Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][CH2:29][C:30]#[N:31]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH2:29][C:30]#[N:31])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (150 mg, 0.55 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (202 mg, 1.46 mmol) and 4-chlorobutyronitrile (152 mg, 1.46 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (71 mg, yield 29%).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1

Procedure:
In 3 mL of ethyl acetate was dissolved 0.25 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate, and 0.07 g of maleic acid was added thereto, after which the resulting mixture was heated to effect dissolution. The reaction mixture was cooled and the crystals precipitated were collected by filtration to obtain 0.15 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate maleate.
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH3:3].Br[C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:40]([S:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:22]2[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=[C:19]([C:13]4[S:14][C:10]([CH2:9][NH:8][CH2:7][CH2:6][CH2:5][O:4][CH:2]([CH3:3])[CH3:1])=[CH:11][CH:12]=4)[CH:20]=3)[NH:24][CH:23]=2)[CH2:36][CH2:35]1)(=[O:39])=[O:38])[CH3:41]
Reactant: CC(C)OCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCCOC(C)C)s4)cc23)CC1
Yield: 9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyl}amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid. The crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). After purification on an Agilent MDAP twice as shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, the impure title compound was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL) to give 7.6 mg of the title compound (9%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>CC(N(C)C)=O>[N+:17]([C:16]1[C:11]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Nc2ncccc2[N+](=O)[O-])nc1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a well stirred solution of 6-aminonicotinonitrile (0.631 g, 5.29 mmol) in dry DMA (10 ml), CS2CO3 (2.157 g, 6.62 mmol) and 2-chloro-3-nitropyridine (0.700 g, 4.415 mmol) were added and reaction mixture was heated at 80° C. under nitrogen atmosphere for 24 h. After completion the reaction mixture was cooled to room temperature, extracted with ethyl acetate (2×100 ml), combined organic layers washed with water (2×50 ml) and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield 543 mg of the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[C:26]([O:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH2:17][CH3:18])[CH:11]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc(O)cc(C)c1OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCc1ccccc1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a mixture of 6.3 g of 4-benzyloxy-3-ethyl-5-methylphenol, 3.2 g of triethylamine and 50 ml of chloroform was added dropwise 4.0 g of benzoyl chloride with stirring at 0° C. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure. To the residue was added 100 ml of 10% hydrochloric acid, which was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with 10% hydrochloric acid, aqueous sodium hydrogencarbonate solution and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, which afforded 8.4 g of crude 4-benzyloxy-3-ethyl-5-methylphenyl benzoate (yield, 93%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:31]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:25])=[O:24])=[CH:35][CH:34]=4)=[O:32])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2ccccn2)cc1
Reactant: Fc1ccc2nc(N3CCNCC3)oc2c1
Product: O=C(c1ccc(NS(=O)(=O)c2ccccn2)cc1)N1CCN(c2nc3ccc(F)cc3o2)CC1

Procedure:
Compound 13 is prepared using synthesis method 2 using intermediates 3a and 5c (yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:9]2)=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[C:3]([CH:23]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CCO1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CN(c2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CCO1
Reaction time: 1 h
Yield: 64.3 %

Procedure:
In methylene chloride (1.5 ml) was dissolved t-butyl [4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholin-2-yl]methylcarbamate (30 mg, 0.05 mmol). To the resulting solution were added anisole (30 μl) and trifluoroacetic acid (150 μl) at room temperature. The resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (3% methanol/chloroform→3% methanol, 3% t-butylamine/chloroform) to give the title compound (17 mg, 67%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C(O)=O)[CH3:25].C[Mg]Br.Cl>O1CCCC1.C(OCC)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: CCOC(=O)CC(=O)O
Agent: C[Mg]Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
To a suspension of 5-bromo-2-chloropyridine-3-carboxylic acid (Intermediate 11, 7.0 g, 29.7 mmol) in anhydrous tetrahydrofuran (70 mL), 1,1′-carbonylbis(1H-imidazole) (CDI) (5.8 g, 35.7 mmol) was added. The reaction mixture was heated to reflux for 2 h then cooled to room temperature and the crude solution was used in the next step with out further purification. A solution of 3-ethoxy-3-oxopropanoic acid (3.93 g, 29.7 mmol) in anhydrous tetrahydrofuran (80 mL) was cooled to 0° C. and methyl magnesium bromide in diethyl ether (16 mL, 3M solution) was added in drop wise manner. After stirring for 20 min at 0° C., the crude solution which was prepared from Intermediate 11 and CDI was added and the reaction was heated to 60° C. After heating for 16 h, the reaction mixture was cooled to room temperature and then poured into water. The pH was adjusted to 5 with concentrated hydrochloric acid solution, and the solution was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulphate and concentrated under reduce pressure to afford ethyl 3-(5-bromo-2-chloropyridin-3-yl)-3-oxopropanoate (5.0 g, 55%) as a reddish oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Br:13]Br.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Br:13][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: BrBr
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc2c(Br)c(F)ccc2n1

Procedure:
In step (1) of the reaction scheme, the known compound 6-fluoroquinaldine of Formula II is brominated with liquid bromine in the presence of aluminum chloride in a suitable solvent such as 1,2-dichoroethane. The reaction mixture is heated at reflux for several hours to provide the novel intermediate 5-bromo-6-fluoroquinaldine of Formula III.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:46][CH3:47])=[C:5]([CH:43]=[CH:44][CH:45]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@H:23]([O:34][NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:22]1[OH:42])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:48]([C:51]1[CH:56]=[C:55]([N+:57]([O-:59])=[O:58])[CH:54]=[CH:53][C:52]=1F)([O-:50])=[O:49]>CO>[CH3:1][O:2][C:3]1[C:4]([O:46][CH3:47])=[C:5]([CH:43]=[CH:44][CH:45]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@H:23]([O:34][N:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:52]2[CH:53]=[CH:54][C:55]([N+:57]([O-:59])=[O:58])=[CH:56][C:51]=2[N+:48]([O-:50])=[O:49])[C@@H:22]1[OH:42])([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCCCCNO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CO
Product: CCCCCCN(O[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(=O)[nH]c1=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
5′-O-(dimethoxytrityl)-2′-O-(hexylamino)uridine (0.88 grams, 1.37 mmol) was dissolved in methanol (20 mL). 2,4-Dinitrofluorobenzene (DNFB, 0.25 grams, 1.37 mmol) was added and the mixture shaken on a mechanical shaker. The reaction was monitored by TLC. After 90 minutes, another 0.25 grams of DNFB was added and the reaction mixture shaken an additional 30 minutes, followed by addition of another 0.25 grams of DNFB. After shaking 2.5 hours, the mixture was concentrated in vacuo and chromatographed on a silica gel column, eluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate. The desired product (0.51 grams, 46%) eluted with 100% ethyl acetate (Rf 0.85 by TLC).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([NH2:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15](OCC)(OCC)OCC.OS(O)(=O)=O>C1COCC1>[CH3:7][O:6][C:4]([C:3]1[C:2]([NH2:1])=[C:11]([F:12])[C:10]2[N:13]=[CH:15][NH:14][C:9]=2[CH:8]=1)=[O:5]
Reactant: COC(=O)c1cc(N)c(N)c(F)c1N
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]cnc2c(F)c1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a stirred solution of methyl 2,4,5-triamino-3-fluorobenzoate (9) (7.58 g, 38.1 mmol) in THF (152 mL, 20 vol) was added triethyl orthoformate (20.3 g, 22.8 mL, 137.0 mmol), followed by dropwise addition of H2SO4 (9.33 g, 18 M, 94.1 mmol). The mixture was then heated at 60° C. for 6 hours, at which point no starting material was detected by HPLC analysis. The solid product was filtered and rinsed with THF (150 mL, 20 vol), then transferred to a reaction vessel, suspended in water (150 mL) and the resulting mixture was neutralized to about pH 7.5 with 2 N NaOH. After stirring for 30 minutes, the suspension was filtered and the solid product was dried in a vacuum oven at 55° C., overnight to provide 6-amino-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (12) 7.5 g, 94% yield (100% area by HPLC). 1H NMR (400 Hz, d6 DMSO) δ 3.53 (1H, br s, NH), 3.85, (3H, s, OMe), 6.10 (2H, br s, NH2), 7.90 (1H, s, Ar—H), 7.20 (1H, s, Ar—H). MS APCI (+) m/z 210 (M+1) detected with MS APCI (+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16]>CS(C)=O>[NH2:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH:21][CH2:20][CH2:19][NH:18][C:15](=[O:17])[CH3:16])[CH:3]=1
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(=O)NCCN
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(N)nc(-c2ccccc2)n1
Temperature: 130 °C
Yield: 66 %

Procedure:
6-Chloro-2-phenylpyrimidin-4-amine (2.87 g) was dissolved in DMSO (50 ml) and N-acetylethylenediamine (14.28 g) added. The stirred solution was heated at 130° C. for 8 hrs then partitioned between ethyl acetate (500 ml) and saturated brine solution (400 ml). The organic phase was dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by flash chromatography on silica gel eluting with first ethyl acetate then a mixture of ethyl acetate and methanol (9:1 then 8:2 v/v) yielded the title compound (2.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34](O)[C:35]#[CH:36].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=2[C:14]([O:16][CH2:36][C:35]#[CH:34])=[O:15])[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1
Reactant: C#CCO
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOC(=O)c1c(F)cccc1Oc1nc(OC)cc(OC)n1
Yield: 53.1 %

Procedure:
2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoic acid (3.0 g) and carbonyldiimidazole (1.8 g) was dissolved in tetrahydrofuran (50 ml), and the solution was refluxed under heating for one hour. The reaction solution was cooled. Then, propargyl alcohol (2.0 g) and potassium carbonate (1.7 g) were added thereto, and the mixture was refluxed under heating for one hour. The mixture was poured into water and extracted with ethyl ether. The extract was washed with water and dried. Then, the solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography to obtain propargyl 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoate (1.8 g). Yield: 53%, white crystals, Melting point: 49°-50° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:22])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=2)[C:3]([OH:23])=[O:2])=[O:22])=[C:15]([Cl:21])[CH:16]=1
Reactant: COC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(COc1ccc(Br)cc1Cl)Nc1cc(C(=O)O)ccn1
Yield: 24.9 %

Procedure:
A solution of 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester (50 mg, 0.125 mmol) and lithium Iodide (189 mg, 1.25 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resultant crude product was purified by HPLC (MeOH/MC=10%) to afford 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]-isonicotinic acid as a colorless solid (0.012 g, 25% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2
Reactant: COC(=O)c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CCC2(C)C
Reactant: c1ccsc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 329.0 mg (3.93 mmol) of thiophene in 2.0 mL THF at 0° C. was added 251.8 mg (3.93 mmol, 1.56 mL of 2.5M solution in hexanes) of n-butyllithium. After stirring for 3 h at 0° C., a solution of 845.0 mg (6.28 mmol) of ZnCl2 in 5.0 mL THF was added and the resulting solution stirred for 30 minutes. This solution was added to a second flask containing 570.0 mg (1.57 mmol) of methyl 5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate (Compound E4) and 76.0 mg (0.063 mmol) of tetrakis(triphenylphosphine)palladium(O) in 4.0 mL THF, and the resulting solution was heated to 50° C. for 3 h. Upon cooling to room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl. Extraction with EtOAc was followed by washing of the combined organic layers with H2O and saturated aqueous NaCl, and drying over MgSO4. The dry solution was concentrated under reduced pressure and the title compound was isolated from the residue as a yellow oil by column chromatography (5-10% EtOAc/hexanes).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[O:27]([NH2:29])[CH3:28]>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([NH:29][O:27][CH3:28])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Product: CONC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with Methoxylamine hydrochloride (9.8 mg, 0.12 mmol) in THF to provide 168. LC/MS (ESI+): m/z 369 (M+H). 1H NMR (400 MHz, DMSO) δ 8.45 (t, J=16.8, 1H), 7.95 (d, J=26.9, 2H), 7.49 (dd, J=20.1, 18.6, 2H), 5.86 (dt, J=13.1, 6.4, 1H), 4.56 (d, J=2.8, 4H), 3.72 (s, 2H), 1.61-1.32 (m, 5H)
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[C:26]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=N[CH:28]=[CH:29][N:30]=2)[CH2:20][CH2:19]1>C(Cl)Cl>[NH:34]1[CH2:33][CH2:32][CH:31]([C:26]2[C:25]([O:24][CH:21]3[CH2:20][CH2:19][N:18]([C:9]4[CH:10]=[CH:11][C:16]5[C:17](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:8]=4)[CH2:23][CH2:22]3)=[N:30][CH:29]=[CH:28][CH:2]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc(OC2CCN(c3ccc4ccccc4n3)CC2)c(C2CCNCC2)c1
Temperature: 25 °C
Yield: 27 %

Procedure:
Trifluoroacetic acid (0.272 mL, 3.53 mmol) was added to a solution of tert-butyl 4-(3-(1-(quinolin-2-yl)piperidin-4-yloxy)pyrazin-2-yl)piperidine-1-carboxylate (1726 mg, 3.53 mmol) in DCM (2 mL) and stirred at RT until the starting material was completely consumed. The mixture was then diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The brown solid was triturated with acetone and dried to give the title compound as a white solid (370 mg, 27% yield). [M+1] 390.2. IC50 (uM) 0.05444.1H NMR (CDCl3, 400 MHz) δ (ppm): 1.53-1.69 (m, 1H) 1.86-2.00 (m, 2H) 2.12-2.34 (m, 6H) 3.03-3.14 (m, 2H) 3.23-3.32 (m, 1H) 3.53-3.71 (m, 4H) 4.13-4.22 (m, 2H) 5.35-5.43 (m, 1H) 7.06 (d, J=9.19 Hz, 1H) 7.20-7.26 (m, 1H) 7.52-7.59 (m, 1H) 7.62 (d, J=7.82 Hz, 1H) 7.67-7.82 (m, 1H) 7.89-7.95 (m, 1H) 7.97 (d, J=2.74 Hz, 1H) 8.06 (d, J=2.74 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13](=O)[CH3:14])[C:10](=O)[CH3:11])=[CH:5][CH:4]=1.Cl.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:13]([CH3:14])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]([CH3:11])=[N:32]2)=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C(C(C)=O)C(C)=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(C)nn(-c3ccc(OCc4ccccc4)cc3)c2C)cc1
Yield: 61.8 %

Procedure:
A solution of 3-(4-methoxyphenyl)pentane-2,4-dione (50 mg, 0.24 mmol, prepared according to Ghosh et al, Bioorg. Med. Chem. 2003, 11, 629) and (4-benzyloxyphenyl)hydrazine hydrochloride (61 mg, 0.24 mmol) in ethanol (3 mL) was heated at 80° C. overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1 N HCl (2×) and saturated sodium bicarbonate (1×), dried (MgSO4), and concentrated to give 57 mg of the crude pyrazole. LC-MS (C25H24N2O2 calculated 384) m/z 385 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl([F:16])(=O)(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1([F:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1
Product: CCOC(=O)C1(F)CCCCC1

Procedure:
By the procedure of Example 13, cyclohexane carboxylic acid ethyl ester was fluorinated with perchlorylfluoride to yield 1-fluorocyclohexanecarboxylic acid ethyl ester.