Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(F)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(F)c1CBr
Temperature: 25 °C
Yield: 266.1 %

Procedure:
A solution of 3-fluoro-2-methyl-benzoic acid methyl ester (3.64 g, 21.67 mmol) in carbon tetrachloride (100 mL) was treated with N-bromosuccinimide (3.85 g, 21.63 mmol) and benzoyl peroxide (0.1 g). The reaction mixture was then heated at reflux temperature and after 3 h the heat was removed and it was stirred at room temperature over the weekend. The reaction was then filtered to remove the solids and concentrated in vacuo to yield a light yellow oil. The reaction was then repeated with the remaining 3-fluoro-2-methyl-benzoic acid methyl ester (6.1 g, 36.3 mmol) in carbon tetrachloride using N-bromosuccinimide (6.5 g, 36.5 mmol) and benzoyl peroxide (0.1 g) heating at reflux. The reaction mixture was then filtered and concentrated in vacuo. The two material from the two reactions was combined and purified by flash column chromatography (silica gel, 10% diethyl ether/hexanes) to afford 2-bromomethyl-3-fluoro-benzoic acid methyl ester (14.22 g, 99%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])#[N:2].[NH2:20][OH:21]>C(O)C>[NH2:2][C:1](=[N:20][OH:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:8]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl [(3-cyanobenzyl)(methyl)amino]acetate (9 g, 34.6 mmol) in ethanol (60 mL) under N2, was added hydroxylamine (6 g, 178.8 mmol) in one portion. After being stirred at RT for 12 h, the reaction mixture was concentrated under reduced pressure to afford a colorless oil. It was triturated in diisopropyl ether, affording the title product as a white solid that was filtrated and dried under vacuo (8.5 g, 84%). 1H NMR (DMSO-d6, 300 MHz) δ 9.57 (1H, s), 7.59 (1H, s), 7.52-7.53 (1H, m), 7.29-7.31 (2H, m), 5.75 (2H, s), 3.61 (2H, s), 3.15 (2H, s), 2.23 (3H, s), 1.41 (9H, s). LC/MS (Method A): 294.0 (M+H)+. HPLC (Method B) Rt 3.31 min (Purity: 97.5%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[O:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:19]([NH:26][CH:27](C)[CH2:28][O:29][C:30]1[CH:38]=[C:34]([C:35]([NH2:37])=[O:36])[C:33]([OH:39])=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)C>[C:35]([C:34]1[CH:38]=[C:30]([CH:31]=[CH:32][C:33]=1[OH:39])[O:29][CH2:28][CH2:27][N:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH:16]([OH:18])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:13][CH:12]=1)(=[O:36])[NH2:37]
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O

Procedure:
A solution of 14.3 g of 1-[2-(cyclopropyl-methoxy)ethyl]-4-(2,3-epoxypropoxy)-benzene (German Offenlegungsschrift No. 2,649,605) and 16.3 g of 5-[2-(benzylamino)propoxy]-salicylamide in 200 ml of isopropanol is refluxed for 18 hours. The reaction mixture is concentrated by evaporation to leave crude 1-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-2-propanol in the form of brown oil, which can be further processed without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][C:14]([C:28]3[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=3)=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=3)[N:16]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH2:39]([O:41][C:42]([N:44]=[C:45]=[O:46])=[O:43])[CH3:40].CO>C(Cl)(Cl)Cl>[CH2:39]([O:41][C:42]([NH:44][C:45]([N:13]1[C:14]([C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=2)=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:21][CH:22]=2)[N:16]=[C:12]1[C:5]1[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:46])=[O:43])[CH3:40]
Reactant: CCN(CC)c1ccc(-c2nc(-c3cc(OC)c(O)c(OC)c3)[nH]c2-c2ccc(N(CC)CC)cc2)cc1
Reactant: CCOC(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)NC(=O)n1c(-c2cc(OC)c(O)c(OC)c2)nc(-c2ccc(N(CC)CC)cc2)c1-c1ccc(N(CC)CC)cc1
Reaction time: 5 h
Yield: 61.3 %

Procedure:
In 20 ml of chloroform, 0.8 g of 2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis(4-diethylaminophenyl)imidazole obtained in Example 1 (2) was dissolved. Then, 0.7 g of ethoxycarbonyl isocyanate (mfd. by Aldrich Chemical Co. Inc.) was added to the resulting solution and the reaction was carried out at room temperature for 5 hours with stirring. After the reaction, 5 ml of methanol was added to the reaction solution to decompose excess ethoxycarbonyl isocyanate, followed by removal of the solvent by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: a mixed solvent of ethyl acetate and n-hexane) to give 0.6 g of green crystals of 1-(ethoxycarbonylaminocarbonyl)-2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis(4-diethylaminophenyl)imidazol having a m.p. of 60° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([CH2:13]O)[CH2:11][CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:35](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.N(C(OCC)=O)=NC(OCC)=O>C(#N)C.ClCCl>[NH2:35][CH2:13][C@@H:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9](=[O:15])[CH2:10][CH2:11]1
Reactant: O=C1CC[C@H](CO)N1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: NC[C@H]1CCC(=O)N1c1ccc(F)cc1
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a dichloromethane (10 mL)-acetonitrile (2.0 mL) solution of (R)-1-(4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-2-one (500 mg, 2.39 mmol) synthesized in Reference Synthesis Example 215, triphenylphosphine (753 mg, 2.87 mmol), di-tert-butyl iminodicarboxylate (626 mg, 2.87 mmol), and diethyl azodicarboxylate (40% toluene solution) (1.25 g, 2.87 mmol) were added at room temperature and the resultant mixture was stirred for 1 hour and 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and 4 M hydrogen chloride/1,4-dioxane solution (7.5 mL) was added to the obtained residue, followed by stirring the resultant mixture for 1 day. After completion of the reaction, water and ethyl acetate were added to the reaction solution and the resultant mixture was washed with ethyl acetate. Thereafter, 1 M sodium hydroxide aqueous solution was added to the water phase and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound (120 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[C:27]([O:31][C:32](=[O:54])[NH:33][CH:34](S(C1C=CC=CC=1)(=O)=O)[C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=1[S:43][CH3:44])([CH3:30])([CH3:29])[CH3:28]>O>[C:27]([O:31][C:32](=[O:54])[NH:33][CH:34]([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=1[S:43][CH3:44])[C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:12]=1[NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:19])([F:20])[F:3])[CH:6]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Sodium hydride (60% in mineral oil, 154 mg, 3.85 mmol) is added in portions to a mixture of 3-(3-trifluoromethyl-phenylamino)-cyclohex-2-enone (INTERMEDIATE 3; 960 mg, 3.76 mmol) and 2-methyltetrahydrofuran (8 mL). After 30 min [benzenesulfonyl-(4-cyano-2-methylsulfanyl-phenyl)-methyl]-carbamic acid tert-butyl ester (Step 1, 1.56 g, 3.73 mmol) is added and the mixture is stirred at room temperature for 50 min. Water and 2-methyltetrahydrofuran are added and the phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 2.13 g. ESI mass spectrum: [M+H]+=532; Retention time HPLC: 1.22 min (Z018_S04).
Reaction SMILES: [CH:1]([NH:5][C:6]([CH:8]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)[C:9]([CH3:17])([CH3:16])[CH2:10]OS(C)(=O)=O)=[O:7])([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[C@@H:1]([N:5]1[CH2:17][C:9]([CH3:16])([CH3:10])[C@@H:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=2)[C:6]1=[O:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@H](C)N1CC(C)(C)[C@@H](Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reaction time: 8 h

Procedure:
To a stirring solution comprised of a mixture of methanesulfonic acid 3-sec-butylcarbamoyl-3-(4-cyano-3-trifluoromethyl-phenoxy)-2,2-dimethyl-propyl ester diastereomers (1.89 g; 4.2 mmol) in tetrahydrofuran (10 mL) at ambient temperature under a nitrogen atmosphere is added a 60% sodium hydride mineral oil dispersion (0.34 g; 8.4 mmol) in portions. The reaction mixture is stirred overnight. The reaction mixture is carefully neutralized with saturated aqueous ammonium chloride and is extracted with ethyl acetate. The organic phase is washed with a brine solution and is dried over anhydrous magnesium sulfate. The organic solution is concentrated in vacuo to afford 1.47 g of a viscous residue comprised of two diastereomers; HPLC UV purity: 92% (two diastereomers.) The diastereomers are separated by flash silica column chromatography (Biotage Horizon chromatography system; 100 g of silica gel, Biotage 40+M silica cartridge.) Elution with a gradient (100% hexanes to 30% ethyl acetate over 3204 mL) will afford complete separation of the diastereomers: (3R,S)-(+)-4-(1-sec-Butyl-4,4-dimethyl-2-oxo-pyrrolidin-3-yloxy)-2-trifluoromethyl-benzonitrile. 0.365 g;; [α]58924° C.=+238° (in dichloromethane);microanalysis for C18H21F3N2O2: % C(calc/found) 61.01/60.81, % H 5.97/6.06, % N 7.91/7.66, % F 16.08/16.25.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].[O:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][NH2:34]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:25])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:34][CH2:33][C@H:29]2[CH2:30][CH2:31][CH2:32][O:28]2)=[O:19])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: NC[C@H]1CCCO1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC[C@H]2CCCO2)C1(C)C

Procedure:
The product from Example 173 and (R)-(tetrahydrofuran-2-yl)methanamine (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.24 (s, 3H), 1.26-1.52 (m, 5H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.74-1.89 (m, 3H), 1.95-2.08 (m, 1H), 2.62-2.83 (m, 4H), 2.91-2.99 (m, 1H), 3.22-3.33 (m, 2H), 3.56-3.84 (m, 2H), 7.58-7.62 (m, 1H), 8.50 (s, 1H). (ESI+) m/z 478 (M+H)+. Anal. calcd. for C26H43N3O3S: C, 65.37; H, 9.07; N, 8.80. Found: C, 65.39; H, 8.91; N, 8.66.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:13][F:14])([CH2:11][F:12])[CH:8]=[C:7]([C:15]([O:17]CC)=[O:16])[C:6]=2[CH:20]=1.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:13][F:14])([CH2:11][F:12])[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(Cl)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
A mixture of 0.07 g of ethyl 6-chloro-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate, 0.05 g of KOH and 3 ml of ethyl alcohol was stirred at room temperature for 1 hour. Ice water and conc. HCl was added to the reaction mixture and precipitated crystals were collected by filtration to obtain 0.05 g of 6-chloro-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylic acid with a melting point of 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][CH3:36])[CH2:30]1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:35]([CH:31]2[CH2:32][CH2:33][CH2:34][CH:29]([O:28][CH3:27])[CH2:30]2)[CH3:36])[N:3]=1
Reactant: CNC1CCCC(OC)C1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCCC(N(C)c2cc(C)c(C(=O)NCc3cccc(F)c3)c(Cl)n2)C1
Temperature: 110 °C
Yield: 71.1 %

Procedure:
To a solution of 1.19 g (3.8 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2) in DMF (12 ml) were added 1.05 g (7.6 mmol) K2CO3 and 683 mg (3.8 mmol) 3-methoxy-N-methylcyclohexanamine and the reaction mixture was heated at 110° C. for 16 h. The mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 850 mg (2.7 mmol, 32%) 2-chloro-N-(3-fluorobenzyl)-6-((3-methoxycyclohexyl)(methyl)amino)-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([OH:14])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2nc(O)ccc2c1
Temperature: 80 °C
Yield: 78.9 %

Procedure:
To a solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (0.46 g, 2.4 mmol) and NBS (0.53 g, 3.0 mmol) in CHCl3 (20 mL) was added benzoyl peroxide (cat. amount) at RT. The mixture was refluxed at 80° C. for 3 h. More NBS (0.25 g) was added and the reaction mixture was refluxed at 80° C. for 1 h. The solvent was evaporated and the residue was dissolved in EtOH. The solid was filtered, washed with EtOH and dried under vacuum to obtain 6-nitroquinolin-2-ol as a pale yellow solid (0.36 g, 79% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.71 (d, J=−2.0 Hz, 1H), 8.34 (dd, J=2.8, and 9.2 Hz, 1H), 8.14 (d, J=9.6 Hz, 1H), 7.44 (d, J=9.2 Hz, 1H), 6.68 (dd, J=1.6, and 9.6 Hz, 1H). LC-MS (EI) m/z: 191.0 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]4[C:18](=O)[CH2:19][CH2:20][O:21][C:15]4=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[CH3:23][O:24][NH2:25].Cl.CC([O-])=O.[K+]>CO>[CH3:23][O:24][N:25]=[C:18]1[C:16]2=[N:17][C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)=[CH:13][CH:14]=[C:15]2[O:21][CH2:20][CH2:19]1
Reactant: O=C1CCOc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C1CCOc2ccc(-c3cnn(-c4cccnc4)c3)nc21

Procedure:
6-[1-(3-Pyridyl)pyrazol-4-yl]-2,3-dihydropyrano[3,2-b]pyridin-4-one (120 mg, 0.41 mmol), CH3ONH2.HCl (38 mg, 0.82 mmol) and KOAc (81 mg, 0.82 mmol) were suspended in methanol (3 ml) under N2. The reaction mixture was refluxed overnight and purified by chromatography on silica (EtOAc) to get the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CCN(C(C)C)C(C)C.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([Si:24]([CH3:26])([CH3:25])[O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-chloro-2-hydroxy-benzaldehyde (9.3 g) in DMF (45 mL) was added DIPEA (20 mL) and tert-butyl-chloro-dimethyl-silane (19 g). The mixture was stirred at room temperature for 1.5 h. Then the mixture was poured into ice water (200 mL), extracted with ether (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4. The solvent was removed to give the title compound which was used directly for next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.CC[N:13]([CH:17]([CH3:19])[CH3:18])C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)CC1>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:13][CH:17]2[CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
2-Chloropyrimidine-4-carboxylic acid (0.516 g, 3.25 mmol) (Maybridge Chemicals, Maybridge, UK), DIPEA (0.94 mL, 5.42 mmol) and PyBop (1.69 g, 3.25 mmol) were weighed into a 150 mL RBF and dissolved in dioxane (15 mL). The solution was stirred at RT, then cooled to 0° C., and stirred for 5 min. Cyclopropylamine (0.38 mL, 5.42 mmol) was added, and the solution was stirred at 0° C. for 1 h. The mixture became solid. Additional dioxane was added (6 mL), the flask was removed from the ice bath and the contents were stirred at RT for 68 h. EtOAc was added and the mixture was washed with water (75 mL), 1 N NaOH (75 mL) and brine (75 mL). The crude material was purified by flash chromatography using an ISCO Combiflash Rf(25 g Thomson Single Step silica gel column; 20-100% EtOAc in hexanes) to afford 2-chloro-N-cyclopropylpyrimidine-4-carboxamide (0.139 g, 0.703 mmol, 25.9% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 197.9 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:37])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29]CC5C=CC=CC=5)=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[BrH:39]>C(O)(=O)C.CCOCC>[BrH:39].[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:37])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(OCc3ccccc3)cn2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(O)cn2)cc1
Yield: 62 %

Procedure:
To a stirred solution of N-cyclopropyl-4-methyl-3-{[4-(5-benzyloxypyridin-2-ylmethoxy)benzoyl]amino}benzamide (1.0 g, 1.97 mmol) in glacial acetic acid (10 mL) was added a solution of HBr (48% in acetic acid, 30 mL). After 6 hours at 25° C. the solution was diluted with ether (100 mL) and the resultant precipitate filtered off and dried to give the title compound as a pale yellow solid (610 mg, 62%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.84 (m, 1H), 5.36 (s, 2H), 7.18 (d, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.78-7.84 (m, 3H), 8.00 (d, 2H), 8.36 (m, 2H), 9.86 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5]1)(=O)C>Cl>[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Agent: Cl
Product: O=C(O)CCC1CCNCC1
Reaction time: 6 h
Yield: 99.1 %

Procedure:
In 208 ml of conc. hydrochloric acid, 99.63 g of 3-(1-acetyl-4-piperidinyl)propionic acid was suspended; the suspension was stirred under refluxing conditions for six hours. The reaction mixture was then concentrated to half under reduced pressure and allowed to stand at 0° C. overnight. The crystalline precipitate was collected by filtration and washed with cold ethanol. After drying, 77.9 g of 3-(4-piperidinyl)propionic acid was obtained. Of this product, 77.5 g was dissolved in a mixture of 360 ml of dichloromethane and 400 ml of 3N sodium hydroxide aqueous solution. To the mixture, 34 ml of methyl chlorocarbonate was added dropwise at 0° C., and stirred at room temperature for five hours. After the pH of the aqueous layer was adjusted to 8 by addition of a 50% sodium hydroxide aqueous solution, the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. To the residue, isopropyl ether-hexane was added to yield 76.5 g of the title compound as colorless crystals having a melting point of 88°-90° C.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6]O)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O>C(Cl)Cl>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6][Cl:15])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(C)C)c1CO
Solvent: ClCCl
Product: Cc1cccc(C(C)C)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 2-isopropyl-6-methylbenzylalcohol (1.7 g, 10.4 mmol) in methylene chloride (20 ml) was added thionyl chloride (1.7 g, 14 mmol) and the reaction was stirred for 1 h. at room temperature. The solvent was evaporated under reduced pressure and the residue was filrated through silica gel using methylenechloride as eluent. The solvent was evaporated under reduced pressure to give 1.83 g (96%) of the title compound as an oil.