Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].I[CH3:33]>CN(C)C=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]([CH3:33])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3OC)CC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C)c(C)cc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
1-[(4,5-dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.2 g, 0.5 mmole) was dissolved in dimethylformamide(15 ml), sodium hydride(12 mg, 0.5 mmole) was added thereto slowly, and then the resulting mixture was stirred at room temperature for 15 min, then followed by addition of iodomethane(71 mg, 0.5 mmole) and subsequently at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dried, filtered and purified by column chromatography to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:18])=[CH:32][C:33]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc2cc(Br)ccc12
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1-c1ccc2c(C)noc2c1
Yield: 45.2 %

Procedure:
Example 7 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and 4-methyl-N-(3-morpholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 9, 21 mg) to give the title compound as an oil (9.6 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[S:9][C:10]=1[C:11]([C:13]1[CH:17]=[CH:16][N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=1)=[O:12].Cl.C(=O)([O-])O.[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:28][C:29]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[O:30])[S:9][C:10]=1[C:11]([C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1)=[O:12]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2cc[nH]c2)s1)c1ccncc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Compound 352 (155 mg, 0.298 mmol) and 0.1 mol/L hydrochloric acid (2.5 mL) were dissolved in ethanol (2.5 mL), followed by stirring at 90° C. for 2 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the entitled Compound 353 (89.0 mg, 82%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Br)([CH3:10])([CH3:9])[CH3:8].[Cl:19][C:20]1[N:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=1.O>CS(C)=O.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][O:26][C:23]1[CH:22]=[N:21][C:20]([Cl:19])=[N:25][CH:24]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Oc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCCCOc1cnc(Cl)nc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Potassium carbonate (2.54 g) was added to a solution of 5-bromovaleric acid tert-butyl ester (4.3 g) obtained in Reference Example 1 (1) above and 2-chloropyrimidin-5-ol (2 g) in dimethylsulfoxide (8.6 ml) and the mixture was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, water and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=49:1→9:1) to give 5-(2-chloropyrimidin-5-yloxy)valeric acid tert-butyl ester (3.82 g). MS (m/z): 287/289 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([CH3:25])[C:22](Cl)=[O:23])=[CH:17][CH:16]=1)[CH:12]([CH3:14])[CH3:13]>>[C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7][C:22](=[O:23])[C@@H:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=1)[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(C)Cc1ccc([C@@H](C)C(=O)Cl)cc1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Product: CC(=O)N[C@@H](CSC(=O)[C@H](C)c1ccc(CC(C)C)cc1)C(=O)O

Procedure:
By operating in a way similar to that described in the Example 2, and starting from N-acetyl-(R)-cysteine (39.5 g) and (2R)-2-(4-isobutyl-phenyl)-propionyl chloride (45.4 g) the desired product is obtained (18 g) as a solid melting at 102°-104° C.; [α]D20 =-79.6° (c=1%, EtOH).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH:22]3[NH:29]C(=O)O)[CH2:20]1)[CH2:26]2)[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl.O1CCOCC1>[NH2:29][CH:22]1[CH:23]2[CH2:28][C:19]3([CH2:18][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:17])[CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:26][CH:25]([CH2:27][CH:21]1[CH2:20]3)[CH2:24]2
Reactant: O=C(O)NC1C2CC3CC1CC(CN(Cc1ccccc1)C(=O)Cc1ccccc1)(C3)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1C2CC3CC1CC(CN(Cc1ccccc1)C(=O)Cc1ccccc1)(C3)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a three-necked flask under nitrogen, 0.49 g of tert-butyl ester of {5-[(benzyl-phenylacetyl-amino)-methyl]adamantan-2-yl}-carbamic acid is dissolved in 1.7 ml of anhydrous dichloromethane. It is cooled to 0° C. and 3.64 ml of 4N solution of hydrochloric acid in dioxane is added. The reaction mixture is stirred for 1 h at room temperature and then concentrated to dryness. 20 ml of water is added, the reaction mixture is basified with potassium carbonate and it is extracted with dichloromethane until exhaustion of the aqueous phase. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. 0.35 g of N-(4-amino-adamantan-1-ylmethyl)-N-benzyl-2-phenyl-acetamide is obtained, and is used subsequently as it is.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([CH3:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])=[CH:24][CH:23]=2)[N:7]=1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 105 °C
Yield: 29.3 %

Procedure:
A suspension of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6) (0.200 g, 0.690 mmol), tert-butyl (1-(4-aminophenyl)ethyl)carbamate (A131) (0.326 g, 1.38 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), Cs2CO3 (0.675 g, 2.07 mmol) and Xantphos (16 mg, 0.028 mmol) in 1,4-dioxane (3 mL) was heated under microwave irradiation at 105° C. for 6 hours. The resulting mixture was filtered through a plug of silica gel, washing with 20% MeOH in K1 DCM and then the volatiles evaporated in vacuo. The residue was purified using silica gel column chromatography (CombiFlash Rf, 12 g SiO2 Cartridge, 5-80% EtOAc in cyclohexane) to give the title compound A132 as a white solid (0.099 g, 29%); LCMS-B: rt 6.832 min; m/z 490 [M+H]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15])[CH2:7][CH2:6]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>C(Cl)(Cl)(Cl)Cl>[CH:8]1([CH2:11][CH2:12][CH2:13][C:14]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=2[O:25][CH3:26])=[O:15])[CH2:9][CH2:10][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Cl)CCCC1CCCCC1
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)CCCC2CCCCC2)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
3.53 g of AlCl3 and 5 g of 4-cyclohexanebutyryl chloride in 100 ml of CCl4 are mixed together and 5 g of 1,3-dimethoxybenzene are added dropwise, at 0° C. After stirring for 3 hours at 0° C., the entire mixture is poured onto dilute ice-cold HCl solution. The organic phase is separated out by settling and is then washed with 0.5N NaOH. After drying over MgSO4 and evaporation of the solvent, the residue is chromatographed on a column of silica H, eluting with toluene, to give 4.5 g of the expected compound in the form of an oil.
Reaction SMILES: FC1[CH:3]=[C:4]([C:9]2C=C(CO)C(=O)N(CC(C)C)N=2)[CH:5]=CC=1F.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[NH:34][N:35]=1>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[N:34]([CH2:3][CH:4]([CH3:9])[CH3:5])[N:35]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CO)c1=O
Reactant: COC(=O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O
Yield: 84.8 %

Procedure:
Following the procedure of Example 1 (6), 6-(2,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow oil (yield: 84.8%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].O.[C:13]([O:16][C@H:17]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:20][O:19][C@H:18]1Br)(=[O:15])[CH3:14]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:13]([O:16][C@H:17]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:20][O:19][C@H:18]1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:15])[CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](Oc2ccc(C=O)cc2)OC[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
p-Hydroxybenzaldehyde (2.2 g, 18 mmol), dichloromethane 18 mL, a 5% aqueous solution of sodium hydroxide (20 mL) were put in a 100 mL round bottom flask and stirred vigorously. At that time, the water phase turned yellow. To the resulting mixture, tetrabutylammonium bromide (1.0 g, 3.0 mmol) was added, and then a solution of 2,3,4-tri-O-acetyl-β-D-arabinopyranosyl bromide (4.0 g, 12 mmol) in dichloromethane (about 6 mL) was added dropwise. A reaction vessel was protected from light, and the resulting mixture was stirred vigorously at room temperature for 2 days. The separated organic phase was washed with 50 mL of a 5% aqueous solution of sodium hydroxide three times and then with 50 mL of water three times, dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound. Light brown solid. Yield 1.9 g, 43%. The product was unstable at room temperature, and stored in the freezer.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17](=[O:31])[N:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[NH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: O=c1c2c(CCc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reaction time: 3.5 h
Yield: 92.6 %

Procedure:
To a solution of 3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (131 mg, 0.32 mmol, prepared in Example 11) in DMF (4 ml) and methanol (4 ml) was added activated carbon-palladium (13 mg), and the mixture was stirred under hydrogen atmosphere for 3.5 hours, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (113 mg, 93%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.O>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:1]([O:5][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][Br:6])[CH2:2][C:3]#[CH:4]
Reactant: BrCCCCCCBr
Reactant: C#CCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: C#CCCOCCCCCCBr

Procedure:
3-Butyn-1-ol (42.4 ml) was stirred vigorously with 1,6-dibromohexane (260 ml) and tetrabutylammonium bisulphate (2.4 g) in 50% aqueous sodium hydroxide solution (200 ml) under nitrogen for 3 days. Water (ca 700 ml) was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane (2×100 ml) and the combined organic layers were washed with water, dried (MgSO4) and concentrated. The residue in petroleum ether (bp 40-60°) was loaded onto a column of silica gel (1.5 kg) and the column was eluted with petroleum ether (bp 40-60°), then 10% diethyl ether in petroleum ether (bp 40-60°) to give the title compound (103.3 g), δ (CDCl3) 3.56(2H, t, J 7 Hz), 3.47(2H, t, J 7 Hz), 3.42(2H, t, J 7 Hz), 2.45(2H, m), 1.99(1H, t, J 2 Hz), 1.87(2H, m), 1.60(2H, m) and 1.50 to 1.33 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2cccc(Cl)c2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-3-bromomethyl benzene using the conditions described in Example 237C to provide 4-(3-chloro-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([Cl:20])[C:14]=1F)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]([CH:38]=[C:39]([O:41][C@H:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:40]=1)[C:34]([O:36][CH3:37])=[O:35].O>C(#N)C.C(OCC)(=O)C>[Cl:20][C:15]1[C:14]2[O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]=2[CH:18]=[CH:17][C:16]=1[O:30][C:31]1[CH:32]=[C:33]([CH:38]=[C:39]([O:41][C@H:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)cc(O[C@H]2CCOC2)c1
Yield: 25.1 %

Procedure:
A solution of N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (647 mg, 1.78 mmol) in acetonitrile (10 mL) was heated with potassium carbonate (492 mg, 3.56 mmol) and methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (424 mg, 1.78 mmol) at 160° C. for 2.5 hours in a microwave reactor. Water (15 mL) and ethyl acetate (20 mL) was added to the reaction mixture, the layers separated and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extract was washed with brine (10 mL) and dried (MgSO4), filtered and evaporated to a residue which was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a clear oil (200 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.C(O)(C)(C)C>CO>[N:26]1([C:2]2[CH:7]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:5]=[C:4]([NH2:25])[N:3]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCNC1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCCNCC2)nc(N)n1

Procedure:
A mixture of 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (18 mg, 0.050 mmol), 1,4-diazepane (15.0 mg, 0.150 mmol, Aldrich, Cat. No. H16604)) and N,N-diisopropylethylamine (20.0 uL, 0.115 mmol) in tert-butyl alcohol (0.5 mL, 5 mmol) was heated at 120° C. overnight. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. (M+H)+: m/z=419.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([N:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[C:6]1=[O:20])[CH3:4]>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7]([CH3:18])([CH3:19])[C:6](=[O:20])[N:5]([CH:3]([O:2][CH3:1])[CH3:4])[C:10]=2[CH:11]=1
Reactant: COC(C)N1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: COC(C)N1C(=O)C(C)(C)Oc2ccc(N)cc21
Reaction time: 3 h

Procedure:
A mixture of 4N-(1-methoxyethyl)-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (378 mg, 1.35 mmol, 1 equiv.) in 10 mL of MeOH in the presence of 38 mg of Pd/C was hydrogenated at room temperature for 3 h. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated to give the product in quantitative yield.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CC(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-].[F:19][C:20]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>CO>[C:22]([C:21]1[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:20]=1[F:19])#[CH:1]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(C=O)c1F
Agent: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(OC)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
Potassium carbonate (3.6 g, 26.0 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (2.4 mL, 15.6 mmol) were added sequentially to a solution of 2-fluoro-3-methoxybenzaldehyde (2.0 g, 13.0 mmol) in methanol (100 mL), and the reaction was allowed to stir at room temperature for 16 h. After concentrating the reaction mixture under reduced pressure, the crude material was purified by flash chromatography (40 g silica gel column, 0-40% gradient ethyl acetate in hexanes) to provide a clear colorless oil (1.8 g, 92%). MS (GCMS) m/z 150. 1H NMR (400 MHz, CHLOROFORM-d) δ3.31 (d, J=0.78 Hz, 1H) 3.90 (s, 3H) 6.93-7.11 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[Br:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35].C(Cl)Cl>C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2Br)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a 10 ml vial was loaded 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (60 mg, 0.179 mmol), diisoprpoylethylamine (0.093 ml, 0.54 mmol), 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (87 mg, 0.27 mmol), N,N-dimethylaminopyridine (4.4 mg, 0.036 mmol) and 1 ml methylene chloride. The resulting reaction solution was stirred at room temperature for one hour. It was diluted with 20 ml ethyl acetate, washed sequentially with 20 ml 1N HCl, 20 ml 10% KOH and 20 ml brine. Organics were dried over sodium sulfate, filtered and concentrated to give 91 mg white solid. A fraction of this crude product (20 mg) was further purified on a reverse phase column eluted with water/acetonitrile gradient solvent to give 16 mg desired product as fluffy white solid after lyophilizing.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCc2cc(OCCN3CCOCC3)ccc21

Procedure:
To a solution of 5-hydroxy-1-indanone (610 mg, 4.1 mmol) in acetonitrile (30 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (3.8 g, 20.5 mmol) and potassium carbonate (680 mg 4.9 mmol) and the mixture was heated to reflux for about 3 days. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel using ethyl acetate as the mobile phase to provide the desired product. MS (ESI): m/z 262 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C[Al](C)C.[CH3:12][C:13]1[N:14]=[C:15]([CH2:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[S:16][C:17]=1[C:18](O)=[O:19]>O1CCOCC1.C1(C)C=CC=CC=1>[O:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:18]([C:17]2[S:16][C:15]([CH2:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[N:14][C:13]=2[CH3:12])=[O:19])[CH2:3][CH2:4]1
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Reactant: NC1CCOCC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC1CCOCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a stirred suspension of 4-aminotetrahydropyran (123 mg, 1.2 mmol) in dioxane (5 mL) under argon at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 mmol). After 1 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.3 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 3 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (40 mg, 32%) as a colourless oil. MS: m/e=412.4 [M+H]+.