Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([Zn])C1C=CC=CC=1.Br[C:18]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22]C)=[O:21]>C1COCC1.[Zn]>[CH3:9][C:27]1[C:18]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:19]([CH:24]=[CH:25][C:26]=1[N+:28]([O-:30])=[O:29])[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: [Zn]Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccc(C(=O)O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of benzyl bromide (2.0 mL, 17.3 mmol) in THF (10 mL) was added dropwise at 0° C. to a stirred suspension of zinc dust (1.7 g, 26 mmol) in THF (10 mL) which had been activated according to the method described by Knochel (J.O.C. 53, 2392, 1988). The mixture was left to warm to ambient temperature and stir for 3 h. An aliquot (6.5 mmol) of the supernatent containing the benzyl zinc reagent was then added to a stirred solution of compound 27 (3.85 mmol) and Pd(dba)3 (0.0385 mmol) in THF (10 mL) at ambient temperature under argon. After 1 hr a second aliquot (6.5 mmol) of the benzyl zinc reagent was added. The resulting black reaction mixture was quenched with 2N HCl (250 mL) and extracted with Ethyl acetate (2×100 mL). The combined organics were washed with water (50 mL) and brine (50 mL), filtered through phase separating paper and evaporated to an orange gum. This was purified by chromatography on silica (Merck, 9385) eluting with 10% ethyl acetate/i-hexane to give methyl 2-benzyl-4-nitro-benzoic acid (compound 28).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:32][C:33]1[C:34]([C:44]([O:46][CH3:47])=[O:45])=[CH:35][C:36]2[CH2:37][CH2:38][CH2:39][C:40](=[O:43])[C:41]=2[CH:42]=1.[OH2:48].C(#N)C>C1COCC1>[C:18]([OH:43])([C:20]([F:23])([F:22])[F:21])=[O:48].[F:21][C:20]([F:23])([F:22])[C:18]([OH:43])=[O:48].[F:32][C:33]1[C:34]([C:44]([O:46][CH3:47])=[O:45])=[CH:35][C:36]2[CH2:37][CH2:38][CH2:39][C:40]([OH:43])([C:11]3[S:12][C:8]([C:6]4[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]5[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=5)[N:5]=4)=[CH:9][N:10]=3)[C:41]=2[CH:42]=1
Reactant: COC(=O)c1cc2c(cc1F)C(=O)CCC2
Reactant: O
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)c1cc2c(cc1F)C(O)(c1ncc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)s1)CCC2
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (600 mg, 1.78 mmol) in THF (5.9 mL) under argon at −78° C. was slowly added lithium diisopropylamide (2.0 M in THF, 2.68 mL, 5.35 mmol), and the resulting mixture was stirred for 30 minutes at that temperature. A solution of methyl 3-fluoro-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (496 mg, 2.230 mmol) in THF (2 mL) was added, and the reaction mixture was allowed to warm to rt over 2 h. After an additional 12 h, the reaction was quenched with methanol (10 mL) and concentrated under reduced pressure. Reverse-phase HPLC (C18 column, water-acetonitrile, TFA modifier) afforded (rac)-methyl 3-fluoro-5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylate, trifluoroacetate salt (355.1 mg, 0.528 mmol, 30% yield) as a yellow solid. MS ESI calcd for C27H22F4N4O3S [M+H]+ 559, found 559. 1H NMR (500 MHz, DMSO) δ 10.22 (s, 1H), 8.65 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.69 (d, J=7.4 Hz, 1H), 7.37 (s, 1H), 7.21 (d, J=5.2 Hz, 1H), 7.14-7.06 (m, 2H), 3.82 (s, 3H), 2.89-2.77 (m, 2H), 2.41-2.32 (m, 1H), 2.30 (s, 3H), 2.13-2.06 (m, 1H), 2.00-1.85 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])#[CH:2]
Reactant: C#Cc1cccc(O)c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#Cc1cccc(OCCN(C)C)c1
Temperature: 65 °C
Yield: 31.7 %

Procedure:
3-Ethynylphenol (1.18 g, 10 mmol), 2-chloro-N,N-dimethylethanamine (1.44 g, 10 mmol), Cesium carbonate (7.0 g, 21 mmol) was dissolved in dimethyl formamide (20 mL) and the mixture was heated to 65° C. for 1 h. The mixture was cooled to RT and the partitioned between water and dichloromethane. The organic layer was separated, washed with 2N NaOH and then extracted with 1N HCl. The HCl solution was then neutralized with aqueous NaOH and extracted with dichloromethane. The organic layer was dried and concentrated to afford 2-(3-ethynylphenoxy)-N,N-dimethylethanamine (0.6 g) as an oil. LC/MS; (M+H)+=190.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]1([CH:12]=[CH:11][C:9](O)=CC=1)O.[CH:13]1CC=CC=1>C1C=CC=CC=1>[C:1]([CH:2]1[CH2:13][CH:12]2[CH2:5][CH:3]1[CH2:9][CH2:11]2)#[N:4]
Reactant: C1=CCC=C1
Reactant: C=CC#N
Reactant: Oc1ccc(O)cc1
Solvent: c1ccccc1
Product: N#CC1CC2CCC1C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
159 g (3 moles) of acrylonitrile were dissolved in 100 ml of benzene and warmed to 50°C. after adding a pinch of hydroquinone. 196 g (3 moles) of cyclopentadiene were added dropwise at this temperature, with intensive stirring. In the course thereof, the temperature of the reaction mixture rose (it should not exceed 70°C.). After the exothermic reaction had subsided, the mixture was stirred for 1 hour at 80°C. The solvent was then distilled off and the residue was rectified in vacuo. This gave 272 g (76% of theory) of 2-cyano-bicyclo[2,2,1]heptene-5 of boiling point 82°-87°C/15 mm Hg.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])([CH:12]2[CH2:17][CH2:16][C:15](=COC)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:29]([OH:31])=O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([CH:6]1[CH2:7][CH2:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])([C:12]2([CH:29]=[O:31])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(=COC)CC2)CC1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(c2cccc(F)c2F)(C2(C=O)CCCCC2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The compound (39) (8.1 g), formic acid (87%; 9.5 g) and toluene (100 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30° C., and then water (100 ml) and toluene (200 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving a white solid. This residue was dissolved in toluene (50 ml). The solution was added to a mixture of sodium hydroxide (95%; 0.5 g) and Solmix A-11 (32 ml) which had been cooled to 7° C., and the solution obtained was stirred at 10° C. for 2 hours. Then, an aqueous 2N-sodium hydroxide solution (16 ml) was added thereto, and the mixture was stirred at 5° C. for 2 hours. The reaction mixture obtained was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was concentrated, purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder and dried, giving 7.5 g of 1-[4-pentyl-(2,3-difluorophenyl)cyclohexyl]-cyclohexanecarboaldehyde (40). The yield based on the compound (39) was 97.1%.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:21]=[CH:20][C:9]([C:10]([NH:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:11])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)C(C)C)(C)C.C([N:48]=[C:49]=[S:50])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>C(Cl)Cl>[CH3:4][CH:3]([CH3:5])[C@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:11])=[CH:20][CH:21]=1)[NH:1][C:49]([NH2:48])=[S:50]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)[C@@H](N)c1ccc(C(=O)NOC2CCCCO2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)[C@@H](NC(N)=S)c1ccc(C(=O)NOC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide (0.1643 g, 0.562 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) in DCM (2.5 mL) was cooled in an ice bath and added to a solution of Fmoc-isothiocyanate (0.173 g, 0.616 mmol) in DCM (2.5 mL, 38 mmol) cooled at 0° C. in an ice bath. The reaction solution was stirred at rt for 1 h. Piperidine (1.0 mL, 2.0 mmol, 2.0 M in MeOH) was then added and the reaction stirred at rt for an additional 2 h. The reaction was concentrated and the residue was purified by flash chromatography (EtOAc:hex, 7:3 to 1:0) to afford 4-((R)-2-methyl-1-thioureidopropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide as a white solid. LC-MS: (FA) ES+ 352.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][Br:32])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-nitrophenyl)methanol (2.0 g, 8.65 mmol) and triphenylphosphine (4.5 g, 17.3 mmol) were combined in tetrahydrofuran (40 mL) and cooled to 0° C. N-Bromosuccinimide (3.2 g, 18.2 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 2.2 g (84%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 8.27 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 4.45 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:27]([O:34][C:35](ON1C(=O)CCC1=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:27]([O:34][C:35]([N:13]1[CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC[C@@H](C(=O)O)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of cis-(+/−)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (1.0 eq.) in dichloromethane (0.2 M) was added DIEA (1.1 eq.), followed by N-(benzyloxycarbonyloxy)succinimide (1.0 eq.); the reaction was stirred at r.t. overnight. The solvent was removed under reduced pressure. To the crude was added EtOAc and 1N HCl. After extraction, the organic layer was washed with brine, dried and filtered, and concentrated to yield cis-(+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (99% yield) LCMS (m/z): 379.2 (MH+); LC Rt=3.55 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9]CC)[CH2:4][CH2:3]1.C(O)CO>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH:8]2[O:9][CH2:14][CH2:13][O:12]2)[CH2:6][CH2:7]1
Reactant: CCOC(OCC)N1CCN(C)CC1
Solvent: OCCO
Solvent: CCO
Product: CN1CCN(C2OCCO2)CC1
Reaction time: 18 h

Procedure:
The amide acetal produced in Example 1 (3.03 g, 0.015 mole) was combined while stirring with ethylene glycol (0.93 g, 0.015 mole) in a glass flask at ambient temperature under nitrogen. The reaction was continued with stirring for 18 hours. The by-product ethanol formed during the reaction was removed by vacuum and the reaction continued for an additional 18 hours with stirring under vacuum. The resulting product was found to have a boiling point of about 220° C., and identified as the desired product by NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(C)(=O)=O)cc3)ccnc2n1

Procedure:
The product from Example 6 (100 mg, 0.228 mmol) was reacted with methane sulfonyl chloride (28 mg, 0.251 mmol), N,N-diisopropylethylamine (88.4 mg, 0.684 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (20 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.77-1.90 (m, 2H) 2.40 (s, 3H) 2.98 (t, J=7.54 Hz, 2H) 3.43 (s, 3H) 6.34 (d, J=6.99 Hz, 1H) 7.19 (d, 2H) 7.27 (d, 2H) 7.36-7.40 (m, 2H) 7.48 (d, 1H) 7.78 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.91 (d, J=8.46 Hz, 1H); MS (DCI NH3+) 480 m/z (M+H)+.
Reaction SMILES: COC[O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1.Cl.[Na+].[Cl-].O>O1CCCC1.C(OC)(C)(C)C>[OH:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1
Reactant: COCOC[C@@H]1CCC[C@H](COCC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC[C@H]1CCC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
1.9 g of tert-butyl [cis-3-(methoxymethoxymethyl)cyclohexylmethoxy]-acetate are dissolved in 10 ml of tetrahydrofuran, 5 ml of conc. HCl are added and the mixture is stirred at room temperature for 2 h. 10 ml of sat. NaCl solution, 10 ml of water and 30 ml of methyl tert-butyl ether are then added, the phases are separated and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated. Flash chromatography on silica gel (heptane/ethyl acetate 3/1) gives 600 mg of tert-butyl (cis-3-hydroxymethyl-cyclohexylmethoxy)acetate as a colorless oil (TLC (heptane/ethyl acetate 2/1): Rf, starting material=0.68, Rf, product=0.18). 260 mg of this are dissolved in 5 ml of dimethylformamide, and 170 mg of tert-butyidimethylsilyl chloride are added. The solution is then cooled to 0° C., and 160 mg of imidazole are added. The solution is stirred at room temperature for 15 h, and 20 ml of sat. NaCl solution, 10 ml of water and 30 ml of methyl tert-butyl ether are then added. The phases are separated and the organic phase is washed with sat. NaCl solution, dried over MgSO4 and concentrated. This gives 350 mg of tert-butyl [cis-3-(tert-butyldimethyl-silanyloxymethyl)cyclohexylmethoxy]acetate as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=2)=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:36]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=2)[C:28]2[C:29]([C:30]#[N:31])=[C:32]([F:35])[CH:33]=[CH:34][C:27]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1c(F)ccc(N)c1Nc1cncc(F)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of ((S)-1-carbamoyl-ethyl)carbamic acid tert-butyl ester (1.81 g, 9.63 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (1.54 g, 8.08 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). 3-Amino-6-fluoro-2-(5-fluoropyridin-3-ylamino)benzonitrile (948 mg, 3.86 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.20 min, [M+H-tBu]+=344, 100%, [M+H]+=400, 10%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[S-:21][C:22]#[N:23].[K+].[O:25]1CCOC[CH2:26]1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([NH:23][C:22](=[S:21])[O:25][CH3:26])=[O:16])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: C1COCCO1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=S)NC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 0 °C

Procedure:
In chloroform (40 ml) was dissolved (4'-methylbiphenyl-2-yl)carboxylic acid (10 g). To the solution was added thionyl chloride (7 ml), and the mixture was heated for 3 hours under reflux. The reaction mixture was poured into ice-water, then the organic layer was separated, washed with water and concentrated to dryness to give a syrup, which was dissolved in dioxane (80 ml). To the solution was added powdered potassium thiocyanate (9.16 g), and the mixture was heated for one hour under reflux. The reaction mixture was allowed to cool, and then insolubles were filtered off. After addition of methanol (15 ml) to the filtrate, the solution was heated for 15 minutes under reflux. The reaction solution was concentrated to dryness, and the resulting crystals were crystallized from isopropyl ether to afford the title compound as white plates (7.4 g, 55%), m.p.149°-150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1C.[Cl:18][S:19]([OH:22])(=O)=[O:20].Cl[CH2:24]Cl>>[Cl:18][S:19]([C:7]1[C:6]([CH3:24])=[CH:5][C:4]([O:9][CH2:10][C:11]([CH3:16])([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:3][C:2]=1[CH3:1])(=[O:22])=[O:20]
Reactant: COC(=O)C(C)(C)COc1ccc(C)c(C)c1
Reactant: ClCCl
Reactant: O=S(=O)(O)Cl
Product: COC(=O)C(C)(C)COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Temperature: -2 °C
Yield: 29 %

Procedure:
Methyl 3-(3,4-dimethylphenyloxy)-2,2-dimethylpropionate (Intermediate A8, 23.6 g, 0.100 mol) was added dropwise over 30 min to rapidly stirred chlorosulfonic acid (46.6 g, 0.400 mol) while the reaction temperature was maintained at −2° C. The reaction mixture was then poured into a stirred mixture of 300 g ice and 300 mL of dichloromethane. The aqueous phase was extracted with additional dichloromethane, and the combined organic layers were washed with water, 0.5 M sodium bicarbonate (×2), and water. The solvent was removed at aspirator pressure and the residue was purified by several passes of flash chromatography (silica gel: hexanes→2% ethyl acetate in hexanes) to yield 9.6 g (29%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][S:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCSCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(Br)cc(NC2CCSCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2.5 g, 10.24 mmol) and dihydro-2H-thiopyran-4(3H)-one (1.42 g, 12.29 mmol) in dichloroethane (50 mL), acetic acid (3.6 ml, 61.47 mmol) was added and reaction stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (6.5 g, 30.73 mmol) was added and stirred at room temperature overnight. The reaction mixture was neutralized with sat. NaHCO3 and compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure. Column chromatography purification of crude gave methyl 5-bromo-2-methyl-3-((tetrahydro-2H-thiopyran-4-yl)amino)benzoate (2.5 g, 71.0%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14].C([O:20]O)(C)(C)C.[Se](=O)=O>ClCCl.CC(C)(CC(C)C)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([OH:20])/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: CC(C)CC(C)(C)C
Solvent: ClCCl
Product: NC(=O)/C=C1/c2cc(F)cc(F)c2CC1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4,6-difluoro-1-indanylidene)acetamide (10.0 g, 0.05 mol, prepared as in Example 5g in dichloromethane (250 mL) was added portionwise over a 10 min. period to a mixture of 70% aqueous t-butylhydroperoxide (19.8 mL, 0.15 mol, Aldrich) and selenium dioxide (3.7 g, 0.03 mol, Aldrich) in dichloromethane (500 mL) at ambient temperature. After 18 h, additional t-butylhydroperoxide (10 mL of a 5.0M solution in 2,2,4-trimethylpentane, 0.05 mol, Aldrich) and selenium dioxide (1.8 g, 0.02 mol) were added and the mixture was stirred at ambient temperature. After 18 h, additional t-butylhydroperoxide (10 mL of 70% aqueous solution, 0.08 mol) and selenium dioxide (3.7 g, 0.05 mol) were added and the mixture was stirred at ambient temperature for 8 days. The resulting solid was filtered off and washed with dichloromethane to give 5.85 g of crude (Z)-2-(4,6-difluoro-2-hydroxy-1-indanylidene)acetamide. After 7 days at ambient temperature a second crop of crude (Z)-2-(4,6difluoro-2-hydroxy-1-indanylidene)acetamide was obtained from the filtrate. Column chromatography on silica gel using ethyl acetate as the eluent followed by a second column chromatography on silica gel using ethyl acetate:hexanes (3:2) as eluent and trituration of the resulting solid with pentane gave 2.38 g of (Z)-2-(4,6-difluoro2-hydroxy-1-indanylidene)acetamide as a pink solid: m.p. 235°-237° C.;