Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCc1ccc(O)cc1
Reactant: BrCC1CCCCC1
Product: OCc1ccc(OCC2CCCCC2)cc1

Procedure:
3-3 was prepared as described for the synthesis of 1-6 except 4-hydroxy-benzyl alcohol (3-1) and cyclohexylmethyl bromide (3-2) were used in Step A to yield 4-(cyclohexylmethoxy)benzyl alcohol directly. mp: 241°-3° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C[O:24][B:25](OC)[O:26]C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[B:25]([OH:26])[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: COc1cccc(OCc2ccccc2)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(OCc2ccccc2)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a mixture of 1-(benzyloxy)-2-bromo-3-methoxybenzene (2.66 g, 9.07 mmol) in THF (20 mL) was added butyllithium (2.5 M in THF, 4 mL, 9.98 mmol) at −78° C. dropwise over 15 minutes. The mixture was stirred at −78° C. for 30 minutes, then trimethylborate (4.0 mL, 36.3 mmol) was added. The mixture was allowed to warm to RT and stirred overnight. The mixture was quenched with 1 M aqueous HCl to pH 2 and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Heptane) to afford the desired product as a white solid (1.07 g, 46% yield). MS (M+1)=259.4.
Reaction SMILES: [OH-:1].[Na+].C([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])(C)(C)C>C(O)C>[CH2:8]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:32])[CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])[CH2:10][CH2:11][CH3:12]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCOC(=O)c1ccccc1-c1ccc(Cn2c(CCCC)nc(C(O)C(C)C)c2C(N)=O)cc1

Procedure:
20 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 297 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2-methylpropyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 20 ml of ethanol, and the resulting mixture was heated under reflux for 8 hours. An the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 151 mg of the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCO
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)CS1
Yield: 52.2 %

Procedure:
To a solution of (1R,2R)-2-aminocyclohexanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.17 g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (971 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26](S(C5C=CC=CC=5)(=O)=O)[CH:27]=[CH:28][C:21]=34)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[NH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.[OH-].[Na+].Cl>CC(O)C>[N:47]1([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]5[NH:26][CH:27]=[CH:28][C:21]=45)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2ccnc3[nH]ccc23)cc2[nH]ncc12)c1csc(CN2CCCCC2)n1
Temperature: 90 °C
Reaction time: 29 h

Procedure:
2-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (40 mg) and piperidine (0.5 ml) were added to a microwave vial then heated in the microwave for 15 min at 90° C. The solvent was blown off under nitrogen. IPA (3 ml) and 2M NaOH (aq) (2 ml) were added and the reaction mixture was stirred for 29 h. The reaction was heated to 50° C. for 5 min then cooled to RT for stirring overnight. The mixture was neutralised to pH 7 with 2M HCl (aq.) and the solvent was removed under a stream of nitrogen. The resultant solid was dissolved in DMSO (2 ml), filtered and purified by MDAP (method K). The fractions were combined and solvent was removed under nitrogen. The residue was dissolved in water:1,4-dioxane (1:1) then freeze-dried to give title compound, as an orange solid, 15 mg.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH2:30][F:31])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH2:30][F:31])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OCF
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OCF
Yield: 65.7 %

Procedure:
37.4 mg of N-iodosuccinimide was added little by little to a solution containing 47.8 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine obtained in Example 111 and 4.0 ml of N,N-dimethylformamide under stirring in an ice-bath, followed by stirring overnight as it was. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was successively washed with an aqueous sodium thiosulfate solution, water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 43.9 mg of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:34])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([I:34])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nc(I)c2cc(Br)ccc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (1.0 g, 3.37 mmol) was dissolved in dry dichloromethane (30 mL) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (3.5 g, 6.754 mmol) was added in one portion as a solid. The solution was protected from light and permitted to stir overnight at room temperature. Upon completion, the reaction was quenched by addition of aqueous sodium thiosulfate (2.0 g in 50 mL of water. The layers were separated and the organic phase washed with 1M hydrochloric acid, brine and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (3-15% ethyl acetate in hexanes) to provide the iodo-isoquinoline in 77% yield which was used immediately in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc2c([N+](=O)[O-])c(C)ccc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A stirred solution of 1-chloro-6-methyl-5-nitroisoquinoline (1.2 g, 5.4 mmol) and sodium methoxide (0.6 g, 95%, 11 mmol) in methanol (20 mL) in a sealed-tube was heated to 80° C. for 2 h, cooled to room temperature and partitioned between ethyl acetate (3×30 mL) and water (50 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product as a beige solid (0.87 g, 74%). A sample recrystallised from ethanol gave mp 94° C.; Found: C, 60.45; H, 4.58; N, 12.74%. C11H10N2O3 requires C, 60.55; H, 4.62; N, 12.83%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:23])[CH2:18][CH2:17]4)[CH:13]=[CH:12][N:11]3[CH:32]=2)=[CH:4][CH:3]=1.[CH3:33][C:34](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:35]>S(=O)(=O)(O)O>[C:34]([C:32]1[N:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:18][CH2:17]3)=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:35])[CH3:33]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccn3cc(-c4ccc(F)cc4)nc3c2)CC1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(-c2ccc(F)cc2)nc2cc(C3CCN(C(=O)OCc4ccccc4)CC3)ccn12
Temperature: 140 °C

Procedure:
Imidazopyridine 34 (290 mg, 0.675 mmol) was dissolved in acetic (50 mL) in a 250 mL round bottom flask. Three drops of sulfuric acid were then added, and the reaction was heated to 140° C. for 24 hours. The reaction was then concentrated under reduced pressure, then diluted with both ethyl acetate and saturated sodium bicarbonate solution, and extracted repeatedly into ethyl acetate. Organic fractions were pooled, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then dissolved in 5 mL methylene chloride, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% heptane and ended at 100% ethyl acetate. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 35: 180 mg (56%). 1H NMR (400 MHz, CDCl3) δ 1.67 (m, 2H), 1.92 (m, 2H), 2.17 (s, 3H), 2.81 (m, 1H), 2.93 (bs, 2H), 4.38 (bs, 2H), 5.16 (s, 2H), 6.48 (d, J=7.2 Hz, 1H), 6.96 (t, J=8.8 Hz, 2H), 7.24 (m, 5H), 7.57 (s, 1H), 7.76 (m, 2H), 7.86 (d, J=7.2 Hz, 1H). MS (ESI+) 472.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:30]([F:33])([F:32])[F:31])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+].Cl>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:30]([F:33])([F:31])[F:32])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[C:18]([C:25]([OH:27])=[O:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 0 °C
Yield: 92.3 %

Procedure:
Ethyl 2-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyrimidine-5-carboxylate (2.4 g) was added to a mixture solution comprising 1,4-dioxane (40 mL) and an aqueous solution (40 mL) of sodium hydroxide (2.0 g), and then heated at 80° C. for 10 hours. After cooling, the reaction solution was poured over ice water, acidified by adding concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure to obtain the title compound (2.1 g, 92%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C(OC(=O)C)(=O)C>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:8]1
Reactant: N#CCC(=O)O
Reactant: c1ccc2[nH]ccc2c1
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)c1c[nH]c2ccccc12
Temperature: 50 °C
Yield: 85 %

Procedure:
In a flask, cyanoacetic acid (5.0 g, 58.8 mmol, 1.2 eq) was dissolved in acetic anhydride (50 mL) and heated at 50° C. Indole (5.8 g, 50.0 mmol, 1.0 eq) was added and the reaction was heated at 80° C. for 5 min. A white precipitate crushed out of the solution; the reaction was cooled to room temperature and then filtered. The solid obtained (620.0 mg, 85% yield) was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([F:14])([F:13])[C:4]([F:12])([F:11])[C:5]([F:10])([F:9])[CH2:6][CH2:7]I.[P:17](OCC)([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][P:17]([CH2:7][CH2:6][C:5]([F:10])([F:9])[C:4]([F:12])([F:11])[C:3]([F:14])([F:13])[C:2]([F:16])([F:15])[F:1])(=[O:18])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 160 °C
Yield: 90 %

Procedure:
Neat 1,1,1,2,2,3,3,4,4-nonafluoro-6-iodohexane (10 mmol) was added to 50 mmol of triethyl phosphate. The reaction mixture was heated at 160° C. overnight to produce diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate, which was isolated by fractional distillation (90-95% yield). Neat trimethylsilyl bromide (21 mmol) was added slowly to a solution of diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate (7 mmol) in dry CH2Cl2 (25 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, after which time water (30 mmol) was added to the reaction mixture. Volatiles were removed in vacuo leaving (3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonic acid as a white crystal (>95% yield). The procedure for producing the phosphonic acid salt was similar as described for Intermediate 1.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:21]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
In 180 ml of tetrahydrofuran were dissolved 21.2 g of methyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta-[b]furan-7-carboxylate and 16.9 g of 4-chlorobutyric acid chloride. To the solution below 20° C., 9.10 g of pyridine was added dropwise. The solution was stirred at room temperature for 1 hour and combined with 40 g of a 5% aqueous solution of sodium hydrogen carbonate, followed by ordinary work-up. There was obtained 30.4 g of a crude product (crude yield 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[H-].[Na+]>CN(C=O)C>[NH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:7]=1
Reactant: Nc1cc(Br)ncc1[N+](=O)[O-]
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2cc(N)c([N+](=O)[O-])cn2)c1
Temperature: 65 °C

Procedure:
Under nitrogen, to a solution of 2-bromo-5-nitro-4-pyridineamine (3.67 g, 16.8 mmol) and methyl 3-hydroxybenzoate (2.82 g, 18.5 mmol) in DMF (100 mL), was added NaH (810 mg, 60% suspension, 20.2 mmol). 5 min later, the reaction mixture was heated to 65° C. The reaction mixture was concentrated, taken up in EtOAC, washed with NaOH solution (1.0N), saturated NH4Cl solution and brine, dried over Na2SO4, filtered and concentrated to afford the title compound, which was used directly to next step without further purification. MS (ES+) m/e 290 [+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.C([O:21][P:22]([CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:26])[O:23]CC)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[P:22]([CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:30][CH2:29][CH2:28][CH2:27][P:22]([OH:21])([OH:23])=[O:26])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)([OH:26])([OH:23])=[O:21]
Reactant: CCOP(=O)(CCCCBr)OCC
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(OCCCCP(=O)(O)O)cc2C(=O)c2ccc(OCCCCP(=O)(O)O)cc21
Reaction time: 8 h

Procedure:
2,6-dihydroxyanthraquinone (1.19 g, 4.98 mmol) and diethyl(4-bromobutyl)phosphonate (3.0 g, 10 mmol) were heated at 60 ° C. in 5 ml DMF in the presence of 0.8 g of K2CO3 for 72 hours. The solution was extracted with CH2Cl2. The CH2Cl2 solution was dried, leaving a yellow solid. The ester was purified by column chromatography. The bisphosphonate ester was converted to the acid by overnight stirring with 4-fold excess of bromotrimethylsilane in dry dichloromethane followed by addition of water. The bisphosphonic acid derivative was washed with CH2Cl2, filtered and collected.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13]>>[CH2:11]([NH:14][C:15]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN=C=O
Reactant: O=c1[nH]sc2ccccc12
Product: C=CCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6c (67% yield) was synthesized from benzo[d]isothiazol-3-one and allyl isocyanate as a white solid. mp 116-119° C.; IR(CHCl3) 3290, 1711, 1664, 1537 cm−1; 1H-NMR (CDCl3) δ 4.05-4.10 (m, 2H), 5.18-5.34 (m, 2H), 5.83-5.99 (m, 1H), 7.43 (t, J=7.2 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.70 (t, J=7.2 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 8.99 (br s, 1H); ESIMS m/e 235 (M++1).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 55 mg (40%) product as a white solid. MS (ISP) 463.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18].Cl>O.O1CCCC1>[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:24])(=[O:19])[CH3:18]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NCc1ccc(C(=O)O)cc1
Yield: 32.6 %

Procedure:
4-Aminomethylbenzoic acid (1.50 g) and sodium hydrogen carbonate (1.68 g) are suspended in water (20 ml), and thereto is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (2.86 g) in tetrahydrofuran (6 ml) with vigorously stirring. After the reaction is completed, the reaction mixture is acidified with hydrochloric acid and is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol to give the title compound (1.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[OH:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])=[O:19]
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C=Nc1ccccc1Br
Product: Cc1ccc(NC(=O)Nc2ccccc2Br)c(O)c1

Procedure:
The urea was prepared from 2-hydroxy 4-methyl aniline (0.274 g, 2 mmol) and 2-bromo phenyl isocyanate (0.40 g, 2 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane (249 mg, 39%). EI-MS m/z 319 (M−H)−
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=1)=[O:3].[NH2:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:10][C:8]1[CH:9]=[C:4]([C:2]2[O:3][C:23](=[O:24])[C:22]3[CH:21]=[N:20][CH:19]=[CH:18][C:17]=3[N:16]=2)[CH:5]=[C:6]([CH3:15])[C:7]=1[O:11][C:12](=[O:14])[CH3:13]
Reactant: Nc1ccncc1C(=O)O
Reactant: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(-c2nc3ccncc3c(=O)o2)cc1C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of acetic acid 4-chlorocarbonyl-2,6-dimethylphenyl ester (2.32 g, 10.0 mmol) in anhydrous CH2Cl2 (30 mL) were added 4-amino-nicotinic acid (4) (1.10 g, 8.00 mmol) and pyridine (2.37 g, 30.0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 40 hours. Solvent was evaporated. The residue was diluted with methanol (20 mL). The solid separated was filtered, washed with methanol (2×10 mL) and dried under vacuum to give acetic acid 2,6-dimethyl-4-(4-oxo-4H-pyrido[4,3-d][1,3]oxazin-2-yl)-phenyl ester (6) as yellow solid. Yield: 1.99 g (64%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[C:13]([S:22][CH2:23][CH3:24])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=O)=[CH:7][C:6]([C:25]([F:28])([F:27])[F:26])=[CH:5][N:4]=1.CN(C=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:23]([S:22][C:13]1[C:12]([C:10]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:25]([F:28])([F:27])[F:26])[CH:7]=[C:8]3[N:9]=2)=[CH:17][CH:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]=1)[CH3:24]
Reactant: CCSc1nc(C(F)(F)F)ccc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCSc1nc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 703 mg of 2-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 630 mg of p-toluenesolufonic acid-hydrate, 2.5 ml of DMF and 0.5 ml of toluene was heated and stirred at 150° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane, and then dried to obtain 616 mg of 2-(2-ethylsulfanyl-6-trifluoromethylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 4).