Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:19])([CH3:18])[C:8](=[O:17])[N:9]2[CH3:16])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1.C(=O)([O-])[O-].C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([NH:6][C:7]([CH3:19])([CH3:18])[C:8](=[O:17])[N:9]3[CH3:16])=[CH:4][CH:3]=2)[CH:22]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)c1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1c(-c2cc(Cl)ccc2OC)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A mixture of 7-bromo-8-methoxycarbonyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 9, 3.75 g, 11.5 mmol), 5-chloro-2-methoxyphenylboronic acid (2.57 g, 13.8 mmol), cessium carbonate (7.49 g, 23.0 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.33 g, 1.16 mmol) was suspended in anhydrous N,N-dimethylformamide (70 ml) and stirred at 80° C. overnight under argon atmosphere. After cooling down, ethyl acetate (300 mL), diethylether (150 mL) and water (400 mL) were added and partitioned. The organic layer was washed with water (250 mL) and saturated brine (150 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (3.84 g) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:44]=[CH:43][C:24]([C:25]([N:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[C:29]([CH2:38][C:39]([OH:41])=O)=[C:28]2[CH3:42])=[O:26])=[CH:23][CH:22]=1.[CH2:45]([CH2:47][NH2:48])O.C(N(CC)CC)C>C(#N)C.C(Cl)(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[C:29]([CH2:38][C:39]3[O:41][CH2:45][CH2:47][N:48]=3)=[C:28]2[CH3:42])=[O:26])=[CH:43][CH:44]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(CC1=NCCO1)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A solution of 3.93 g of triphenylphosphine in 80 ml of absolute acetonitrile was added dropwise under stirring at 25° C. under argon to a solution of 1.789 g of 1-p-chlorobenzoyl-2-methyl-5-methoxyindol-3-acetic acid, 0.305 g of ethanolamine, 2.02 g of triethylamine, and 3.176 g of carbon tetrachloride in 100 ml of absolute acetonitrile, for a period of three and a half hours. After 18 hours at 24° C., the mixture was evaporated under vacuum and the crystalline residue agitated with 200 ml of ethyl ether and 75 ml of 2 N aqueous sodium hydroxide solution. After separation of the aqueous phase and secondary extraction with three times 40 ml of ethyl ether, the combined ether extracts were dried (Na2SO4) and concentrated, during which step triphenylphosphine oxide was crystallized. The filtrate was evaporated and chromatographed with toluene on 210 g of aluminum oxide, activity stage IV (alkaline; Woelm); after a forerun of 300 ml, the subsequent 800 ml of eluate yielded 1.38g of a light-yellow, oily (4-chlorophenyl)-[5-methoxy-2-methyl-3-(oxazolin-2-ylmethyl)-1-indolyl]ketone.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:23])([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:16]([N:24]=[N+:25]=[N-:26])[CH3:17])([F:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 3-fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (Example A15, 0.25 g, 0.72 mmol) in N,N-dimethylformamide (5 mL) is added sodium azide (0.13 g, 2 mmol). The reaction mixture is heated at 120° C. overnight. The mixture is diluted with water and extracted with ethyl acetate. The extracts are washed with brine, dried over Na2SO4 and concentrated to afford the title compound (0.160 g). 1H NMR (200 MHz, CDCl3): δ 7.28 (s, 5H), 5.08 (s, 2H), 3.80–3.25 (m, 5H), 2.13–1.75 (m, 2H), 1.40 (d, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:16]([NH:19][CH2:20][C:21](O)=[O:22])(=[O:18])[CH3:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)C(C)C)(C)C>[C:16]([NH:19][CH2:20][C:21]([N:5]([CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:22])(=[O:18])[CH3:17]
Reactant: COC(CNCc1ccc(F)cc1)OC
Reactant: CC(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(C)=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)amine (366.5 g, 1.72 mol), N-acetylglycine (213.7 g, 1.83 mol), EDC (350.0 g, 1.83 mol), and HOBt (29.1 g, 0.19 mol) in anhydrous DMF (2.5 L), N,N-diisopropylethylamine (˜250 mL) was added until the solution is about pH 8. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between dichloromethane (4 L) and water (1 L). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [F:1]C1C=CC=CC=1CN1C=C(C2C3C(=NC=C(C4C=C(NS(C)(=O)=O)C=CC=4)C=3)NC=2)C=N1.F[C:35]1[CH:80]=[CH:79][C:78]([F:81])=[CH:77][C:36]=1[CH2:37][N:38]1[C:42]([CH3:43])=[C:41]([C:44]2[C:52]3[C:47](=[N:48][CH:49]=[C:50]([C:53]4[CH:54]=[CH:55][C:56]([O:64][CH3:65])=[C:57]([S:59]([NH:62][CH3:63])(=[O:61])=[O:60])[CH:58]=4)[CH:51]=3)[N:46](S(C3C=CC(C)=CC=3)(=O)=O)[CH:45]=2)[C:40]([CH3:76])=[N:39]1.[OH-].[Li+]>C1COCC1.CO.O>[F:81][C:78]1[CH:77]=[C:36]([CH:35]=[C:80]([F:1])[CH:79]=1)[CH2:37][N:38]1[C:42]([CH3:43])=[C:41]([C:44]2[C:52]3[C:47](=[N:48][CH:49]=[C:50]([C:53]4[CH:54]=[CH:55][C:56]([O:64][CH3:65])=[C:57]([S:59]([NH:62][CH3:63])(=[O:60])=[O:61])[CH:58]=4)[CH:51]=3)[NH:46][CH:45]=2)[C:40]([CH3:76])=[N:39]1
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5F)c4)c3c2)c1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)ccc4F)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c3c2)ccc1OC
Yield: 11.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example 1, 5-(3-(1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (180 mg, 0.2604 mmol) was hydrolyzed by lithium hydroxide (109 mg, 2.604 mmol), THF/Methanol/water (24/12/6 ml) to yield 16 mg (11.4% yield) of the titled compound after purification by preparative TLC (SiO2-1000 micron eluted by 3% MeOH in CHCl3). 1H NMR (CD3OD, 300 MHz): δ 8.382 (m, 1H), 7.940-7.935 (d, 1H), 7.816-7.779 (m, 2H), 7.342 (s, 1H), 7.241-7.213 (d, 1H), 6.68-6.64 (m, 1H), 5.275 (s, 2H), 3.914 (s, 3H), 2.441 (s, 3H), 2.128-2.101 (d, 6H). MS: m/z=538.1 (M+1); HPLC: 95.69% in method B.
Reaction SMILES: Cl.[CH3:2][N:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:13](=[O:19])[C:12]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:4].CC([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41]C(C)=O)[C@@H:36]([O:45]C(C)=O)[C@@H:35]1[O:49]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH:16]([N:15]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([N:3]([CH3:2])[CH3:4])=[CH:6][CH:7]=2)=[C:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:13]([O:19][C@@H:38]2[O:39][C@H:34]([CH2:33][OH:32])[C@@H:35]([OH:49])[C@H:36]([OH:45])[C@H:37]2[OH:41])=[N:14]1)([CH3:17])[CH3:18]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(Cc2c(-c3ccc(N(C)C)cc3)n(C(C)C)[nH]c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)C)c2-c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a suspension of 5-[4-(N,N-dimethylamino)phenyl]-1-isopropyl-4-(4-methoxyphenyl)methyl-3H-pyrazole-3-on hydrochloride (0.051 g), acetobromo-α-D-glucose (0.16 g) and benzyl(n-tributyl)ammonium chloride (0.12 g) in dichloromethane (3 mL) was added sodium hydroxide (2 mol/L, 0.19 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent:ethyl acetate). The obtained semi purified 1-isopropyl-4-(4-methoxyphenylmethyl)-5-[4-(N,N-dimethyl-amino)phenyl]-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazoel was dissolved in methanol, and sodium methoxide (28% methanol solution, 0.02 mL) was added to the solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18UG80, 5μM, 20×50 mm, flowrate 30 mL/min linear gradient, water/methanol=90/10-10/90) to give the title compound (0.040 g).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.C(OC(=O)C)(=O)C.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:29]([N:31]2[C:37]3[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:36]=3[CH:35]([OH:43])[CH2:34][CH2:33][CH2:32]2)=[O:30])=[C:26]([CH3:28])[CH:27]=1)=[O:20].[OH-].[Na+]>O.C(O)(=O)C>[Cl:42][C:40]1[CH:39]=[CH:38][C:37]2[N:31]([C:29](=[O:30])[C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH3:12])=[CH:27][C:26]=3[CH3:28])[CH2:32][CH2:33][CH2:34][CH:35]([O:43][CH2:1][S:2][CH3:4])[C:36]=2[CH:41]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Dimethylsulfoxide (DMSO) (3 ml), acetic anhydride (1.5 ml), and acetic acid (1.5 ml) were added to tolvaptan (1.0 g, 2.2 mmol), and the mixture was stirred at 70° C. for 4 hours. Water and 1N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=80:20→20:80). The purified product was concentrated under reduced pressure to obtain 0.62 g of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine as white amorphous solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH:14]=1)(C(C)(C)C)(C)C.C(OCC)C>C(O)(=O)C.C1COCC1.O.ClCCl>[F:32][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]2=[O:31])[CH:19]=[CH:20][C:15]=1[N:13]1[CH:14]=[C:10]([CH2:9][OH:8])[N:11]=[CH:12]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO[Si](C)(C)C(C)(C)C)c3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
N-[(5S)-3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (6.0 g) was dissolved in a mixture of acetic acid (60 ml), THF (20 ml) and water (20 ml), and left to stir overnight at ambient temperature. Solvents were evporated at 40° in vacuo to give a gum. This was dissolved in dichloromethane (25 ml), and dry diethyl ether (100 ml) stirred in. The precipitate was triturated and stirred until properly solid, then filtered, washed with ether, and dried in vacuo to give product (3.7 g).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:33]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[N:14]([CH3:33])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Solvent: CI
Solvent: ClCCl
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 50 °C
Yield: 29.1 %

Procedure:
To a solution of 2-(4-(4-fluorophenoxy)benzylthio)-5-((2-methoxypyrimidin-5-yl)methyl) pyrimidin-4(1H)-one (100 mg, 0.222 mmol) and Hunig's base (0.058 mL, 0.333 mmol) in DCM (4 mL) was added MeI (0.021 mL, 0.333 mmol). The mixture was heated at 50° C. for 2 h. Purification via reverse phase flash chromatography then afforded the title compound (30 mg, 29.1% yield). LCMS: rt=3.05 min, [M+H+]=465.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)(=O)=O.[CH3:18][NH:19][CH3:20]>CO.O1CCCC1>[CH3:18][N:19]([CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
To a solution of tert-butyl 3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate (1.05 g) in methanol (20 ml) was added a 2M solution of dimethylamine in tetrahydrofuran (20 ml), followed by heating in a sealed tube at 70° C. for 40 hr. The reaction mixture was allowed to cool down to room temperature. The reaction mixture was concentrated, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to provide the titled compound as a yellow oil (678 mg, 79.9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][NH:19][CH2:20][CH3:21]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:18][NH:19][CH2:20][CH3:21]
Reactant: Fc1cc(Br)c(CCl)cc1F
Reactant: CCNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCNCCc1cc(F)c(F)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of 1-bromo-2-chloromethyl-4,5-difluorobenzene are dissolved in 5 ml of acetonitrile. 540 mg of caesium carbonate and 146 μl of methylethylamine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness, after which the product is isolated as oil.
Reaction SMILES: [F:1][C:2]1([F:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]1([F:14])[F:13].C([Li])(CC)C.[B:21](OC)([O:24]C)[O:22]C.Cl>O1CCCC1.COC(C)(C)C>[F:15][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([B:21]([OH:24])[OH:22])[C:10]=2[F:12])[CH:5]=[CH:4][C:3]1([F:13])[F:14]
Reactant: COB(OC)OC
Reactant: Fc1cccc2c1C(F)(F)C(F)(F)C=C2
Agent: Cl
Agent: [Li]C(C)CC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1F)C(F)(F)C(F)(F)C=C2
Reaction time: 3 h

Procedure:
A solution of 4.8 g of 1,1,2,2,8-pentafluoro-1,2-dihydronaphthalene [(Z3) where R1=H] in 75 ml of tetrahydrofuran was mixed with 11 ml of sec-butyllithium (2M in pentane) at a temperature below −75° C. After 3 g of trimethyl borate had been added, the mixture was stirred at the same temperature for 3 hours and subsequently brought to room temperature overnight. After hydrolysis using 10% hydrochloric acid, 150 ml of tert-butyl methyl ether were added, and the organic phase was separated off, washed with water and sodium chloride solution and dried. The 1,1,2,2,8-pentafluoro-1,2-dihydronaphthalene-7-boronic acid obtained was reacted with the equimolar amount of 4-propylbromobenzene, 2 mol-equivalents of sodium carbonate and 1 mol % of tetrakis(triphenylphosphine)palladium(0) in 50 ml of an ethanol/toluene/water 1:2:1 (vol.) mixture by refluxing for one day. After conventional work-up, the organic fraction was subjected to chromatographic purification (silica gel, toluene/heptane 2:1), the product-containing fractions were combined, the solvent mixture was distilled off under reduced pressure, and the residue was recrystallised from acetonitrile, giving 1.6 g of 1,1,2,2,8-pentafluoro-7-(4-propylphenyl)-1,2-dihydronaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.CS(C)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH:10]=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](CCO)c1cccc(F)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](CC=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine sulfur trioxide complex (37.7 g, 237 mmol) was added portionwise over 20 minutes to a stirred cold (0° C.) solution of N-[(1S)-1-(3-fluorophenyl)-3-hydroxypropyl]acetamide (25 g, 118 mmol), DMSO (16.5 ml, 233 mmol) and triethylamine (33 ml, 237 mmol) in dichloromethane (240 ml). After two hours stirring at room temperature, solvent was evaporated under reduced pressure and the residue applied directly to a silica gel column. Eluting with a gradient system starting with ethyl acetate:dichloromethane (50:50 by volume) then ethyl acetate:dichloromethane (80:20 by volume) and finally ethyl acetate gave the title compound as a colourless oil which solidified on standing (13.9 g).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=3)=[N:19][C:18]=2[CH3:33])[CH3:16])=[CH:10][C:9]=1[CH3:34])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:6][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([F:32])[CH:23]=3)=[N:19][C:18]=2[CH3:33])[CH3:16])=[CH:10][C:9]=1[CH3:34])([CH3:35])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OC(C)c2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OC(C)c2sc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)ccc1OC(C)(C)C(=O)O
Yield: 74 %

Procedure:
A solution of example 6 (270 mg) in EtOH (15 mL) was treated with 1N sodium hydroxide (1.54 mL, 3 eq.) and the mixture heated to reflux for 3 hours. The cooled reaction was concentrated and the residue diluted with water (20 mL); 1N hydrochloric acid (2 mL) was added and the resulting suspension extracted with dichloromethane (20 mL). The organic extract was dried over magnesium sulphate and concentrated to give the title compound in 74% yield as a yellow solid (190 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[N:4][NH:5][C:6]=1[CH3:7].F[C:16]1[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][C:17]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][C:2]1[C:3]([N:8]([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])=[N:4][N:5]([C:16]2[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[CH:18][C:17]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:6]=1[CH3:7]
Reactant: CCOC(=O)c1cc(C(=O)OCc2ccccc2)ccc1F
Reactant: CCCN(CCC)c1n[nH]c(C)c1Cl
Product: CCCN(CCC)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C)c1Cl
Yield: 47.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 4-chloro-5-methyl-N,N-dipropyl-1H-pyrazol-3-amine (290 mg, 1.34 mmol) and 1-benzyl 3-ethyl 4-fluoroisophthalate (Intermediate 91B, 447 mg, 1.48 mmol) were converted to the title compound (315 mg, 47%). 1H NMR (CDCl3) δ 8.55 (d, J=2.0 Hz, 1H), 8.27 (dd, J=8.3, 2.1 Hz, 1H), 7.54-7.32 (m, 6H), 5.43 (s, 2H), 4.20 (q, J=7.0 Hz, 2H), 3.32-3.17 (m, 4H), 2.17 (s, 3H), 1.69-1.54 (m, 6H), 1.21 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 498.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[CH:5][CH:4]=1)#[N:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>ClCCl.O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:42][CH2:43][C:44]3[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=3[CH3:50])=[O:16])=[CH:17][CH:18]=2)[CH3:9])=[CH:19][CH:20]=1)#[N:2]
Reactant: CC(Oc1ccc(C#N)cc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccc(C#N)cc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
A mixture of 4-(1-(4-cyanophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (382 mg, 2 mmol), 1-Hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.4 mL) in dichloromethane (55 mL) were stirred at 25° C. for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added to the above mixture. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was evaporated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(4-cyanophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (150 mg, 48%) as a white solid. LRMS (M+H+) m/z: cald. 401.17. found 401.