Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([N:15]([C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH3:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]([O:25][C:19]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([N:15]([CH3:16])[C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(N(C)C(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)N(C)C2(C(=O)O)Cc3ccccc3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
The mixture of 2-[(2-isopropoxy-3-methyl-benzoyl)-methyl-amino]-indan-2-carboxylic acid ethyl ester (118′) (200 mg, 0.51 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (119) as a pale orange solid (170 mg, 91%).
Reaction SMILES: Cl.[C:2]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)N)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]1[C:23](=O)[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])([C:25]([OH:27])=[O:26])[CH2:19]1.C(O)(=O)C>O>[C:2]([N:10]1[C:23]2[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])([C:25]([OH:27])=[O:26])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(C(=O)O)(C(=O)O)CC1
Reactant: NN(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1)n1c2c(c3ccccc31)CC(C(=O)O)(C(=O)O)CC2

Procedure:
1-Benzoyl-1-phenylhydrazine hydrochloride (5 g.) and 4 g. of cyclohexanone-4,4-dicarboxylic acid in 10 ml. of glacial acetic acid were heated at 60°-70°C. for thirty minutes. The mixture was diluted with water and the resulting solid was collected by filtration and washed with water to give 7.1 g. of the title compound; m.p. 160°C. (acetone and hexane).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.[CH2:16]([N:18]1[CH:22]=[C:21]([CH:23]=O)[C:20]([CH3:25])=[N:19]1)[CH3:17].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+].C(O)(=O)C>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:23][C:21]3[C:20]([CH3:25])=[N:19][N:18]([CH2:16][CH3:17])[CH:22]=3)[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: CCn1cc(C=O)c(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCn1cc(CN2CCN(c3nccnc3Cl)CC2)c(C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.9 %

Procedure:
Combine 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (2.21 g, 8.18 mmol), 1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde (1.3 g, 9.40 mmol) and triethylamine (1.31 mL, 9.40 mmol) in dichloroethane (50 mL). Add glacial acetic acid (0.85 mL) followed by sodium triacetoxyborohydride (2.99 g, 14.1 mmol). Stir at room temperature for 20 hr. Dilute with saturated aq. sodium bicarbonate then extract three times using DCM. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 4.5:95.5 methanol (with 2 M ammonia):DCM), to give 3′-chloro-4-(1-ethyl-3-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a yellow oil (1.702 g, 65%). MS (ES): m/z=321 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=4)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[OH-:34].[Na+].OO>C1COCC1.O>[OH:34][CH:22]1[CH:21]([C:18]2[CH:17]=[CH:16][C:15]([N:13]3[CH:14]=[C:10]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)[N:11]=[N:12]3)=[CH:20][CH:19]=2)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
To a stirred solution of borane-methyl sulfide complex (587 μl of a 2.0 M solution in THF; 1.18 mmol; 1.3 eq.) in THF (6.0 mL) maintained at 0° C. under nitrogen atmosphere, was added dropwise a solution of tert-butyl 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (400 mg; 0.90 mmol; 1.0 eq.) in THF (6.0 mL). The reaction mixture was stirred at RT for 12 h. Further borane-methyl sulfide complex (135 μl of a 2.00 M solution in THF; 0.27 mmol; 0.3 eq.) was added and the reaction mixture was stirred at RT for 1 more hour. The reaction mixture was then cooled down to 0° C. before the dropwise addition of NaOH (3.6 mL) followed by hydrogen peroxide (615 μl). It was then allowed to warm to RT and stir O/N. The reaction mixture was then diluted with water and extracted with DCM (four times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (EtOAc:heptanes, gradient from 90:10 to 40:60) to give the title compound as a white foam (90 mg, 22%). HPLC (max plot) 96.4%; Rt % 4.16 min. UPLC/MS: (MS+) 461.4, (MS−) 459.5.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][C@H:24]([O:26][C:27]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CN(C)CCN
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of cholesteryl chloroformate (2.25 g, 5 mmol in 5 ml of dry chloroform) is added dropwise to an excess of a solution of N,N-dimethylethylenediamine (2 ml, 18.2 mmol, in 3 ml of dry chloroform) at 0° C. After extraction of the solvent by evaporation, the residue is purified by 2 successive recrystallizations in absolute ethanol at 4° C., and dried under vacuum. 0.545 g of DC chol is thereby obtained in the form of a white powder. The structure of the compound was verified by NMR and mass spectrometry. The results obtained are in agreement with the data published in the paper cited above.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][Br:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Temperature: 25 °C

Procedure:
In accordance with general method T, 4.70 g (24.00 mmol) of (1) are dissolved in 30 ml of carbon tetrachloride, with heating, and 5.00 g (28.00 mmol) of N-bromosuccinimide and 2 spatula tips of azobisisobutyronitrile are then added. The mixture is refluxed for 6 h with irradiation with a 500 W spotlight. On cooling to room temperature, succinimide separates out, and is filtered off. The filtrate is evaporated on a rotary evaporator in order to obtain the product as a yellow oil. Yield: 5.85 g (88.8%)
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:33]=[C:32]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:38]([O:37][CH2:36][C:34]1[CH:35]=[C:30]([O:29][CH2:28][CH2:27][C:21]2([CH2:20][CH2:19][OH:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:31]=[C:32]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH:33]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCO)CCCCC2)c1
Reaction time: 15 h
Yield: 62.4 %

Procedure:
To a solution of 1-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]-3,5-diacetoxymethylbenzene (1.13 g) dissolved in tetrahydrofuran (7 mL) was added a 1M tetrabutylammonium fluoride/tetrahydrofuran solution (2.8 mL) dropwise at room temperature. The solution was stirred for 15 hours. A 10% aqueous citric acid solution was added to the solution, and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane:ethyl acetate (1:1)] to give the title compound (439 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1)=[O:17]>C(Cl)Cl.[OH-].[Na+]>[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)ccn1
Temperature: 170 °C

Procedure:
3,4-Dinitrophenol (12.3 g, 66.8 mmol) and 4-chloro-pyridine-2-carboxylic acid methylamide prepared similarly as described in patent WO 00/42012 (less than 7.79 g, 45.7 mmol, due to contaminant) in an open 50 mL round-bottom flask provided with stir bar and fitted with running water condenser. The reaction was heated at 150° C. for 1 h and at 170° C. for 16 h. The reaction was cooled to RT and dissolved in CH2Cl2 and 2N NaOH (aq). The layers were separated, and the organic layer was washed with a mix of brine and 2 N NaOH. The aqueous layers were back-extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a hexanes-to-hexanes/EtOAc gradient, to yield the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][C:28]=1[Cl:40]>>[O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][NH:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][C:28]=2[Cl:40])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCCOCc2ccc(OCC3CO3)cc2)cc1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(COCCOc4ccccc4)cc3)c(Cl)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-phenoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[CH:17]([CH2:18]O)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C>ClCCl>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:13]12[CH2:14][NH:15][CH2:16][CH:17]1[CH2:18][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:12]2
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: O=C(NC1=NC2(c3ccccc3F)CNCC2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 198.7 %

Procedure:
Racemic tert-butyl 3-(benzoylcarbamothioylamino)-3-(2-fluorophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.1 g, 4.39 mmol) is dissolved in dichloromethane (75 mL) and partitioned in equal portions between three reaction vessels. The reaction vessels are cooled to 0° C., and to each vessel is added drop wise 1-chloro-N,N,2-trimethylpropenylamine (2.0 mL, 15 mmol). The reactions are warmed to 22° C., and stirred for 4 hours. The contents of each vessel are passed through a 10 g silica gel plug, washed with methanol (30 ml), and the solvent removed under reduced pressure. The residues are purified by reverse phase HPLC eluting with a gradient of 5 to 100% acetonitrile in 10 mM ammonium bicarbonate solution w/5% methanol (pH 10.0) to give the title compound (3.1 g). ES/MS (m/e): 356 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]1([CH2:22][NH2:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:23][CH2:22][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (3.86 g, 20 mmol), naphthalen-1-ylmethanamine (3.14 g, 20 mmol) and K2CO3 (4.14 g, 30 mmol) in DMF (100 mL) was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (500 mL). It was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet ether=1/6 to afford the desired product as a yellow solid (3.21 g, 51%); LC/MS: MS (ES+) m/e 314 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 5.21 (d, J=6.0 Hz, 2H), 6.80 (d, J=8.7 Hz, 1H), 7.43-7.63 (m, 4H), 7.85 (d, J=8.1 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.26 (d, J=8.1 Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 9.20 (t, J=5.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C(N)(=O)C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:12][C:4]1[CH:3]=[C:2]([F:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([NH:42][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:8]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: NCCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(F)c(F)cc1C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4,5-difluoro anthranilic acid (2.0 g, 11.6 mmol) in anhydrous THF (30 mL) was added hydroxybenzotriazole hydrate (HOBt) (1.56 g, 11.6 mmol), diisopropylethyl amine (2.01 mL, 11.6. mmol), and 4-fluorophenylethyl amine (1.52 mL, 11.6 mmol). After all of the HOBt had completely dissolved, EDCl (2.21 g, 11.6 mmol) was added and the resulting orange solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue was chromatographed on silica eluting with 15% EtOAc in hexanes giving the desired benzamide (2) as white crystals (3.07 g, 10.4 mmol, 90%).
Reaction SMILES: [C:1]1([S:7][CH:8](SC2C=CC=CC=2)[CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[N:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[C:1]1([S:7]/[CH:8]=[C:9]2/[C:10](=[N:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:11]3[C:16]([CH2:17][CH2:18]/2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(N=C2c3ccccc3CCC2C(Sc2ccccc2)Sc2ccccc2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C(\Sc1ccccc1)=C1\CCc2ccccc2C1=Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
270 mg (0.58 mmol) of N-{2-[bis(phenylsulphanyl)methyl]-3,4-dihydronaphthalen-1(2H)-ylidene}aniline are dissolved in 25 ml of dichloromethane, 157 mg (0.64 mmol) of 70 percent strength meta-chloroperbenzoic acid are added at 0° C. and the mixture is stirred at 0° C. for 1 h. The mixture is then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by preparative HPLC (RP18, mobile phase: acetonitrile/water) gives 45 mg of N-[(2E)-2-[(phenylsulphanyl)methylene]-3,4-dihydronaphthalen-1(2H)-ylidene]aniline.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[CH3:39][S:40]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)(=[O:42])=[O:41]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH:44]=3)(=[O:51])=[O:50])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccc(S(C)(=O)=O)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3-Methylsulfonylbenzenesulfonyl chloride (available from Matrix Scientific; 138 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 20% ethyl acetate/hexanes, to give {6-fluoro-4-[1-(3-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (120 mg, 64%) as an off-white solid. MS cald. for C25H27FNO6S2 [(M+H)+]: 520, obsd. 520.2.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:11]#[N:12])=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(N)nc(Cl)c1C#N
Temperature: 140 °C
Yield: 5 %

Procedure:
A mixture of 4-chloro-5-iodo-6-methylpyrimidin-2-ylamine (1.35 g, 5.0 mmol), zinc cyanide (288 mg, 2.45 mmol) and tetrakis(triphenylphosphine)palladium (290 mg, 5 mol %) in DMF (20 mL) was purged with argon gas and heated at 140° C., for 15 min, by microwave irradiation. After cooling to RT, the residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) followed by further column chromatography (Si—PCC, gradient 0-7% MeOH in DCM) to afford the title compound (40 mg, 5%) as a pale yellow solid. LCMS (Method C): RT 2.23 min [M+H]+ 169.00. 1H NMR (DMSO-d6, 400 MHz): δ 8.11 (2H, br s), 2.42 (3H, s)
Reaction SMILES: C(C1C=CC([NH:15][C:16](=O)[C@@:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])=CC=1)(=O)C1C=CC=CC=1.FC(F)(F)[C@](O)(C)C(O)=O.FC(F)(F)C(C)=O.[C-]#N.[C-]#N.[Na+].Cl>>[F:19][C:18]([F:21])([F:20])[C:17]([OH:23])([CH3:22])[C:16]#[N:15]
Reactant: C[C@](O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1)C(F)(F)F
Agent: CC(=O)C(F)(F)F
Agent: C[C@](O)(C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(O)(C#N)C(F)(F)F

Procedure:
Scheme 2 shows the preparation of (S)-(-)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide wherein the (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid intermediate is prepared by selective crystallization with a resolving agent rather than by an enzymatic process. As shown in Scheme 2, 1,1,1-trifluoroacetone (1) is reacted with a cyanide such as sodium cyanide in the presence of an acid such as hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2). The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2) is then hydrolyzed with, for example, hydrochloric acid or sulfuric acid to provide racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3). Racemic (3) is then selectively crystallized with a resolving agent such as (1R,2S)-norephedrine (4) to form a salt (5) which may be recrystallized to diastereomeric purity. The purified salt (6) contains (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7). (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (7) after liberation from the salt is reacted with 4-aminobenzophenone (8) and SOCl2 using an organic base such as triethylamine or Hunig's base to form (S)-(-)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (9), which can then be purified by recrystallization.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH2:30][CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CCCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-3-methoxyphenol (254 g, 1251 mmol) was dissolved in DCM (2500 mL) and treated with DIPEA (437 mL, 2502 mmol) under nitrogen atmosphere. tert-Butylchlorodimethylsilane (198 g, 1314 mmol) was added and the reaction mixture was stirred at room temperature overnight. The crude product was diluted with water and the organic layer was extracted then dried over sodium sulfate and concentrated.