Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:10][CH:9]2N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:15](C(C)C)CC)(C)C.[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:15][C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][CH2:9]2)=[O:27])=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1ccnnc1
Reactant: NC1CC1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2(c3ccccc3)CC2)cc1-c1ccnnc1
Temperature: 25 °C

Procedure:
To a solution containing 2-phenylcyclopropanamine hydrochloride (0.13 g, 0.76 mmol), diisopropylethylamine (0.88 mL, 5.0 mmol), 4-methyl-3-(pyridazin-4-yl)benzoic acid (0.14 g, 0.63 mmol) and DMF (4.2 mL) was added HATU (0.48 g, 1.3 mmol) in one portion. The solution was maintained at room temperature for 40 min. and concentrated to a residue. The residue thus obtained was purified on silica gel (0-8% methanol/dichloromethane, 45 min gradient) to afford 4-methyl-N-(1-phenylcyclopropyl)-3-(pyridazin-4-yl)benzamide. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.22-9.28 (m, 1 H), 9.18 (d, J=1.22 Hz, 1 H), 7.75-7.85 (m, 1 H), 7.70 (d, J=1.83 Hz, 1 H), 7.51 (dd, J=5.19, 2.44 Hz, 1 H), 7.37-7.42 (m, 1 H), 7.23-7.33 (m, 5 H), 7.15-7.21 (m, 2 H), 3.70 (dt, J=13.12, 6.56 Hz, 3 H), 3.17 (q, J=7.32 Hz, 3 H), 2.30-2.40 (m, 3 H). LCMS retention time: 1.655 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 330 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.N1([C:30](=[O:38])[CH2:31][CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][O:34]2)C=CN=C1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:11]=[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]1[C:30](=[O:38])[CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(CCC1CCCO1)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CCC2CCCO2)C1
Reaction time: 0.03 h
Yield: 38.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (2.231 ml, 11.88 mmol) was added to a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.127 g, 5.66 mmol) in toluene (3 mL) at 0° C. and the resulting mixture was stirred for 2 minutes. 1-(1H-Imidazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (1.099 g, 5.66 mmol) in toluene (1 mL) was added and the reaction mixture was stirred for 5 minutes before it was quenched with acetic acid (0.972 ml, 16.97 mmol) in water (4 mL). The organic layer was separated and purified by silica flash chromatography using a gradient of ethyl acetate in heptane (0 to 40%) giving tert-butyl 4-oxo-3-(3-(tetrahydrofuran-2-yl)propanoyl)piperidine-1-carboxylate (0.717 g, 38.9%) as the product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Temperature: 60 °C
Yield: 87.8 %

Procedure:
To stirred solution of 2,5-dichloro-3-nitrobenzoic acid (3.2 g, 13.67 mmol) in DMF (30 mL) was added sodium carbonate (4.3 g, 40.56 mmol) and methyl iodide (9.7 g, 68.30 mmol). The reaction mixture was heated at 60° C. for 18 h. On completion, water was added to the reaction mixture, and the product was extracted using DCM. The combined organic layers were dried and concentrated under reduced pressure to give methyl 2,5-dichloro-3-nitrobenzoate (3 g, 90%).
Reaction SMILES: O=O.CC1SC(C)=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=1C1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=C(C)SC=1C.[CH3:43][O:44]/[C:45](=[CH:49]\[C:50]1[C:55]2[S:56][CH:57]=[CH:58][C:54]=2[C:53]([O:59][CH2:60][CH2:61][C:62]2[N:63]=[C:64]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[O:65][C:66]=2[CH3:67])=[CH:52][CH:51]=1)/[C:46]([OH:48])=[O:47].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.CO>[CH3:43][O:44][C@@H:45]([CH2:49][C:50]1[C:55]2[S:56][CH:57]=[CH:58][C:54]=2[C:53]([O:59][CH2:60][CH2:61][C:62]2[N:63]=[C:64]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[O:65][C:66]=2[CH3:67])=[CH:52][CH:51]=1)[C:46]([OH:48])=[O:47]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: Cc1sc(C)c(P(c2ccccc2)c2ccccc2)c1-c1c(C)sc(C)c1P(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 0.62 mg of [Ru(OAc)2((S)-TMBTP)] (0.0008 mmol, S/C 3′000) (prepared according to EP 1,670,792 B1; TMBTP=2,2′,5,5′-Tetramethyl-4,4′-bis(diphenylphosphino)-3,3′-bithiophene) and 5 ml of methanol. The resulting orange solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 4 ml of methanol, 6 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.7% (99.9% conversion) and an enantiomeric purity of 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH:10]([CH3:13])[CH:11]=O)=O)=[CH:5][CH:4]=1.[C:16]([NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])(=[O:18])[CH3:17].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:16]([NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([N:27]2[CH:11]=[C:10]([CH3:13])[CH:9]=[C:7]2[C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])(=[O:18])[CH3:17]
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(C(=O)CC(C)C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(=O)(=O)NC(C)=O)cc2)cc1
Yield: 16.1 %

Procedure:
A solution of 2.82 g (12.8 mmol) of 3-(4-methoxybenzoyl)-2-methylpropionaldehyde [prepared as described in step (i) above] and 2.74 g (12.8 mmol) of 4-acetylaminosulfonylaniline in 30 ml of acetic acid was heated under reflux for 3 hours, after which the acetic acid was removed by distillation under reduced pressure. The residue thus obtained was dissolved in chloroform and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting solution to separate it into liquid phases. The organic extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of hexane and ethyl acetate. It was then recrystallized from ethanol, to give 0.79 g (yield 16%) of the title compound as a white powder, melting at 215-217° C.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:8]=3[CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:23]=[C:24](I)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:21][C:22]1[CH:23]=[C:24]([C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:13]=3[C:12]3[O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:8]=3[CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: OB(O)c1cc2c3ccccc3oc2c2ccccc12
Reactant: Brc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3c4ccccc4oc3c3ccccc23)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
In the atmosphere of argon, 17.0 g of benzo[b]naphtho[2,1-d]furan-5-boronic acid, 18.4 g of 3-bromoiodobenzene, 1.50 g of tetrakistriphenylphosphine palladium (0), 200 mL of toluene and 100 mL of a 2M aqueous sodium carbonate solution were placed in a flask. The resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed. An organic phase was dried with magnesium sulfate and concentrated. Residues were purified by silica gel column chromatography, whereby 21.8 g of 5-(3-bromophenyl)benzo[b]naphtho[2,1-d]furan was obtained.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=1.C(N(CC)CC)C>C(O)C>[CH3:38][S:37][C:33]1[N:34]=[C:35]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:31][N:32]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1nccc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)n1
Yield: 26.8 %

Procedure:
A mixture of 1.50 g (0.0037 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine [U.S. Pat. No. 4,025,629], 0.44 ml (0.00375 mol) of 4-chloro-2-methylthiopyrimidine, 0.52 ml (0.00375 mol) of triethylamine, and 125 ml of ethanol is stirred at reflux for 3 hours. After cooling, the ethanol is removed in vacuo and the residue is stirred with methylene chloride and aqueous sodium bicarbonate. The resultant solid is collected and washed with water and ether. Crystallization from methanol-chloroform gives 0.52 g (26%) of 1-[2-(methylthio)-4-pyrimidinyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, of melting point 166°-267° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[C:5]([CH:7]=O)[N:6]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[NH:11][NH2:12]>>[CH2:15]([O:14][C:10](=[O:13])[NH:11][N:12]=[CH:7][C:5]1[N:6]=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:9])[CH3:16]
Reactant: Cc1nc(C=O)c(C)[nH]1
Reactant: CCOC(=O)NN
Product: CCOC(=O)NN=Cc1nc(C)[nH]c1C

Procedure:
A 6.2 gm. portion of 2,5-dimethyl-4-imidazolecarboxaldehyde and 6.24 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 207.5° - 210° C. (resolidifies 248°-252° C.).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Cl)cc1NCc1cccnc1
Temperature: 150 °C
Yield: 29.9 %

Procedure:
A mixture of 2,4-dichlorobenzoic acid (10 g, 53 mmol), 3-aminomethylpyridine (4.5 ml, 44 mmol), K2CO3 (7.8g, 56 mmol) and CuBr (80 mg, cat) in DMF (20 ml) was heated at 150° C. for 1 hour, cooled to 0° C., diluted with water (80 ml) and carefully acidified with glacial acetic acid. The resulting solid was collected by filtration, washed with water, acetone and ether to give the pure product (>99% by HPLC) as a bluish white solid (3.46 g, 30%), m.p. 235°-236° C.; 1H NMR d (DMSO, 360 MHz, 353 K) 8.60 (bs, 1H, aromatic), 8.49 (bs, 1H, aromatic), 7.79 (d, J=8.5 Hz, 1H, aromatic), 7.72 (d, J=7.8 Hz, 1H, aromatic), 7.35 (dd, J=4.8, 7.6 Hz, 1H, aromatic), 6.74 (d, J=1.8 Hz, 1H, aromatic), 6.59 (dd, J=2.0, 8.4 Hz, 1H, aromatic), 4.51 (s, 2H, CH2); HRMS [M-2H]- calcd for C13 H9N2O2Cl: 260.0353. Found: 260.0348. Anal. calcd for C13H11ClN2O2.1/4H2O: C, 58.44; H, 4.33; N, 10.48. Found: C, 58.30; H, 4.10; N, 10.25.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]([CH3:16])([CH2:14]O)[CH3:13]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:10][CH2:11][C:12]([CH3:16])([CH3:14])[CH2:13][O:7]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Yield: 92.9 %

Procedure:
A mixture of 4-bromobenzaldehyde (100 g, 0.54 mole), neopentyl glycol (115 g, 1.10 mole), and p-toluenesulfonic acid (800 mg, 4 mmole) in benzene (800 mL) was heated to reflux using a Dean Stark apparatus for 16 h. The reaction mixture was cooled to room temperature and most of the benzene was removed. The residue was partitioned between ethyl acetate (500 mL) and cold water (150 mL). The organic phase was washed with water (2×150 mL) and brine (1×150 mL), then dried (Na2SO4) and concentrated to give the desired product (136 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[NH2:28].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[NH:28][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1)=[O:18]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.5 %

Procedure:
As shown in Reaction Scheme 10, 4′-nitro-1,1′-biphenyl-4-carboxylic acid (4.66 g, 19.2 mmol) was dissolved in methylene chloride (110 mL), and then oxalyl chloride (2.51 mL, 28.7 mmol) was added, followed by 3 drops of N,N-dimethylformamide. The resulting mixture was stirred at rt for 45 min, concentrated under reduced pressure, and further dried under vacuum for 30 min. The residue was dissolved in methylene chloride (75 mL) and added dropwise to an ice-cold mixture of methyl 2-methylalaninate hydrochloride (3.83 g, 24.9 mmol), methylene chloride (75 mL), and triethylamine (6.68 mL, 47.9 mmol). The resulting solution was stirred at rt for 1 h and then at 55° C. for 2 h. The mixture was allowed to cool to rt and was then washed with 1N aqueous HCl solution (5 mL) and water (2×20 mL). The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage® system, 4:1 hexanes/EtOAc) to afford methyl 2-methyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate (6.21 g, 95%). 1H NMR (400 MHz, CDCl3) δ 1.73 (s, 6H), 3.82 (s, 3H), 6.89 (broad s, 1H), 7.69 (d, 2H), 7.77 (d, 2H), 7.92 (d, 2H), 8.31 (d, 2H); LC-MS m/z 342.9 (MH+), retention time 2.98 minutes.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]12.N1C=CC=CC=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:6][CH:4]2[CH2:5][O:1][CH:2]3[CH:9]([OH:10])[CH2:8][O:7][CH:3]23)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1COC2C(O)COC12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2COC3C(O)COC23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of hexahydrofuro[3,2-b]furan-3,6-diol (10.00 g, 68.4 mmol) in dichloromethane (60 mL) was added pyridine (1.08 g, 13.7 mmol) and then the mixture was cooled to 0° C., and 4-methylbenzenesulfonyl chloride (15.66 g, 82.1 mmol) was added. The mixture was stirred at 0° C. for 30 min, and then warmed to room temperature overnight. The resulting mixture was diluted with dichloromethane (250 mL), washed with 1M HCl (300 mL) followed by water (300 mL) and brine (300 mL). The separated organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with a silica gel column chromatography (EtOAc/PE (v/v)=2/1) to afford the desired product as colorless oil (10.24 g, 49.8%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:17]=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.CCCCCC.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>O1CCCC1>[C:7]1([CH:17]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[O:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 90 %

Procedure:
22.4 g (0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml of tetrahydrofuran and 12.4 g (1.1 mol) of potassium t-butoxide was slowly added thereto. To this solution was slowly added 15.6 g (0.10 mol) of 1-naphtaldehyde dissolved in 20 ml of tetrahydrofuran and the mixture was stirred for 8 hours. The organic solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, concentrated and subjected to column chromatography(eluent: hexane/ethyl acetate=95/5, v/v) to give 20.3 g (0.090 mol, Yield 90%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([C:30]([O:32][CH3:33])=[O:31])[CH3:29])=[CH:23][C:22]=2[OH:34])[N:18]=[C:17]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([C:44]([O:46][CH3:47])=[O:45])[CH3:43])=[CH:37][C:36]=2[OH:48])[N:16]=1.O.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53](S(O)(=O)=O)=[CH:52][CH:51]=1.C(O)[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68].CO>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:11]([O:13][CH2:14][CH2:15][CH2:3][CH2:2][CH2:7][CH2:6][CH2:5][CH3:4])=[O:12])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([C:30]([O:32][CH2:33][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH3:62])=[O:31])[CH3:29])=[CH:23][C:22]=2[OH:34])[N:18]=[C:17]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([C:44]([O:46][CH2:47][CH2:60][CH2:50][CH2:55][CH2:54][CH2:53][CH2:52][CH3:51])=[O:45])[CH3:43])=[CH:37][C:36]=2[OH:48])[N:16]=1
Reactant: CCCCCCCCO
Reactant: COC(=O)C(C)Oc1ccc(-c2nc(-c3ccc(OC(C)C(=O)OC)cc3O)nc(-c3ccc(OC(C)C(=O)OC)cc3O)n2)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCOC(=O)C(C)Oc1ccc(-c2nc(-c3ccc(OC(C)C(=O)OCCCCCCCC)cc3O)nc(-c3ccc(OC(C)C(=O)OCCCCCCCC)cc3O)n2)c(O)c1

Procedure:
15.60 g (0.0235 mol) of 2,4,6-tris(2-hydroxy-4-(1-methoxycarbonylethoxy)phenyl)-1,3,5-triazine are refluxed for 10 h with 0.45 g (0.00235 mol) of p-toluenesulfonic acid monohydrate and 14.85 ml (0.094 mol) of octanol (isomer mixture) in 50 ml of xylene until methanol is no longer split off. The reaction mixture is then cooled, washed with water and dried using MgSO4. The solvent is concentrated and the residue is chromatographed over silica gel, giving a yellowish resinous substance of the following structure:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].Cl.[CH3:16][NH:17][O:18][CH3:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]([N:17]([CH3:16])[O:18][CH3:19])[N:6]=1)[CH2:2][CH3:3]
Reactant: CNOC
Reactant: CCCNc1ncnc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(N(C)OC)n1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (10.00 g, 43.53 mmol), N,O-dimethylhydroxylamine hydrochloride (8.49 g, 87.06 mmol) and NaOH (3.13 g, 78.35 mmol) in 1,4-dioxane (120 mL) and water (30 mL) was heated at 60° C. for 6 h, after which the volatiles were removed under reduced pressure. Saturated NaHCO3 solution (500 mL) was added to the residue and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water (300 mL), then with a brine solution (300 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resultant residue was filtered through silica gel using eluent CH2Cl2/EtOH (9/1 v/v) to yield N-(4,6-bis-n-propylamino[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) (9.96 g, 90% yield).
Reaction SMILES: C([O-])(O)=[O:2].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[C:20]1[C:29]([F:30])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:31]=[C:32]([CH3:48])[N:33]([C@H:34]4[CH2:39][CH2:38][N:37]([CH:40](CC=O)[C:41]([O-:43])=O)[CH2:36][C@@H:35]4[F:47])[C:23]=3[C:22]=2[CH:21]=1.CO.C(Cl)Cl>CO>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[C:20]1[C:29]([F:30])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:31]=[C:32]([CH3:48])[N:33]([C@H:34]4[CH2:39][CH2:38][N:37]([C:40](=[O:2])[CH2:41][OH:43])[CH2:36][C@@H:35]4[F:47])[C:23]=3[C:22]=2[CH:21]=1
Reactant: O=C([O-])O
Reactant: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(CC=O)C(=O)[O-])C[C@@H]1F
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(=O)CO)C[C@@H]1F
Reaction time: 24 h
Yield: 81.7 %

Procedure:
NaHCO3 (11 g, 0.1309 mol) was added to a stirred solution of 2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate (8 g, 0.013 mol) in MeOH (300 mL) at RT and stirred for 24 h. The reaction was monitored by TLC (5% MeOH/DCM), after completion of reaction, the reaction mixture was filtered and wand washed with MeOH (100 mL). The filtrate was concentrated to remove methanol and the residue was dissolved in DCM (200 mL) and washed with water, brine solution, dried over sodium sulphate and evaporated under vacuum. The residue was purified by column chromatography on silica gel (0-4% MeOH/DCM) to afford the 1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone (6.0 g, 81% yield). Obtained solid was recrystallized in EtOH (alternatively in MeOH) 1HNMR (CDCl3, 400 MHz): δ 9.33 (s, 1H), 8.65-8.64 (d, 2H), 8.08-8.05 (d, 1H), 8.00-7.85 (m, 1H), 7.51-7.30 (m, 2H), 7.30-7.28 (dd, 1H), 7.15-7.13 (m, 1H), 5.65-5.25 (m, 1H), 4.96-4.75 (m, 1H), 4.35-4.15 (m, 2H), 3.92-3.74 (m, 2H), 3.35-3.15 (m, 1H), 3.05-2.85 (m, 2H), 2.80 (s, 3H), 2.45-2.15 (m, 2H); LCMS: 100%, m/z=565.1 (M+1); HPLC (Method-3): 99.80%, Chiral HPLC: 99.48%, rt=20.38 min., Column. AG/CHIRALPAK AD-H/03. Free Form