Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([S:19](Cl)(=[O:21])=[O:20])=[C:14]([F:23])[CH:13]=1>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:19]([C:15]2[CH:16]=[C:17]([F:18])[C:12]([Br:11])=[CH:13][C:14]=2[F:23])(=[O:21])=[O:20])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Product: CC(=O)c1sc(NS(=O)(=O)c2cc(F)c(Br)cc2F)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (21.0 mg) with purty >90%: MS (pos) m/z 411.2, 413.2.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][CH:15]2[CH2:19][CH2:18][C@@H:17]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][CH:15]2[CH2:19][CH2:18][C@@H:17]([C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc([C@@H]2CCC(N[C@H](C)c3ccc(F)c4ccccc34)C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](NC1CC[C@@H](c2ccc(OCC(=O)O)cc2)C1)c1ccc(F)c2ccccc12

Procedure:
A solution of methyl {4-[(1R)-3-{[(1R)-1-(4-fluoronaphthalen-1-yl)ethyl]amino}cyclopentyl]phenoxy}acetate (72 mg, 0.17 mmol) and potassium hydroxide (56 mg, 1.0 mmol) in methanol (2 mL) and water (0.5 mL) was heated under reflux for 2 hours. 2N hydrochloric acid was added to the reaction solution to make the pH 7, and the solution was purified by high performance liquid chromatography (water:acetonitrile) to give the title compound (a mixture of diastereomers) (36 mg, 52%).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[F:11][C:7]1[CH:8]=[C:9]([F:10])[C:2]2[S:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(F)cc(F)c1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc(F)cc(F)c2s1

Procedure:
Using 3.94 g (24.6 mmol) of 2,3,5-trifluorobenzaldehyde, 1.48 g (36.9 mmol) of sodium hydride (60% pure) and 2.88 g (27.1 mmol) of methyl mercaptoacetate, 3.58 g (56% of theory) of the title compound are obtained in a purity of 89%. Recrystallization from methanol gives the product in a purity of 97%.
Reaction SMILES: C(OC1C(OCC)=CC=C2C=1C=CN2)C1C=CC=CC=1.C([O:28][C:29]1[C:37]([O:38][CH3:39])=[C:36]2[C:32]([CH:33]=[CH:34][NH:35]2)=[CH:31][CH:30]=1)C1C=CC=CC=1>>[OH:28][C:29]1[C:37]([O:38][CH3:39])=[C:36]2[C:32]([CH:33]=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: COc1c(OCc2ccccc2)ccc2cc[nH]c12
Agent: CCOc1ccc2[nH]ccc2c1OCc1ccccc1
Product: COc1c(O)ccc2cc[nH]c12
Yield: 86 %

Procedure:
This compound is obtained according to the operating method described in Example ld, in which the 4-benzyloxy-5-ethoxyindole is replaced by 6-benzyloxy-7-methoxyindole. A white powder is obtained (yield: 86%, m.p.=83°-84° C.).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[H-].[Na+].ClC(OCC)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.C(O)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:6])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25]
Reactant: Cc1ncccc1C(=O)O
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a slurry of 2-methyl-nicotinic acid (10.2 g, 74.45 mmol) in THF (30 mL) chilled to −10° C. was added sodium hydride (60% in mineral oil; 3.89 g, 89.3 mmol) portionwise and the reaction mixture stirred till no further gas evolution was noticed. Ethyl chloroformate (6.0 mL, 74.45 mmol) was added slowly at the same temperature and stirring continued for another 1 h, whereby a thick white slurry developed. Simultaneously, in a separate vessel, diethyl malonate (11.9 mL, 74.45 mmol) was added dropwise to a slurry of sodium hydride (60% in mineral oil; 3.24 g, 74.45 mmol)) in THF (20 mL) at −10° C., stirred for 30 min and slowly added to the slurry of the mixed anhydride. The reaction mixture was allowed to warm to r.t. and stirred overnight. The pH was adjusted to ˜pH 6 with acetic acid and evaporated to dryness. The residue was partitioned between water and ethyl acetate, the organics separated, then washed with water, brine, dried over sodium sulfate, filtered and concentrated to yield 2-(2-methyl-pyridine-3-carbonyl)-malonic acid diethyl ester (18.16 g, 87%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10](/[CH:13]=[N:14]/[S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C@H:13]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccn(-c2ccc(Cl)cc2)n1
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccn(-c2ccc(Cl)cc2)n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH4Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na2SO4) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.01 g). LCMS (B) m/z 326.3 (M+H)+
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH:20]=[CH:21][CH:22]=2)=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH:15]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[OH:8])[CH3:16])[CH:18]=1
Reactant: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-c1cccc(C(C)c2cccc(-c3ccccc3)c2O)c1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A solution of impure 23 (0.5 g, 1.06 mmol) in methanol (20 mL) and ethyl acetate (40 mL) was treated with 20% palladium on activated carbon (50% wet, 0.05 g) and was hydrogenated at 40 psi in a Parr shaker for 3 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (45 g) with 2% ethyl acetate in hexane (3 L) to afford pure D1 (0.33 g, 82%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(Cl)Cl.B(F)(F)F.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(=O)(=O)(O)O.O>[CH:10]1[C:2]2[C:1](=[O:11])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: -40 °C
Yield: 82 %

Procedure:
22.2 g of phthalic anhydride (0.15 mole) were charged into a stainless steel autoclave at ambient temperature with 10 cm3 of methylene chloride. The autoclave was cooled with liquid nitrogen. 30 g of HF (1.5 mole) and 102 g of BF3 (1.5 mole) were introduced. The temperature was brought to -40° C. and 12.9 g of benzene (0.165 mole) were introduced during 15 minutes. The temperature was maintained at -40° C. for one hour under 15 bars pressure, followed by decompression and degasification under vacuum to evaporate HF, BF3 and CH2Cl2 ; 10% caustic soda was then added to give a pH of 9. The solution was filtered, then acidified by addition of concentrated HCl. The O.B.B. acid precipitated in the form of very pure white crystals. The whole of the O.B.B. acid obtained was treated for 1 hour at 150° C. in 100% sulfuric acid. After cooling and dilution with water, 25.6 g of anthraquinone of 99.8% purity were obtained, i.e., an overall chemical yield of 82%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN1C(=O)CCC1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(N)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 5.0 g (19.3 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 3.94 g (21.2 mmol) N-Boc-piperazine using 2.94 mL (21.2 mmol) triethylamine in 30 mL NMP. Work up is performed by addition of 500 mL water to the reaction mixture and stirring for 30 min. The solid material is filtered off, washed with water (50 mL three times) yielding 7.25 g (17.7 mmol) of the desired product with sufficient purity.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21](C2C=CC=CC=2)[NH2:22])[CH:18]=[CH:19][CH:20]=1.[C:29](Cl)(=[O:39])[O:30][C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1.O>N1C=CC=CC=1>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[C@@H:31]([O:30][C:29](=[O:39])[N:22]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]3[O:1][CH2:5][CH2:4][O:3]3)[CH:16]=1)[CH2:32]2
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O[C@H]1CN2CCC1CC2)N(Cc1cccc(OCCCCCCCCC2OCCO2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 154.1 %

Procedure:
To a stirred solution of (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)-(phenyl)-methanamine (0.62 g, 1.62 mmol) in pyridine (10 mL) at 0° C., (R)-quinuclidin-3-yl carbonochloridate (0.48 g, 2.1 mmol) was added. The reaction was stirred at 0° C. for 1 hour and then allowed to warm to RT for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on a KP-NH Biotage cartridge eluting with 0-20% methanol in ethyl acetate to afford the title compound (0.67 g, 78%).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[C:17](=[O:19])=[O:18].Cl>CCCCCC.O1CCCC1>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]([O:7][CH3:6])[C:13]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: COc1cc(C)cc(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C)cc(OC)c1C(=O)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
104 ml of 1.6M n-butyllithium solution in hexane are added to 200 ml of tetrahydrofuran, followed by dropwise addition of 25 ml of 3,5-dimethoxytoluene, at a temperature between 0° and 5° C. The reaction medium is stirred at 5° C. for 1 h 30, followed by introduction of excess gaseous CO2 over 30 minutes. The mixture is introduced into 200 ml of aqueous 0.5N HCl solution and the aqueous phase is extracted with ethyl acetate. The residue is concentrated and chromatographied on a silica column (eluent: dichloromethane/methanol - 93/7).
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:17]1([NH:16][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCC1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Yield: 17.5 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (800 mg, 4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (43 ml) was added cyclohexanone (1.97 ml, 19 mmol; [108-94-1]), acetic acid (0.22 ml, 4 mmol) and sodium triacetoxyborohydride (2.43 g, 11 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 12 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting brown oil was dissolved in MeOH (20 ml) and heated under reflux conditions for 30 min. Removal of the solvent under reduced pressure left a brown oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (206 mg, 0.7 mmol; 18%) as yellow oil. MS: m/e=292.4 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[Na+]>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(CN2CCN(c3ccnc4[nH]ccc34)CC2)cc1
Yield: 81.3 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.50 g, 16.4 mmol) and N-benzyl piperazine (3.18 g, 18.0 mmol) were melted at 175° C. for 3 hours in a sealed tube, resulting in the formation of a crystalline solid mass. A solution of 0.1 M aqueous NaOH (10 mL) was added and the solid was broken up to give a suspension. Filtration gave 4-(4-benzyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine as a white solid (3.90 g). LCMS (APCI+) m/z 293 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[S:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[N:14]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[S:13]1[CH:17]=[C:16]([CH:18]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[N:15]=[N:14]1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: O=Cc1csnn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2cccs2)=NC1=Cc1csnn1
Temperature: 90 °C
Yield: 38 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,2,3-thiadiazol-4-carboxaldehyde (37 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 30 mg of the above-captioned compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[C:12]1([OH:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:22])=[CH:13][CH:14]=1)=[O:9]
Reactant: COC(=O)C(=O)Cl
Reactant: Oc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccc(O)c2ccccc12
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a suspension of AlCl3 (1.11 g, 8.3 mmol) in 50 mL DCM, methylchloroglyoxylate (1.02 g, 8.3 mmol) was added. The resulting solution was stirred for 5 min., after which naphthalen-1-ol (1 g, 6.9 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (10-30% EtOAc/Hex), to afford the target compound in 38% yield. Calculated mass=230. Observed mass=231.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc(O)cc1
Temperature: 100 °C

Procedure:
To a three-neck flask, fitted with a mechanical stirrer, thermometer, and condenser were added 94 g phenol and 98 g concentrated sulfuric acid and the mixture was stirred and heated at 100° C. for two hours under nitrogen atmosphere to form phenolsulfonic acid. To this reaction mixture were added 193 g water and 37 g calcium hydroxide and this mixture was stirred and heated at 95° C. for two hours. The reaction mixture was filtered to remove precipitated calcium sulfate to yield a 39.4% aqueous solution of the phenolsulfonic acid calcium salt. A portion of this salt solution (98 g containing 38.6 g salt), 70 g 4,4'-dihydroxydiphenylsulfone, 38.5 g of 37% aqueous formaldehyde, and 7.4 g calcium hydroxide were reacted for 15 hours at 97° C. under nitrogen atmosphere to form the substantially sulfonic acid-free, water-soluble sulfonated 4,4'-dihydroxydiphenylsulfone-formaldehyde calcium salt. This calcium salt product was diluted to 30% solids using 106 g water and the pH was adjusted to 7.6 with 3.5 g calcium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:14][C:7]=2[C:6]=1[OH:22])=[O:4].[Cu][C:24]#[N:25]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:24]#[N:25])[C:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:14][C:7]=2[C:6]=1[OH:22])=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(-c3ccc(F)cc3)csc2c1O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(-c3ccc(F)cc3)csc2c1O
Temperature: 150 °C
Yield: 30.1 %

Procedure:
A mixture of 4-bromo-3-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (58.5 mg, 0.153 mmol), example 32-a, and copper(I) cyanide (27.4 mg, 0.306 mmol) suspended in 1.5 mL of DMF was heated at 150° C. for 30 minutes. The resultant mixture was partitioned between ethyl acetate and water, and the organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-20% methanol in methylene chloride to produce 15.1 mg of a white solid. MS: (+) m/z 329.0 (M+1).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][N:20]=1>C(N(CC)CC)C>[O:25]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[C:1]1[C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Oc1cccnc1Br
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(c1cc3ncccc3o1)O2

Procedure:
This compound was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromo-3-hydroxypyridine under the conditions described in Example 26, but using twice as much triethylamine and lengthening the reaction time to 3 days. Chromatography of the crude product over the 40-fold amount of silica gel using 10% (V/V) of ethyl acetate in methylene chloride followed by crystallization from ether/hexane and recrystallization from ethyl acetate/hexane gave off-white crystals with m.p. 168°-169°.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]2[CH:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][O:9]2)[CH:4]=1)[CH3:2].[CH2:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH:24]=[C:23](C=O)[C:22]2=[O:31])[CH3:18].[OH:32]OS([O-])=O.[K+].CCOC(C)=O>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]2[CH:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][O:9]2)[CH:4]=1)[CH3:2].[CH2:17]([C:19]1[CH:28]=[CH:27][CH:26]2[CH:21]([C:22](=[O:31])[C:23]([OH:32])=[CH:24][O:25]2)[CH:20]=1)[CH3:18]
Reactant: CCc1ccc2occ(C=O)c(=O)c2c1
Reactant: O=S([O-])OO
Agent: CCC1=CC2C(=O)C(C(=O)O)=COC2C=C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1=CC2C(=O)C(O)=COC2C=C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To prepare 6-ethyl-4-oxo-4a,8a-dihydro-4H-chromene-3-carboxylic acid, 6-ethyl-3-formyl chromone (0.25 g) was dissolved in DMF (10 mL), and OXONE (0.76 g) was added and stirred at room temperature for 3 hours with the reaction having a final volume (12 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 6-ethyl-4-oxo-4a,8a-dihydro-4H-chromene-3-carboxylic acid in 52% yield and 6-ethyl-3-hydroxy-4a,8a-dihydro-chromene-4-one in 34% yield after purification by silica gel column chromatography.
Reaction SMILES: FC1C=C(C=CC=1[N+]([O-])=O)OCC1C=CC(C)=CN=1.[CH3:20][C:21]1[CH:44]=[C:43]([O:45][C:46]([F:49])([F:48])[F:47])[CH:42]=[CH:41][C:22]=1[CH2:23][NH:24][C:25]1[C:26]([NH2:40])=[CH:27][CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=2)[CH:30]=1.[C:50]1(=[O:60])[C@@H:58]2[C@@H:53]([CH2:54][CH2:55][CH2:56][CH2:57]2)[C:52](=O)[O:51]1>>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][O:31][C:29]2[CH:28]=[CH:27][C:26]3[N:40]=[C:52]([C@H:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C@H:58]4[C:50]([OH:60])=[O:51])[N:24]([CH2:23][C:22]4[CH:41]=[CH:42][C:43]([O:45][C:46]([F:48])([F:49])[F:47])=[CH:44][C:21]=4[CH3:20])[C:25]=3[CH:30]=2)=[N:34][CH:35]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Cc1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3C)c2)nc1
Agent: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(OC(F)(F)F)cc4C)c3c2)nc1

Procedure:
The title compound was prepared using analogous conditions described in Example 92 using 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine in Step B and N1-(2-methyl-4-(trifluoromethoxy)benzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and cis-hexahydroisobenzofuran-1,3-dione in Step D. MS (ESI): mass calcd. for C30H30F3N3O4, 553.20; m/z found, 553.9 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=7.3, 1H), 7.37 (d, J=8.2, 1H), 7.32 (s, 1H), 7.15 (s, 2H), 6.95 (d, J=7.9, 1H), 6.36 (d, J=8.3, 1H), 5.60 (s, 2H), 5.11 (s, 2H), 3.59 (s, 1H), 2.71 (s, 1H), 2.50 (s, 3H), 2.28 (s, 3H), 1.75 (brs, 4H), 1.60-1.30 (m, 4H).