Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:23]([Mg]Br)[CH2:24][CH2:25][CH2:26][CH3:27].Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC[Mg]Br
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A solution of 9.15 g (29.7 mmol) of ethyl 3-(2,4-dimethoxyphenyl)-2-ethoxycarbonyl-2-propenoate (prepared as described in Preparation 1) in 9 ml of diethyl ether was added to 72 ml (36 mmol) of a 0.5M ice-cooled solution of pentylmagnesium bromide in diethyl ether, and the resulting mixture was stirred at the same temperature for 1.5 hours. At the end of this title, the reaction mixture was poured into a 10% aqueous solution of hydrochloric acid in ice, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 200 g of silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.65 g (yield 77%) of the title compound as an oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.O>C1(C)C(C)=CC=CC=1>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: Cc1ccccc1C
Product: Nc1ccc(N=Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A solution of 15.3 g (100 mmol) 2-nitro-p-phenylenediamine and 13.6 g (110 mmol) 4-fluorobenzaldehyde in 400 ml xylene is heated under reflux in the presence of 0.5 g of an acid ion exchanger (for example Nafion) for 3 hours in a water separator. Insoluble constituents are filtered out hot and the mixture is allowed to stand overnight at room temperature. An orange-yellow solid crystallizes out. This solid is suction filtered, washed with a little toluene and dried in a vacuum. 22.0 g (85% of theory) 2-amino-5-(4-fluorobenzylideneamino)-nitrobenzene is obtained as orange-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(F)cc1)OCC
Temperature: 150 °C
Reaction time: 22 h

Procedure:
4-fluorobenzyl bromide (100 g) and triethyl phosphite (120 ml) were mixed, and the mixture was stirred at 150° C. for 22 hours. The obtained reaction mixture was distilled under reduced pressure (bp 115-120° C./1.5 mmHg) to give diethyl 4-fluorobenzylphosphonate (125 g). To a solution of 4-fluorobenzylphosphonate (60.8 g), 15-Crown-5 (4 ml) in THF (400 ml) was added 60% sodium hydride in mineral oil (9.75 g) under ice cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 1-tert-butoxycarbonyl-4-piperidone (42.0 g) in THF (150 ml) under ice cooling, and the mixture was stirred at room temperature for 22 hours. After the addition of water under ice cooling, the mixture was extracted with ethyl acetate;, and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium chloride, successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 650 g, hexane/ethyl acetate=30/1 to 10/1), and the desired fraction was concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-fluorobenzylidene)piperidine (47.0 g).
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[C:29]([F:40])=[C:30]2[C:35](=[C:36]([O:38][CH3:39])[CH:37]=1)[O:34][CH2:33][CH2:32][CH2:31]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[NH:54][NH2:55])=[O:48])[CH3:45]>C(N(CC)CC)C>[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[N:54]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[C:29]([F:40])=[C:30]3[C:35](=[C:36]([O:38][CH3:39])[CH:37]=2)[O:34][CH2:33][CH2:32][CH2:31]3)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:55]1)=[O:48])[CH3:45]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Reactant: CCOC(=O)c1scnc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 20 h
Yield: 56.6 %

Procedure:
To 4 ml of a DMF solution containing 111 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (189a)), 37 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester (Example (185c)) and 0.031 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 20 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 4 ml of methanol and 0.032 ml of acetic acid, and then 83 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (74 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[N:20]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:18]([CH3:32])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:32][C:18]1[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[N:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cnc(Cl)nc1Cc1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cc1cccc(C(F)(F)F)c1
Yield: 51.9 %

Procedure:
A stirred mixture of 4-(trifluoromethyl)benzene boronic acid (430 mg, 2.3 mmol), the title compound of Step A (500 mg, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (120 mg, 0.17 mmol) and sodium carbonate (550 mg, 5.2 mmol) in a mixture of 6 mL of water and 2 mL of tetrahydrofuran was heated at reflux for 1.5 h. The reaction mixture was then partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (20 to 25% ethyl acetate in hexane) followed by trituration with 10% diethyl ether in hexane afforded 350 mg of the title compound of Step B, a compound of this invention, as a yellow-tinted solid melting at 112-113° C. 1H NMR (CDCl3): δ8.55 (m, 3H), 7.70 (d, 2H), 7.60 (s, 1H), 7.55-7.40 (m, 3H), 4.25 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3]1.[C:12]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:21][CH3:22])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](=[N:19][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[S:21][CH3:22])[CH2:6][CH2:7]1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CN1CCC(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSC(=NC(=O)OC(C)(C)C)N(CCCC1CCN(C)CC1)C(=O)OC(C)(C)C
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL round bottom flask were added 3-(1-methyl-piperidin-4-yl) -propan-1-ol (0.23 g, 0.0014 mol), 1,3-di-Boc-2-methylisothiourea (0.42 g, 0.0014 mol), PPh3 (0.42 g, 0.0016 mol) and THF (anhydrous, 8.0 mL). The resultant, stirred stirring solution was cooled to 2.0° C. To the resultant solution was then added DEAD (0.27 mL, 0.0016 mol) drop wise. The reaction was aged cold for 30 min, warmed to room temperature and aged for 14 h. The THF was removed via rotovap and the residue taken up in MTBE (10 mL). The resultant solution was extracted with saturated aqueous NaHCO3 (2×10 mL) and diluted with hexanes (20 mL). After 10 min, the resultant slurry was filtered and the filtrate concentrated via rotovap. The residue was taken up in hexanes (25 mL) and filtered after 10 min. The filtrate was concentrated to yield N-[3-(1-methylpiperidin-4-yl)-propyl]-N,N′-di-Boc-methylisothiourea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(Cl)c1

Procedure:
3,4-Dichloronitrobenzene (10 g), piperazine (30 g) and dioxan (10 ml) were stirred for 4 hours under gentle reflux (internal temp. 120°-130°). The mixture was then cooled and water (50 ml) was added; the desired product crystallized out and was filtered off, washed with water and dried: yield of the compound 11.32 g. A small portion (0.6 g) was recrystallized from petroleum b.p. 60°-80°/ethyl acetate, yielding the product, (0.36 g), m.p. 100°-102°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19]O)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:22].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][Br:22])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCCC(CO)C2)cc1OC
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CCN2CCCC(CBr)C2)cc1OC
Temperature: 0 °C
Reaction time: 15 h

Procedure:
4.4 g (0.0157 mol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3(hydroxymethyl)-piperidine are dissolved in 70 ml of carbon tetrachloride and cooled to 0° C. Then 1.63 ml (0.0173 mol) of phosphorus tribromide is added, whereupon a bulky precipitate is immediately formed. The mixture is stirred for 15 hours at ambient temperature, water is added and the mixture is neutralized with 2 molar sodium hydroxide solution. The organic phase is separated off, washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 310 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 5%). Yield: 2.0 g (37.2% of theory), Rf value: 0.5 (aluminium oxide neutral, eluant: 2% ethanol in methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24]>>[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:14][CH2:13][CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:10]1)=[O:24]
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: Nc1cccc(C(=O)O)c1
Product: Nc1cccc(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared in a similar manner to the method of Example 14, Step b using the product from Example 3, Step b and 3-aminobenzoic acid to give the sub-title product (0.183 g).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1cc(Cl)ccc1Cl
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(Cl)ccc1Cl
Yield: 75.5 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (7.50 g, 36.2 mmol) and 2,5-dichloroaniline (5.30 g, 32.6 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (8.64 g, 68%) was obtained.
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.C(OCC)C>[C:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
The resulting N-BOC-2-amino-2-methyl-1-propanol (3.69 g, 19.5 mmol) was dissolved in methylene chloride (74 ml) and added to a stirred suspension of Dess-Martin periodinane (10.75 g, 25.35 mmol; Aldrich Chemical Company, Milwaukee, WI) in methylene chloride (89 ml). After stirring for 20 minutes under nitrogen, the reaction mixture was diluted with diethyl ether (370 ml), poured into sodium hydroxide (148 ml, 1.3M) and stirred for ten minutes. The aqueous sodium hydroxide layer was separated and discarded. The remaining organic solution was washed successively with sodium hydroxide (148 ml, 1.3M) and H2O (185 ml). After drying over magnesium sulfate, the solvent was removed in vacuo to yield 3.21 grams of N-BOC-2-amino-2-methyl-l-propanal.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=2)[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1.O.Cl>C(O)C.[Fe]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc(N)ccc21
Yield: 40.1 %

Procedure:
3-(1H-Benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-ylamine can be obtained in the following way: 485 mg of powdered iron are added, in small fractions, to a solution, brought to reflux, of 350 mg of 3-(1H-benzimidazol-2-yl)-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole, of 15 ml of ethanol, of 200 μl of distilled water and of 320 μl 12N hydrochloric acid and the mixture is maintained at reflux for 16 hours. After returning to a temperature in the region of 20° C., the medium is diluted with 60 ml of ethanol, stirred, and then filtered through a bed of Celite® 535, which is then washed with ethanol. The filtrate is basified to a pH in the region of 9 with a saturated aqueous sodium hydrogencarbonate solution. The precipitate thus formed is removed by filtration, and washed with ethanol, and the filtrate is then concentrated to dryness under reduced pressure. The evaporation residue is dissolved in distilled water and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 130 mg of 3-(1H-benzimidazol-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-ylamine are thus obtained in the form of an orange lac (Rf=0.34, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (50/50 by volume); mass analysis: El: m/z 379 (M+.) (base peak), m/z 306).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][C:39]#[C:40][CH:41]2[CH2:43][CH2:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][C:39]#[C:40][CH:41]2[CH2:43][CH2:42]2)=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: OC[C@H]1O[C@H](c2ccc(Cl)c(Cc3ccc(OCC#CC4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Compound AW was prepared by reaction of (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D2) with 3-cyclopropylprop-2-ynyl 4-methylbenzenesulfonate (intermediate AU) in the presence of Cs2CO3 using the same procedure as described above for compound AV. 1H NMR (CD3OD): δ 7.34˜7.30 (3H, m), 7.11˜7.08 (2H, d, J=8.8 Hz), 6.86˜6.84 (2H, d, J=8.8 Hz), 4.61 (2H, d, J=1.6 Hz), 4.58 (1H, d, J=4 Hz), 4.19˜4.17 (1H, m), 4.03˜4.00 (4H, m), 3.94˜3.93 (1H, q), 3.84˜3.80 (1H, m), 3.68˜3.64 (1H, q), 1.29˜1.24 (1H, m), 0.78˜0.75 (2H, m), 0.62˜0.59 (2H, m).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=C([CH:27]=[CH:28][CH:29]=4)C(O)=O)[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1.CN(C)C=O>ClCCl>[F:7][C:8]1[C:17]2[NH:16][CH:15]=[C:14]3[C:18](=[O:30])[N:19]([C:21]4[CH:22]=[C:1]([CH:27]=[CH:28][CH:29]=4)[C:2]([Cl:4])=[O:3])[N:20]=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 50 °C
Yield: 95.9 %

Procedure:
Oxalyl chloride (20 ml, 0.2 mol) was added dropwise over 2 min to a stirred solution of 3-(6-fluoro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (intermediate 3) (2.0 g, 6.1 mmol) in dichloromethane (10 ml) at room temperature. N,N-Dimethylformamide (50 μl) was then added and the resulting mixture heated to 50° C. for 1 h. The solution was then cooled to room temperature and then concentrated in vacuo to leave the title compound (intermediate 4) (2.0 g, 96%) as a beige solid.
Reaction SMILES: F[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[N:7]2.[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.C(N(CC)CC)C>CS(C)=O>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([C:2]2[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:4]([CH3:18])[C:5]([C:16]#[N:17])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[N:7]3)[CH2:28]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(O)C3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(O)C3)nc2c1C#N
Temperature: 150 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
7-Fluoro-2-(3-hydroxyazetidin-1-yl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-143) (120 mg, 0.37 mmol) was dissolved in dimethyl sulfoxide (6 ml), then (3S)-3-(dimethylamino)pyrrolidine (71 μl, 0.56 mmol) and triethylamine (189 μl, 1.11 mmol) were added, followed by stirring at 150° C. under nitrogen atmosphere for 5 hours. After cooling and fractionation with water and ethyl acetate, the organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (9:1, v/v/) gave the entitled compound (36.4 mg, 23%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:4][CH:5]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccc(Cl)cc1)c1ccc(CN2CCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
Acetonitrile (55 ml) was added to [4-(bromomethyl)phenyl](4-chlorophenyl)methanone (6.71 g, 21.7 mmol), potassium carbonate (5.99 g, 43.3 mmol) and pyrrolidine (3.62 ml, 43.3 mmol), and the mixture was stirred at 80° C. for 16 hrs. The solvent was concentrated, and diethyl ether was added to the residue. The mixture was extracted with 1N hydrochloric acid. The extract was basified with potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate) to give the title compound (4.79 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17]>C1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(C(C)C)cc1
Reactant: NCC(O)c1ccccc1
Solvent: c1ccccc1
Product: CC(Cc1ccc(C(C)C)cc1)NCC(O)c1ccccc1
Yield: 88.2 %

Procedure:
A mixture of 4-isopropylphenylacetone (2.64 g) and 2-hydroxy-2-phenylethanamine (2.05 g) were refluxed in benzene (70 ml) under Dean & Stark conditions for 4 h. The solvent was removed under reduced pressure, replaced with ethanol (100 ml) and the solution hydrogenated using Pt as catalyst. The filtered solution was evaporated and the residual oil chromatographed on Kieselgel 60 (150 g). Elution with 2% methanol-chloroform gave the title compound as an oil (3.92 g). Treatment of this with a methanolic solution of fumaric acid and recrystallisation of the solid from ethylacetate gave the title compound (58:42 mixture of diastereoisomers) as the hemi fumarate containing one mole of water, mp 55-57.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=O)=[CH:6][CH:5]=1>>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]2[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]([OH:13])=[N:2][N:1]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: NN
Product: Oc1nnc(-c2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3 M ethanolic solution of hydrazine (20 ml, 60 mmol) is added to 2-(4-chlorobenzoyl)benzoic acid (5.5 g, 20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation gives 4-(4-chlorophenyl)-1-hydroxy-phthalazine.