Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1.C(O)(=[O:31])C>O>[O:31]=[C:2]1[NH:3][C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:7]1[CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Reactant: CC(=O)O
Solvent: O
Product: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)[nH]c1=O
Temperature: 150 °C

Procedure:
A mixture of methyl 2-(4-chloro-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate in acetic acid and water (4/1 v/v; 30 mL/mmol) is stirred at 150° C. until completion. The reaction mixture is concentrated under reduced pressure, dissolved in dichloromethane and purified by flash chromatography on silica gel using a linear gradient of ethyl acetate in heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([CH:26]3[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)=[O:25])=[C:16]2[N:15]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([CH:26]3[CH2:27][NH:28][CH2:29]3)=[O:25])=[C:16]2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12)C1CNC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To (R)-tert-butyl 3-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)azetidine-1-carboxylate (Example 46; 17 mg, 0.033 mmol), was added 0.5 mL 50% TFA solution in DCM and stirred at ambient temperature for 10 minutes. The reaction was concentrated, treated with ether, and filtered, giving the final product (TFA salt) as a fine beige powder (12 mg, 88% yield). MS (apci) m/z=415.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].C(N(CC)C1C=CC=CC=1)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)(Cl)Cl>[CH3:30][O:31][CH2:32][O:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1cc([N+](=O)[O-])c(CO)c(OC)c1OC
Reactant: COCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COCOCc1c([N+](=O)[O-])cc(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 2-hydroxymethyl-1-nitro-3,4,5-trimethoxybenzene (6.5 g, 26.7 mmol) and N,N-diethylaniline (9.96 g, 66.8 mmol) in dry chloroform (150 ml) was added dropwise chloromethylmethyl ether (4.28 g, 53.5 mmol) in an ice-bath. After stirring at room temperature overnight, the reaction mixture was washed successively with 1% hydrochloric acid, water, 10% sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent was removed by evaporation in vacuo and the residue was crystallized from hexane to give 7.62 g (99%) of 2-methoxymethoxymethyl-1-nitro-3,4,5-trimethoxybenzene, mp. 39-40 ° C. 1H-NMR (CDCl3): δ3.40 (3H, s, CH2OMe), 3.93 (6H, s, 2×OMe), 3.94 (3H, s, 1×OMe), 4.73 and 4.82 (each 2H, s, 2 ×CH2), 7.29 (1H, s, H-6). Analyses: Calculated for C12H17NO7 : C, 50.17; H, 5.59; N, 4.88. Found: C, 50.18; H, 5.92; N, 4.80.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]#[N:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1.[CH:24]1([C:29]([NH:31][NH2:32])=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CO>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:22]=[C:29]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[NH:31][N:32]=3)[C:9]=2[CH3:23])=[CH:6][CH:7]=1
Reactant: Cc1c(C#N)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NNC(=O)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: Cc1c(-c2n[nH]c(C3CCCC3)n2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (300 mg, 0.83 mmol), cyclopentanecarbohydrazide (116 mg, 0.90 mmol) and potassium carbonate (57 mg, 0.41 mmol) dissolved in 1-butanol (2 ml) was placed in a sealed tube, stirred at room temperature for 10 minutes and then refluxed at 150° C. for 1 day. The mixture was cooled down to room temperature and methanol (4 ml) was added thereto, followed by filtering. The filtrate was purified by reverse phase preparative HPLC, to obtain the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:21]=[C:20](I)[S:19][C:13]=3[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:21]=[C:20]([C:28]#[C:27][CH2:26][OH:29])[S:19][C:13]=3[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-2-iodo-7-isopropyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 26) (0.717 g) in diethylamine (20 mL) is added copper iodide (0.084 g) and Pd(PPh3)2Cl2 (0.052 g) followed by addition of propargyl alcohol (0.12 mL). The reaction is stirred at rt for 18 h. The diethylamine is removed in vacuo and the resulting brown solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield an orange solid which is recrystallized from ethanol then methanol to yield 0.281 g (46%) of the title compound as a yellow, crystalline solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])=[O:21]>N1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: COc1ccccc1OC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccncc1
Product: COc1ccccc1OC(=O)OC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and 2-methoxyphenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(2-methoxyphenoxycarbonyloxy)-2(1H)-pyrimidinone as the residue.
Reaction SMILES: Cl.[F:2][C:3]1([F:19])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:11][C:5]=2[O:4]1.CCN(CC)CC.C1([O:33][C:34](=O)[NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)C=CC=CC=1>CC#N>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:34]([N:15]2[CH2:16][CH2:17][CH2:18][CH:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:3]([F:2])([F:19])[O:4][C:5]=4[CH:11]=3)[CH2:14]2)=[O:33])[CH:37]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC1(F)Oc2ccc(CC3CCCNC3)cc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cccnc1)N1CCCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 35 °C
Yield: 94 %

Procedure:
To a solution of 3-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-piperidine hydrochloride (100 mg, 0.34 mmol) in CH3CN (2 mL) was added Et3N (0.07 mL, 0.52 mmol). To this reaction mixture, pyridin-3-yl-carbamic acid phenyl ester (77.0 mg, 1.05 mmol) was added and the reaction mixture was heated overnight at 35° C. The reaction mixture was then concentrated and the crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic acid pyridin-3-ylamide (120 mg, 93%). MS (ESI+): calcd for C19H19F2N3O3 m/z 375.14, found 376.2 (M+H)+. 1H NMR (d4-methanol): 8.54 (d, J=2.3, 1H), 8.17-8.13 (m, 1H), 7.86 (ddd, J=8.4, 2.6, 1.4, 1H), 7.34-7.30 (m, 1H), 7.10-7.06 (m, 2H), 6.99 (dd, J=8.2, 1.5, 1H), 4.05-3.95 (m, 2H), 3.04-2.98 (m, 1H), 2.74-2.64 (m, 2H), 2.58-2.53 (m, 1H), 1.86-1.74 (m, 3H), 1.56-1.47 (m, 1H), 1.30-1.22 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[O:19]=[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([CH3:1])[C:7](=[O:8])[NH:6][C:5]=2[CH:9]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C1CCC(=O)O1
Reactant: CC1Oc2ccccc2NC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1Oc2ccc(C(=O)CCC(=O)O)cc2NC1=O
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
3,4-Dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazine (11.4 g) and succinic anhydride (7 g) were added to 93 g of aluminum chloride and 15.3 ml of dimethylformamide. The mixture was stirred at 70° C. for 2.5 hours and then poured onto ice, giving a solid which was collected by filtration and washed with water. Drying under vacuum gave 16.5 g of the title compound (90% yield), mp 198°-200° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:14]([F:17])([F:16])[F:15])[O:7]2.[CH3:23]B1OB(C)OB(C)O1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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].O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:23])=[C:3]2[C:8]=1[O:7][CH:6]([C:14]([F:17])([F:16])[F:15])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4]2
Reactant: CCOC(=O)C1=Cc2c(Br)ccc(OC)c2OC1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2c(C)ccc(OC)c2OC1C(F)(F)F
Temperature: 110 °C
Yield: 74 %

Procedure:
The ethyl 5-bromo-8-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 24 a, Step 1 (2.3 g, 6.037 mmole), trimethylboroxine (0.84 mL, 6.04 mmole), PdCl2(dppf)2.CH2Cl2 (0.487 g, 0.604 mmole), and Cs2CO3 (5.9 g, 18.11 mmole) were mixed in dioxane with 10% water (15 mL). The mixture was heated to 110° C. for 6 hrs and r.t overnight. The mixture was diluted with EtOAc, the organic layer was washed with water and dried over MgSO4. The filtrate was concentrated and purified by Biotage chromatography with 5% EtOAc in hexane to give 1.41 g a yellow solid (74%): LCMS m/z 317.15 (M+H) at 6.225 min.
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:19](=[O:21])[CH3:20].[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28])[CH3:23].CCCCCC>C(Cl)Cl.O>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:12]=[CH:11][C:10]=1[C:19](=[O:21])[CH3:20])=[O:28])[CH3:23]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1N
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)Nc1cc(C(C)(C)C)ccc1C(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
160 μl (1.15 mol) NEt3 were added to a solution of 200 mg (1.0 mmol) 1-(2-amino-4-tert-butylphenyl)ethanone in DCM (20 ml) and the mixture was cooled to 0° C. 170 μl (1.4 mmol) 3-chloro-3-oxopropanoic acid ethyl ester were added at this temperature and the mixture was then stirred for 2 h at RT. Then it was diluted with water and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 19:1) of the residue yielded 190 mg (0.62 mmol, 60%) 3-(2-acetyl-5-tert-butyl-phenylamino)-3-oxopropanoic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[C:13](OC)(OC)([O:15][CH3:16])[CH3:14].C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[C:8](=[C:13](/[O:15][CH3:16])\[CH3:14])/[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: COC(C)(OC)OC
Solvent: CC(=O)OC(C)=O
Product: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution containing 55.8 g. (0.34 mole) of p-fluorobenzoylacetonitrile, 41 g. (0.34 mole) of trimethyl orthoacetate, and 90 g. (0.88 mole) of acetic anhydride is heated to reflux for 5 hours. The excess solvent and volatile by-products are then removed by vacuum distillation and the residue is recrystallized from diethyl ether. Alternatively, the distillation residue may be distilled over on a Kugelrohr apparatus at 160° C./0.25 mm. to provide a viscous oil which may be crystallized from diethyl ether to provide the pure title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1.Cl>[C:11]([O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:13])[CH3:12]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C)c(Br)c(C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 128.9 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (10.1 g, 50.0 mmol) in pyridine (13 mL) was added acetic anhydride (7.66 g, 38.6 mmol), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled, diluted with 0.5 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (12.1 g, yield 99%) as a yellow oil.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([N+:25]([O-])=O)=[CH:13][C:12]=1[F:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.[Zn]>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([NH2:25])=[CH:13][C:12]=1[F:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: Nc1cc(F)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
508 mg (9.5 mmol, 2 eq) of ammonium chloride, followed by 2.23 g (34.2 mmol, 7.2 eq) of zinc powder, are added to a solution of 1.68 g (4.75 mmol, 1 eq) of 1,5-bis(benzyloxy)-2-fluoro-4-nitrobenzene in 50 ml of water. The reaction medium is refluxed for 4 hours. The cooled reaction medium is extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel, elution being carried out with 85/15 heptane/ethyl acetate.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.Cl.[CH2:10]([N:17]1[C:25]2[C:24](=[O:26])[NH:23][C:22]([NH2:27])=[N:21][C:20]=2[N:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>C(O)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:24]([NH:23][C:22]1[NH:27][C:5](=[O:7])[C:6]2[N:17]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:18]=[N:19][C:20]=2[N:21]=1)(=[O:26])[CH3:25]
Reactant: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Yield: 95.7 %

Procedure:
Acetic anhydride (4.44 ml, 45.1 mmols) and 132.8 mg (0.598 mmols) of p-toluenesulfonic acid monohydrate were added to a solution of 4.37 g (13.9 mmols) of 7-benzylguanine dihydrochloride in 9 ml of acetic acid. The mixture was reacted at 105° C. for 3 hours, and then allowed to cool. Water (180 ml) was poured into the reaction solution, and 150 ml of a 5-% sodium hydrogencarbonate aqueous solution and 100 ml of a 1−N sodium hydroxide aqueous solution were added thereto to adjust the pH to 5.3. Crystals were filtered, washed with 50 ml of water, and then dried at 55° C. for 5 hours under reduced pressure to obtain 3.77 g (13.3 mmols) of N2-acetyl-7-benzylguanine as a white solid in a yield of 95.7%.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:32]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=4[F:40])=[C:23]([O:25]C4CCCCO4)[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:32]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=4[F:40])=[C:23]([OH:25])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OC3CCCCO3)c2)ncn1)C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(O)c2)ncn1)C1CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (163 mg) in methanol (1.5 mL) was added pyridinium p-toluenesulfonate (7.5 mg), and the mixture was stirred at 50° C. for 20 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (119 mg) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([O:12][CH3:13])[C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COc1c(F)ccc2ccc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1c(F)ccc2ccc(Cl)nc12
Yield: 90.5 %

Procedure:
A mixture of 7-fluoro-8-methoxy-2-quinolinol (4a) (2.26 g, 11.7 mmol) and POCl3 (5.5 mL, 60 mmol) was refluxed for 1.5 hours. The contents were concentrated and neutralized with NaHCO3 and the mixture heated with water and AcOEt. The solution was filtered to remove undissolved impurities, followed by extraction. The organic layer was washed with saturated NaCl and dried with MgSO4. The product was recrystalized from ***CHCl3-hexanes, which yielded white crystals (2.24 g, 90% yield): mp 85-86° C.; 1H NMR (400 MHz, CDCl3) 8.06 (d, J=8.8Hz, 1H) 7.48 (dd, J=8.8, 5.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.35 (dd, J=9.2, 2.4 Hz, 1H), 4.23 (d, J=2.4 Hz, 3H). 19F NMR (376 MHz, CHCl3) −127.35 (dd, J=10.9, 2.6 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CC(CCCCO)CCCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of 1.28 g (4 mmol) of methyl 8-hydroxy-2,2-dimethyl-4-[3-(3-pyridyl)propyl]octanoate in 20 mL methylene chloride at 0° C. is added 0.9 mL (6.5 mmol) triethylamine followed by 0.4 mL (5.2 mmol) methanesulfonyl chloride. After 1 hour, the reaction is diluted with methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase is dried, filtered and evaporated to give methyl 8-methanesulfonyloxy-2,2-dimethyl-4-[3-(3-pyridyl)propyl]-octanoate as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:23]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)n(C)n1
Yield: 60.9 %

Procedure:
In the same manner as in Example 55 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (98.0 mg, 0.632 mmol), tetrahydrofuran (5 mL), thionyl chloride (109 μL, 1.25 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (185 mg, 0.572 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (160 mg, 61%) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 24 h

Procedure:
Take 2-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (1.00 g, 3.11 mmol) up in MeOH (6 mL) and 1 N NaOH (6 mL) and stir for 24 hr. Add additional 1 N NaOH (6 mL) and stir for an additional 30 hr. Concentrate under reduced pressure. Neutralize the concentrate at 0° C. by the dropwise addition of 1 N HCl (12 mL). Collect the resulting precipitate and wash with water followed by Et2O. Dry the solid in a vac oven to afford the desired acid as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.60-7.67 (m, 1H) 7.68 (s, 2H) 7.70 (d, J=2.15 Hz, 1H) 7.89 (d, J=8.46 Hz, 1H) 8.24 (br. s., 1H) 12.83 (br. s., 1H) 13.23 (br. s., 1H); (M+H)+ 306.9.