Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:6]([CH2:7][OH:8])[O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:19]([NH:18][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[C:15]=1[N:16]=[CH:17][N:9]2[C@H:4]1[C@H:3]([CH2:2][OH:1])[C@@H:6]([CH2:7][OH:8])[O:5]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1CO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 2.5 g of 9-((2R,3R,4S)-3,4-bis-hyroxymethyl-oxetan-2-yl)adenine and 40 mL of pyridine. To the system, at 0° C., was added 4.6 g of benzoyl chloride, the cold bath was removed, and the reaction mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with a small amount of acetone and poured into ice/water. The resulting precipitate was collected by suction filtration and treated with 20 mL of 1M aqueous sodium hydroxide in 40 mL of DMF. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with several portions of chloroform. The chloroform extracts were dried (Na2SO4) and concentrated with a rotary evaporator, and the crude product was rinsed with ether and recrystallized from ethanol-water to obtain 6-benzamido-9-((2R,3R,4S) 3,4-bis(hydroxymethyl)-oxetan-2-yl)purine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>Cl.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2nc(COc3ccc(C)cc3)c(C)o2)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of methyl 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoate (1.0 g, 2.97 mmol, 1.00 equiv) in 6N hydrochloric acid (30 mL) was stirred overnight at 90° C. The reaction mixture was diluted with 50 mL of water then extracted with 3×150 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.24 g (25%) of 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoic acid as a gray solid. LC-MS: (ES, m/z): 324 [M+H]+, 302, 265, 120. H-NMR: 1HNMR (400 MHz, CDCl3, ppm) δ 8.15-8.13 (d, 2H), 8.06-8.04 (d, 2H), 6.94-6.91 (m, 4H), 3.79 (s, 2H), 2.44 (s, 3H,), 2.26 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N:7]1[C:8]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH:22]=[O:23])[N:15]=2)=[CH:9][N:10]2[C:6]=1[C:5]1[CH:24]=[CH:25][CH:2]=[CH:3][C:4]=1[O:13][CH2:12][CH2:11]2
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1nc(C=O)nc1-c1cn2c(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of [5-(8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol 315 (166 mg, 0.51 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (DMP, 238 mg, 0.56 mmol) and resultant solution stirred at RT for 2 h under an atmosphere of nitrogen. The reaction was quenched by the addition of sodium thiosulphate (620 mg in 1 mL water) before the addition of further water and extracted twice with DCM. The combined organic extracts were washed with water then dried (Na2SO4), filtered and concentrated in vacuo to give 5-(4,5-Dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole-3-carbaldehyde as a cream solid (170 mg, quantitative). LCMS: RT=4.30 min, [M+H]+324. 1H NMR 400 MHz (DMSO-d6) δ: 9.91 (1 H, s), 8.43 (1 H, dd, J=8.06, 1.78 Hz), 8.11 (1 H, s), 7.34-7.34 (1 H, m), 7.17-7.17 (1 H, m), 7.07 (1 H, dd, J=8.17, 1.23 Hz), 6.03 (1 H, m), 4.57-4.48 (4 H, m), 1.55 (6 H, d, J=6.60 Hz)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[CH3:16][O:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.0 g) in DMF (20 ml) was added NaH (235 mg; 60% oil suspension) under nitrogen atmosphere, and the mixture was stirred for 30 minutes at room temperature. MeI (665 μl) was added to the mixture, and the whole was stirred for 2 hours. Water was added to the mixture, and the whole was extracted with EtOAc. The extract was washed with water and brine and dried over MgSO4. Concentration under reduced pressure gave a residue, which was purified with silica gel chromatography eluting with n-hexane:EtOAc=5:1 to give tert-butyl 3-(methoxymethyl)azetidine-1-carboxylate (1.04 g).
Reaction SMILES: [C:1](/[CH:4]=[C:5]1\[CH2:6][N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8][CH2:9][CH:10]\1[OH:11])([OH:3])=[O:2].[ClH:31]>C(O)CCC>[ClH:31].[CH2:1]([O:3][C:1](/[CH:4]=[C:5]1\[CH2:6][NH:7][CH2:8][CH2:9][CH:10]\1[OH:11])=[O:2])[CH2:4][CH2:5][CH3:10]
Reactant: O=C(O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)/C=C1\CNCCC1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
50 ml of 1-butanol were added to 5.44 g (13.6 mmol) of (E)-3-carboxymethylidene-4-hydroxy-1-triphenylmethylpiperidine. Hydrogen chloride gas was blown through the resulting mixture, followed by stirring at 60° C. for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was washed with toluene, whereby 3.43 g (yield: 100%) of (E)-3-butoxycarbonylmethylidene-4-hydroxypiperidine hydrochloride were obtained as a white solid.
Reaction SMILES: [Li+].[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([O-:27])=O)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:14])=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)=[O:27])[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: O=C([O-])c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Agent: [Li+]
Product: O=C(c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1)N1CCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure D from 4-[4-(2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenoxymethyl]-benzoic acid lithium salt and azetidine. MS (ES+) 448.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[NH:20][CH:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:30]([O:32]CC)=[O:31].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:29])[NH:20][CH:21]3[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][CH2:26]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C)(C)CC4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate (0.056 g, 0.12 mmol) in 3:1 THF/EtOH (1 ml) was added 1M sodium hydroxide (0.24 ml, 0.24 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was concentrated and the residue was diluted with water and 1M hydrochloric acid. The reaction was extracted twice with EtOAc, and the combined organic layers were washed with saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 42 mg of the title compound (80% yield). MS (apci) m/z=458.1 (M+H).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].O>[CH3:1][CH2:5][CH2:1][CH2:5][O:4][C@H:3]([CH2:2][OH:4])[CH2:3][CH3:2]
Reactant: C1CCOC1
Agent: [W]
Agent: P
Solvent: O
Product: CCCCO[C@@H](CC)CO

Procedure:
Polymerization was carried out by means of the continuous polymerization device as shown in FIGURE. First, into a polymerization tank 1 of 350 ml volume equipped with a stirrer and a reflux condenser, 135 g of phosphotungstic acid with a coordinated water molecules number of 3.3 (H3PW12O40.3.3H2O) was charged and 270 g of THF with a water content of 200 ppm was added, followed by stirring. The polymerization tank was set at a temperature of 60° C. and THF containing water of 0.4 wt. % was fed at a rate of 60 g/hour. The polymerization tank mixture was circulated between the tank and the phase separation tank 2, and the upper layer separated was withdrawn at a rate of 60 g/hour. From the upper layer, THF was removed by distillation, resulting to provide PTMG. After continuous running for 260 hours, 2.0 Kg of a PTMG with a number-average molecular weight of 1750 was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:22][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Cn1ccc2ncnc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1ccc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Temperature: 140 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A suspension of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (28) (300 mg, 1.79 mmol), 4-nitro-2-fluorophenol (422 mg, 2.69 mmol) and cesium carbonate (1.2 g, 3.58 mmol) in diphenyl ether (18 mL) was stirred overnight at 140° C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was triturated with Et2O, filtered, and dried to afford the title compound 29 as a grey solid (258 mg, 49% yield). LRMS (M+1) 289.1 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]2[CH2:16][C:15]2([F:18])[F:17])[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[NH:19][C:20](=[O:35])[C@H:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24].O.[OH-].[Li+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]2[CH2:16][C:15]2([F:17])[F:18])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:19][C:20](=[O:35])[CH:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:27])[C:23]([F:24])([F:25])[F:26]
Reactant: COC(=O)CC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1CC1(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](C(C(=O)Nc1cc(C(CC(=O)O)C2CC2(F)F)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
114 mg (0.21 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate (isomer 1; Example 124A) were dissolved in a mixture of 2 ml of dioxane and 1 ml of water, and 27 mg (0.64 mmol) of lithium hydroxide monohydrate were added. The mixture was stirred at RT overnight. The solution was then diluted with water and acidified with 1 N hydrochloric acid (pH about 2). The precipitated solid was filtered off with suction and dried under high vacuum overnight. This gave 89 mg (80% of theory) of the title compound as a diastereomer mixture in the form of a white solid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([OH:16])[C:14]#[CH:15]>Cl[Cu]>[CH2:13]([OH:16])[C:14]#[C:15][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC/C=C\CCl
Reactant: C#CCO
Agent: Cl[Cu]
Product: CCCCCCCC/C=C\CC#CCO

Procedure:
By the procedure of example 13, (Z)-1-chloro-2-undecene (4.0 g, 21 mmol), the Grignard complex of propargyl alcohol (prepared from 35 mmol of propargyl alcohol and 70 mmol of ethylmagnesium bromide in 35 ml of dry THF), and 252 mg of CuCl were allowed to react at 50° C. for 20 h. under argon. Workup of the reaction mixture and purification of the crude product as described before in example 13 gave 2.54 g (58% by weight yield) of (Z)-5-tetradecen-2-yn-1-ol as a colorless oil, bp 102°-127° C./0.25 mmHg (evaporative distillation).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][C:16]([O:18]CC)=[O:17])[N:10]=[C:9]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:8]=[C:7]2[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=3)[N:35]([CH3:45])[C:34]2=[O:46])[CH2:29][CH2:28]1)[CH3:2].[OH-].[Na+].Cl.CCOCC>CO>[C:16]([CH2:15][O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:42](=[O:43])[C:41]5[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=5)[N:35]([CH3:45])[C:34]4=[O:46])[CH2:29][CH2:28]3)=[N:8][C:9]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])([OH:18])=[O:17]
Reactant: CCOC(=O)COc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC(=O)O
Yield: 101.3 %

Procedure:
In 30 ml of methanol was dissolved 900 mg (1.42 mmol) of Compound 54 obtained in Example 54, 15 ml of 2N-sodium hydroxide was added, and the mixture was stirred under heating at reflux for 4 hour. After cooling, 4N-hydrochloric acid was added to the reaction mixture and the mixtute was neutralized and subjected to extraction with chloroform. The organic layer was washed, dried and concentrated to give the residue. Ether was added to the above residue to give the precipitate which was collected by filtration and dried to give 870 mg (yield: 100%) of Compound 56 as white crystals.
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)C.[C:13](OC(C)(C)C)(=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S(=O)(=O)(O)O>CCCCCCC.O>[CH3:11][C:7]1[CH:6]=[C:5]([C:4](=[O:12])[CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)c1ccnc(C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Product: CC(=O)c1ccnc(C)c1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-isonicotinic acid ethyl ester (3.20 g) and tert-butyl acetate in n-heptane at −5° C. was slowly added lithium hexamethyldisilazide (46.5 mL; 1 M solution in THF). After stirring for 2 h, a solution of sulfuric acid (4.13 mL) in water (20 mL) was added within 20 min keeping the reaction temperature below 10° C. After the addition was completed, the reaction mixture was heated to reflux overnight. Extraction over a sat. solution of NaHCO3 (100 mL) with ethyl acetate (3×50 mL) and drying of the combined organic phases over Na2SO4 provided after evaporation of the organic solvent the title compound as a light brown liquid (2.40 g, 92%), which was used for the consecutive step without any further purification, MS (ESI+): m/z=136.0 [M+H]+.
Reaction SMILES: OC[C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](CNC)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[C:20]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:20][C:11]1[C:16]2[C:15](=[CH:10][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: CNCc1c2ccccc2c(CO)c2ccccc12
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc2cc3ccccc3cc12
Yield: 103.4 %

Procedure:
10-(hydroxymethyl)-9-((methylamino)methyl)anthracene (0.800 g, 3.18 mmol) and K2CO3 (0.56 g, 4.05 mmol) were taken up in 15 mL acetonitrile. A solution of 2,2-dimethylpropane-1,3-diyl(o-(bromomethyl)phenyl)boronate 3 (1.00 g, 3.44 mmol) in 5 mL acetonitrile was added and the mixture was refluxed under nitrogen for 24 h. The mixture was filtered hot on a sintered-glass frit and upon cooling, a yellow solid precipitated. The resulting solid was triturated with acetonitrile/water (4:1, v/v), filtered on a sintered-glass frit and vacuum dried to yield 11 as a bright yellow solid (0.632 g, 51.6% yield): 1H NMR (300.13 MHz, CD3OD) δ 2.58 (s, 3H), 4.58 (s, 2H), 5.22 (s, 2H), 5.61 (s, 2H), 7.62 (m, 6H), 7.80 (m, 2H), 8.18 (m, 2H), 8.58 (m, 2H); 13C—{1H} NMR (75.4 MHz, CD3OD) δ 136.9, 136.2, 135.9, 132.9, 132.7, 131.4, 129.9, 128.3, 127.1, 126.8, 126.5, 124.9, 124.1, 63.8, 57.1, 50.9, 40.7.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([O:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=1)[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][N:6]2[C:13]=1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:21]([OH:23])=[O:22])=[CH:32][CH:33]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(OC(C(=O)OC)c2cccc(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nn2c1Cc1ccc(OC(C(=O)O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.1 %

Procedure:
To a solution of 0.043 g (0.09 mmol) of the product of Step A in 1 mL of methanol was added 0.5 mL of a 1.0N solution of sodium hydroxide and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then adjusted to pH=6 with 0.5 mL of 1.0N hydrochloric acid, then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH-NH4OH (80:15:1). The purified fractions were combined, evaporated and dried in vacuo to afford 0.028 g (67%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][Si](C)(C)C)[C:3]=1[CH:4]=O.[NH3:16]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:16][CH:11]=[CH:10]2
Reactant: N
Reactant: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Product: Fc1cccc2ccncc12
Temperature: 80 °C

Procedure:
2-Fluoro-6-(2-(trimethylsilyl)ethynyl)benzaldehyde (2.3 g, 10.5 mmol) was dissolved in ammonia (2M in methanol, 15 mL, 30 mmol) and the resulting mixture was heated at 80° C. in a sealed tube for 2.5 h. The solvent was removed under high vacuum and the resulting crude product purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 8-fluoroisoquinoline as a pale yellow solid. MS (ESI, pos. ion) m/z: 148 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH3:29]>C(O)C>[NH2:29][C:23]([C:20]1[N:19]=[C:18]([C@H:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[O:22][N:21]=1)=[O:24]
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: N
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)c1nc(C(N)=O)no1

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 27) (400 mg, 1.01 mmol) in ethanol saturated with ammonia gas (20 ml) was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane:ethyl acetate (60:40) to afford the title compound as a white solid (260 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH3:3].O.[NH2:26]N>C(O)C>[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([NH:9][NH2:26])=[NH:8])[CH3:3]
Reactant: NN
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=N)N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=N)NN
Reaction time: 0.5 h
Yield: 74 %

Procedure:
The 2-ethoxy-5-(4-ethylpiperazin-1-yl-sulfonyl)benzamidine hydrochloride prepared in the above preparation example 1 was dissolved into ethanol (200 ml), and 85% hydrazine hydrate (5.9 g, 0.1 mol) was slowly dropped into the solution under ice bath. The mixture was stirred for 30 minutes and then at room temperature for 1 hour. Then, the solution was concentrated to dryness, and added with ethyl acetate to perform a recrystallization. The separated crystal was dried under vacuum to obtain 28 g of product with a yield of 74%. 1H NMR (CDCl3, 300 MHz) δ: 1.02 (3H, t), 1.49 (3H, t), 2.39 (2H, q), 2.51 (4H, t), 3.05 (4H, t), 4.18 (2H, q), 7.00 (1H, d), 7.69 (1H, dd), 8.13 (1H, d). ESI-MS m/z 356.3 (M++1, 100).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:37]1([CH:42]2[CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:44]4[CH2:45][CH2:46][CH:42]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:43]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: C1CCN(C2CCNC2)C1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.59 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 494 [M+H]
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: Fc1ccc(CBr)cc1
Product: O=C(O)c1cc(NCc2ccc(F)cc2)ccc1O
Yield: 56.4 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-fluorobenzyl bromide (740 mg, 3.92 mmole), 480 mg (44% yield) of 5-(4-fluorobenzyl)aminosalicylic acid was obtained as a white solid.: mp>210° C. (decompose).