc(F)c4F)c4ncc(F)cc34)nnc21
Reaction time: 8 h
Yield: 70 %

Procedure:
15 ml of phosphoryl chloride were added to 1.50 g (3.149 mmol) of the compound from Example 82A, and the mixture was stirred overnight. The reaction mixture was then taken up in 222 ml of acetonitrile and, with ice cooling, stirred into 133 ml of concentrated ammonia solution (33% in water). The reaction mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. Ethanol and water were added to the residue. A precipitate formed, which was filtered off and then washed with diethyl ether. Drying under high vacuum gave 982 mg of the title compound (70% of theory).
Reaction SMILES: [F:1]C(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40]([CH:52]2[CH2:57]CCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:36]1[CH:35]=[C:34]([CH2:40][CH2:52][CH2:57][N:24]2[CH2:25][C@@H:26]3[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]3[CH2:23]2)[CH:39]=[CH:38][CH:37]=1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCc3cccc(F)c3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-(3-fluorophenyl)propanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.52 (s, 1H), 7.69-7.61 (m, 2H), 7.33 (t, J=7.5, 2H), 7.27 (ddd, J=3.5, 7.6, 10.6, 2H), 7.14-6.95 (m, 3H), 4.43-4.29 (m, 1H), 3.23 (d, J=10.4, 1H), 2.97 (dd, J=2.2, 8.8, 0.5H), 2.72-2.58 (m, 3H), 2.57-2.44 (m, 1H), 2.44-2.38 (m, 0.5H), 2.36-2.26 (m, 3H), 2.25-2.16 (m, 1H), 2.16-2.09 (m, 1H), 1.93-1.83 (m, 1H), 1.77 (dt, J=7.2, 14.6, 1.5H), 1.72-1.63 (m, 1.5H), 1.47-1.27 (m, 2H), 1.22 (dd, J=6.5, 10.4, 3H), 0.94-0.83 (m, 1H), 0.71 (dd, J=2.7, 6.7, 3H); MS (ESI+) m/z 423 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C(=O)[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.[NH2:29][NH2:30].[C:31](=[O:34])([O-])O.[Na+]>CN(C=O)C>[CH2:20]([C:19]1[C:3]2[C:31](=[O:34])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:2]=2[NH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cc1ccccc1)c1c(O)c2cnccc2n(-c2ccccc2)c1=O
Reactant: O=C([O-])O
Reactant: NN
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cnccc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-phenylacetyl-1,6-naphthyridin-2(1H)-one (42 mg, 0.12 mmol) produced in Synthesis Example 12 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 19 μL), and the mixture was stirred at 100 to 110° C. overnight. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration and dried to give 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,6]naphthyridin-4(5H)-one as a form of crystal (11 mg, yield 25%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]3[S:11][CH:12]=[CH:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17](=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[O:25]=[C:17]([C:13]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=[CH:14][C:10]=2[S:11][CH:12]=1)[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: c1ccc(-c2ccc3sccc3c2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1csc2ccc(-c3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-phenylbenzo[b]thiophene (1.05 g, 5.0 mmol, 1 eq) in DCM (100 mL) at 0° C. was added ethyl 4-chloro-4-oxobutanoate (0.9 g, 21.4 mmol). The resulting mixture was stirred at 0° C. for 30 minutes. SnCl4 (2.3 mL, 6.0 mmol, 1.2 eq) was added and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous HCl solution (50 mL, 3 M) and extracted with diethyl ether. The combined organic layers were dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:16])[C:11]([CH:13]1[CH2:15][CH2:14]1)=O.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:16])=[C:11]([CH:13]3[CH2:15][CH2:14]3)[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Br)nn1
Reactant: CC(Br)C(=O)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C2CC2)nc2ccc(Br)nn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 6-bromopyridazin-3-amine (1.0 g) in DMA (10 ml) were added 2-bromo-1-cyclopropylpropan-1-one (2.04 g) and NaHCO3 (0.966 g) at room temperature, and the mixture was stirred at 80° C. for 16 h. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.10 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:29][C:30](=[O:31])[NH:22][NH:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:23])([F:1])[F:24])[CH:5]=3)[C:14]=2[CH:15]=1)=[O:20])(=[O:27])[CH3:26]
Reactant: CC(=O)OCC(=O)Cl
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Product: CC(=O)OCC(=O)NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Yield: 94 %

Procedure:
In the same manner as in Reference Example 61 and using 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide instead of ethyl 2-aminoisonicotinate and acetoxyacetyl chloride instead of 3-phenylpropanoyl chloride, the title compound (yield 94%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.Cl.[NH2:12][C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.O.CCOC(C)=O>[Cl:33][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C@@H:13]([NH:12][C:8]([C:5]3[S:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=3)=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COc1ncc(C(=O)O)s1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 2-methoxythiazole-5-carboxylic acid (80 mg, 0.50 mmol) and (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (160 mg, 0.45 mmol) in DMF (5 mL) is added HATU (207 mg, 0.55 mmol) and TEA (276 mg, 2.73 mmol). The crude is stirred at room temperature for 2 hrs. The crude is neutralized with 1 N HCl and diluted in water and EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5-carboxamido)butanoate (170 mg). HPLC retention time=1.97 minutes (condition D); MS (m+1)=459.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3H) 2.49-2.69 (m, 2H) 2.93 (dd, J=13.6, 8.1 Hz, 1H) 3.10 (dd, J=13.5, 6.2 Hz, 1H) 4.09 (s, 3H) 4.00-4.15 (m, 2H) 4.53-4.69 (m, 1H) 6.78 (d, J=8.6 Hz, 1H) 7.25-7.32 (m, 3H) 7.35 (t, J=7.71 Hz, 1H) 7.44 (dt, J=7.6, 1.5 Hz, 1H) 7.48-7.54 (m, 3H) 7.55 (t, J=1.8 Hz, 1H).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:29])[C:16]3[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:20][N:19]([CH3:28])[C:17]=3[N:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1.Cl[C:33]([O:35][CH2:36][CH2:37]Cl)=[O:34].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH:22]1([C:21]2[C:16]3[C:15](=[O:29])[NH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:6]5[CH2:37][CH2:36][O:35][C:33]5=[O:34])=[CH:8][C:9]=4[O:30][CH3:31])=[N:18][C:17]=3[N:19]([CH3:28])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)OCCCl
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N2CCOC2=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.5 %

Procedure:
To a 6 ml tetrahydrofuran solution of 150 mg (0.425 mmol) of the compound obtained in Example 44, 79 μl (0.765 mmol) of 2-chloroethyl chloroformate and triethylamine were added, and the mixture was stirred at room temperature for 20 hours. Further, 30 μl (0.29 mmol) of 2-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 4 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. To a 2 ml ethanol solution of the residue, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid, and extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 116 mg (65%) of the captioned compound.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O>C(O)C.ClCCl.[Pt](=O)=O>[NH2:1][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCO
Product: Nc1c(O)cccc1O
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A suspension of 2-nitroresorcinol (4.995 g) and platinum (IV) oxide (356 mg) in ethanol (90 ml) was hydrogenated, at room temperature, at 100 p.s.i. for 4 hours. The reaction mixture was filtered through celite, the filter cake washed with methanol (50 ml), and the combined filtrate evaporated in-vacuo to yield a brown solid. The solid was suspended in dichloromethane (100 ml) and evaporated to dryness to yield the title compound (3.83 g, 95%) as a brown solid. δH (250 Mhz; d6DMSO) 3.85 (2H,br s,NH2), 6.20 (3H,m,ArH), 8.85 (2H,br s,ArOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1(C)[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.N1C=CC=C[CH:23]=1>>[C:13]1([CH3:23])[CH:12]=[CH:11][CH:16]=[CH:15][C:14]=1[S:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])(=[O:18])=[O:19]
Reactant: c1ccncc1
Reactant: CC(=O)c1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccccc1NS(=O)(=O)c1ccccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
25 g of o-aminoacetophenone and 40 g of p-toluene sulfonyl chloride are together dissolved in 150 ml of pyridine and are left to stand at 50°-60° for one hour. The reaction mixture is then added to 1 liter of a stirred ice-water mixture and extracted with methylene chloride after half an hour.
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:39]=[C:38](N)[S:37][N:36]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.O>O1CCCC1>[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:39]=[CH:38][S:37][N:36]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1nsc(N)n1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1ncsn1
Yield: 73.4 %

Procedure:
A solution of t-butyl nitrite (3.2 g) in tetrahydrofuran (20 ml) was added dropwise to a solution of benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (10 g) in tetrahydrofuran (100 ml) at 50° to 53° C. under stirring, and the mixture was stirred at the same temperature for 25 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with an aqueous sodium chloride and dried over magnesium sulfate. The solution was evaporated and the residue was subjected to column chromatography on silica gel. The elution was carried out with a mixture of benzene and ethyl acetate (19:1) and the eluates containing the object compound were evaporated to give benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetate (syn isomer) (7.1 g), mp. 139° to 141° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:12][CH3:13])=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[F:11][C:8]1[C:5]([C:6]#[N:7])=[C:4]([O:12][CH3:13])[C:3]([CH:1]2[CH2:2][O:22]2)=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(F)c(C#N)c1OC
Solvent: ClCCl
Product: COc1c(C2CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Ethenyl-6-fluoro-2-methoxybenzonitrile (1.67 g, 9.43 mmol) was added to DCM (50 mL) at 0° C. then mCPBA (4.88 g, 28.3 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was washed with saturated aqueous Na2S2O3, then with 1N NaOH followed by brine. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by chromatography through a 120 g. Redi-sep column and eluting with a 0-100% EtOAc/hexane solvent system. Isolated pure 6-fluoro-2-methoxy-3-(oxiran-2-yl)benzonitrile.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCC.CCOC(C)=O>[C:20]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
To a solution of methyl 3,4-methylenedioxyphenylacetate (150 mg, 0.77 mmol) in CH2Cl2 (5 mL) was added SnCl4 (1.0M solution in CH2Cl2 ; 1.5 mL, 1.5 mmol) at 0° C. Then benzoyl chloride (130 μL, 1.1 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature. After 24 h, the mixture was added to a saturated NaHCO3 solution (30 mL), diluted with 1:1 hexane/EtOAc (60 mL), washed with water and brine, and dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was separated by chromatography on silica gel (4:1 hexane/EtOAc) to yield the title compound (110 mg, 48%). 1H NMR (CDCl3) 7.78-7.45 (m, 5H), 6.88 (s, 1H), 6.84 (s, 1H), 6.04 (s, 2H), 3.80 (s, 2H), 3.61 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:36]([NH:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:37])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=C=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), phenyl isocyanate (0.00519 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (CD3OD, 400 MHz): δ=1.90 (d, J=6.8 Hz, 3H), 2.58 (br. s., 2H), 3.77 (t, J=5.7 Hz, 2H), 4.25 (d, J=2.5 Hz, 2H), 6.32 (br. s., 1H), 6.52 (d, J=6.8 Hz, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.17-7.32 (m, 3H), 7.34-7.46 (m, 3H) 7.69 (s, 1H), 8.23 (s, 1H). MS (ES+): m/z 541.03/543.05 (100/68) [MH+]. HPLC: tR=3.39 min (ZQ3, polar—5 min).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].O>CN(C)C(=O)C>[F:28][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([CH:29]=[C:3]([NH:2][C:30](=[O:33])[CH2:31][CH3:32])[N:4]=3)[N:7]=2)=[CH:17][C:16]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=1)=[O:20]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cn2nc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) in N,N-dimethylacetamide (2.0 mL) was added propionyl chloride (49.9 μL, 0.57 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) and washed with ethyl acetate to give the title compound (78 mg, 37%) as a white powder.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5](I)[S:4][C:3]=1[CH:9]1[O:13]CCO1.C[O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[OH:15][C:16]1[CH:17]=[C:18]([C:2]2[C:6]([CH3:7])=[C:5]([C:30]3[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=3)[S:4][C:3]=2[CH:9]=[O:13])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(I)sc(C2OCCO2)c1Br
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cccc(B(O)O)c1
Product: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1cccc(O)c1
Yield: 85 %

Procedure:
Starting from 2-(3-bromo-5-iodo-4-methylthien-2-yl)-1,3-dioxolane (9.3 g, 25 mmol) and substituting 3-methoxyphenylboronic acid (4.1 g, 27 mmol) in place of 4-methoxyphenylboronic acid (Example 1, Step 1) and substituting 4-methoxyphenylboronic acid in place of 3-methoxyphenylboronic acid (Example 1, Step 2), the title compound (0.40 g, 85%, m.p. 208-10° C.) was synthesized in essentially the same manner as described in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([NH:55][C:56]2[N:57]=[CH:58][C:59]3[CH2:65][NH:64][CH2:63][CH2:62][C:60]=3[N:61]=2)[CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52]>CN(C=O)C.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:64]1[CH2:63][CH2:62][C:60]2[N:61]=[C:56]([NH:55][C:47]3[CH:46]=[C:45]([O:44][CH3:43])[C:50]([O:51][CH3:52])=[C:49]([O:53][CH3:54])[CH:48]=3)[N:57]=[CH:58][C:59]=2[CH2:65]1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2ccccn2)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-picolinic acid (40.6 mg, 0.33 mmol), N, N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (125 mg, 0.33 mmol) in DMF (2.0 mL) was stirred at room temperature for 5 minutes, then N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (94.8 mg, 0.30 mmol; see Syntheses of Starting Materials section for prep) added and the reaction continued for 1.5 hours at rt. The reaction mixture was treated with an EtOAc/aqueous Na2CO3(aq) solution work-up to give an orange oil. The oil was chromatographed eluting with 5% MeOH in 1:1 EtOAc/CHCl3 giving an off-white solid (107 mg, 85%).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.C1(OC[CH2:21][CH:22]([OH:25])[CH2:23][OH:24])CCCCC1.CO[CH:28](OC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:2]1([CH:12]2[O:25][CH:22]([CH2:21][CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:23][O:24]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(O)CCOC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(C2OCC(CCC3CCCCC3)O2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 965.2 %

Procedure:
43 mg (0.23 mmol) of p-toluenesulfonic acid monohydrate were added, whilst ice-cooling, to a solution of 473 mg (2.51 mmol) of 4-cyclohexyloxy-2-hydroxybutyl alcohol [prepared as described in step above] and 1.14 ml (7.56 mmol) of benzaldehyde dimethyl acetal in 10 ml of methylene chloride, and the resulting mixture was stirred for 2.5 hours at room temperature. In order to stop the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, which was then extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 1:9 by volume mixture of diethyl ether and methylene chloride as the eluent, to give 578 mg (yield 83%) of the title 1.3-dioxolane derivative as an oil.