Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH2:20]([NH:22][CH3:23])[CH3:21]>C(#N)C.[I-].[K+]>[CH2:20]([N:22]([CH3:23])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:21]
Reactant: CCNC
Reactant: N#CC1(c2ccc(OCCCCl)cc2)CCOCC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C)CCCOc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile (3.0 g, 10.7 mmol), potassium iodide (100 mg, 0.60 mmol) and ethylmethylamine (5.0 ml, 58.3 mmol) in acetonitrile (30 mL) was heated to 60° C. overnight. The mixture was cooled, concentrated in vacuo and partitioned between dilute Na2CO3 solution (40 ml) and ethyl acetate (80 ml). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude material was carried out with flash chromatography (silica gel, ethyl acetate/methanol/aqueous ammonia 98:2:0.2 to 85:15:1.5) to afford 4-(4-{3-[ethyl(methyl)amino]propoxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile as a pale yellow oil (2.0 g, 6.6 mmol, 62%). 1H NMR (400 MHz CDCl3) δ 1.06 (t, 3H), 1.91-2.00 (m, 2H), 2.00-2.14 (m, 4H), 2.25 (s, 3H), 2.40-2.50 (m, 2H), 2.53 (t, 2H), 3.89 (m, 2H), 4.00-4.11 (m, 4H), 6.91 (d, 2H), 7.38 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:13])=[N:8]2.[H][H]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:13])[NH:8]2
Reactant: [H][H]
Reactant: COc1cccc2nc(C)ccc12
Solvent: CO
Product: COc1cccc2c1CC[C@H](C)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A 30-mL glass-lined stainless steel reactor with a magnetic stirring bar was charged with 5-methoxy-2-methylquinoline (4.0 g, 23.1 mmol), Ru(OTf)(η6-hexamethylbenzene)((S,S)-TsDPEN)([N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-κO)-ruthenium, prepared according to the procedure in J. Am. Chem. Soc. 2011, 133, 9878-9891) (0.100 g, 0.13 mmol) and methanol (10 mL). The reactor was closed and hydrogen gas was initially introduced in at a pressure of 50 atm, before being reduced to 1 atm. After this procedure was repeated three times, the reactor was pressurized with hydrogen to 50 atm. The resulting mixture was stirred under this hydrogen pressure for 24 h at room temperature. After carefully releasing the hydrogen, the reaction mixture was concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 0-20% ethyl acetate/petroleum ether) to afford (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (4.0 g, 98%, >99% ee) as yellow oil. MS (ES, m/z): 178 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13]COC)=[C:10]([O:17][CH3:18])[CH:9]=[CH:8]2)[CH3:2].C[C:20](C)=[O:21]>Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[C:10]([O:17][CH3:18])[CH:9]=[C:8]2[CH:20]=[O:21])[CH3:2]
Reactant: CCc1cccc2ccc(OC)c(OCOC)c12
Reactant: CC(C)=O
Agent: Cl
Product: CCc1cccc2c(C=O)cc(OC)c(O)c12
Reaction time: 5 h

Procedure:
200 g of 8-ethyl-2-methoxy-1-methoxymethoxynaphthalene was dissolved in 1 liter of acetone, to which dilute hydrochloric acid (concentrated hydrochloric acid 81 ml/water 200 ml) was added under ice-cooling conditions, after which the ice bath was removed, followed by agitation at room temperature for 5 hours. The reaction solution was poured into iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, 178 g of the resultant oily substance was dissolved in dichloromethane, to which 178 ml of titanium tetrachloride was gently added under ice-cooling conditions. After agitation for 30 minutes, 121 ml of dichloromethyl methyl ether was gradually added and agitated for 30 minutes. Iced water was gently added to the reaction solution, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, the resultant residue was washed with a mixture of hexane/isopropyl ether (1:1) to obtain 110 g of the caption compound as yellowish brown crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]1[C@@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C@H:19]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C@@H:18]([CH2:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[O:17][C:15]1([CH:43]1[S:48][CH2:47][CH2:46][CH2:45][S:44]1)[OH:16].CO>O1CCCC1.C(OCC)C>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@H:14]([C@H:20]([C@@H:19]([C@@H:18]([CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)[OH:17])[O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH:15]([CH:43]1[S:44][CH2:45][CH2:46][CH2:47][S:48]1)[OH:16]
Reactant: OC1(C2SCCCS2)O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(C1SCCCS1)[C@H](OC1CCCCO1)[C@@H](OC1CCCCO1)[C@H](OC1CCCCO1)[C@H](O)COC1CCCCO1
Yield: 49.8 %

Procedure:
Lithium aluminum hydride (1.74 g) was added in small portions under ice-cooling to a solution of 2,3,4,6-tetra-O-(tetrahydropyranyl)-1-C-(1,3-dithian-2-yl)-D-glucopyranose (6.9 g) in tetrahydrofuran-ethyl ether (3:1, 100 mL), and stirred at the same temperature for 5 hours Methanol (10 mL) was added to the mixture to work up the reaction, and then evaporated under reduced pressure. To the residue were added ethyl acetate (100 mL) and 2N hydrochloric acid (80 mL), the insoluble substances were filtrated off. The organic layer was separated, washed with water and saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (400 mL). The column was washed with toluene (500 mL) and eluted with toluene-ethyl acetate (3:2) and then with toluene-ethyl acetate (1:2). The compounds supposed to be the two stereoisomers ((1R)- and (1S)-isomers) of 2,3,4,6-tetra-O-(tetrahydropyranyl)-1-C-(1,3-dithian-2-yl)-D-glucitol were eluted separately. The fraction eluted with toluene-ethyl acetate (3:2) was evaporated to dryness under reduced pressure to give a colorless syrup (3.45 g), and the fraction eluted with toluene-ethyl acetate (1:2) was evaporated to dryness under reduced pressure to give a colorless syrup (1.52 g). The isomer eluted with toluene-ethyl acetate (3:2):
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:20][CH2:21][CH2:22][C:23]([C:25](O)=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:45]([N:48]1[C:52]([CH2:53][S@@:54]([C:56]2[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=2)=[O:55])=[CH:51][N:50]=[CH:49]1)[CH2:46][CH3:47]>ClCCl.O1CCCC1.O.N1C=CC=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:33]=[N:32][C:18]3[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:20][CH2:21][CH2:22][C:23]([C:25]([NH:60][C:59]4[CH:61]=[CH:62][C:56]([S@:54]([CH2:53][C:52]5[N:48]([CH2:45][CH2:46][CH3:47])[CH:49]=[N:50][CH:51]=5)=[O:55])=[CH:57][CH:58]=4)=[O:26])=[CH:24][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Reactant: CCCn1cncc1C[S@](=O)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)Nc2ccc([S@@](=O)Cc4cncn4CCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 0.5 h

Procedure:
(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartrate monohydrate (479 mg) was dissolved in ethyl acetate (5 ml) and 1 N hydrochloric acid (2.44 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (2.44 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) twice. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, and then the solvent was again distilled off under reduced pressure-to give (S)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylic acid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, and then oxalyl chloride (0.063 ml) at 0° C. The mixture was returned to room temperature and stirred for 30 minutes under a nitrogen atmosphere, and then the resulting solution was added dropwise to a solution of (S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (1.16 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. The mixture was returned to room temperature and stirred overnight. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice and saturated brine once, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was separated and purified by basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=3:100) to give (S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (294 mg) (Compound 1) as a yellow amorphous material.
Reaction SMILES: [SH2]=N.[CH2:3]([NH:7][C:8](C1C=CC=CC=1C(O)=O)=[O:9])[CH2:4][CH2:5][CH3:6].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CC(C)=O>[C:23]1([CH3:26])[CH:24]=[CH:25][C:20]([NH:19][C:8]([NH:7][CH2:3][CH2:4][CH2:5][CH3:6])=[O:9])=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCCCNC(=O)c1ccccc1C(=O)O
Agent: N=[SH2]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCNC(=O)Nc1ccc(C)cc1
Yield: 79.6 %

Procedure:
5.64 g n-butylcarbamoyl-benzoic acid sulfimide was reacted with 2.14 g p-toluidine and 2.8 ml triethylamine in 20 ml of a 1:1 mixture of water and acetone, as described in example 1. 3.28 g 1-(p-tolyl)-3-(n-butyl)-urea was obtained, melting at 118°-119° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC.C(OCC)(=O)C>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CCCN1c1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCCN1c1ccc(OCc2cccc(F)c2)cc1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
A mixture of 2.73 g (15.4 mmol) of 1-(4-hydroxy-phenyl)-pyrrolidin-2-one, 3.2 g (16.9 mmol) of 3-fluorobenzylbromide and 4.26 g (31 mmol) of potassium carbonate in 100 ml of 2-butanone is heated at 80° C. for 18 hours. After cooling to RT, the reaction mixture is treated with water and ethyl acetate. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure. The solid residue is crystallised from ether to yield 3.86 g (88% of theory) of 1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one as a colorless solid. MS: m/e=286.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
5.20 g (21.57 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 4.3 g (21.57 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 9.84 g (25.89 mmol) of HATU, 13.53 ml (74.68 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 l of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.2 g (69% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[OH:32][C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([C:9]([C:34]2[CH:35]=[N:36][N:37]([CH3:38])[C:33]=2[OH:32])=[O:11])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: Cn1nccc1O
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (195 mg, 6.76 mmol) in chloroform (15 mL) were added oxalyl-chloride (0.5 mL) and DMF in a catalytic amount. The reaction mixture was stirred for 30 minutes at room temperature, and the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous THF (20 mL), and 5-hydroxy-1-methylpyrazole hydrochloride (136 mg, 1.01 mmol), triethylamine (136 mg) and N,N-dimethylaminopyridine (250 mg) were added, followed by reflux with heating for 1 hour. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate (200 mL). The mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous acetonitrile (10 mL), and triethylamine (136 mg) and acetone cyanohydrin in a catalytic amount were added. The mixture was stirred for 12 hours at room temperature. The solvent was distilled off under reduced pressure to obtain crude 5-hydroxy-1-methylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A suspension of ethyl (E)-3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-2-propenoate (0.90 g, 1.8 mmol) and 5% palladium carbon (0.5 g) in ethanol (10 ml) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoate (0.82 g, 90.1%) as an amorphous solid. 1H-NMR(CDCl3) δ: 0.99 (6H, d, J=6.6 Hz), 1.19 (3H, t, J=7.1 Hz), 1.42 (9H, s), 2.18–2.29 (1H, m), 2.51 (2H, t, J=7.8 Hz), 2.90 (2H, t, J=7.8 Hz), 4.01–4.12 (4H, m), 4.19 (2H, d, J=5.6 Hz), 4.40 (1H, bs), 6.74 (1H, d, J=1.6 Hz), 7.21–7.26 (2H, m), 7.31 (1H, dd, J=1.6, 8.4 Hz), 7.46–7.53 (3H, m), 8.39 (1H, d, J=8.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[Si:18]([CH3:21])([CH3:20])[CH3:19].[C:22]([NH:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]([O:35][CH3:36])=[O:34])[C:27]=1[Cl:37])(=[O:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:22]([NH:25][C:26]1[CH:31]=[C:30]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:5]=2[F:17])[N:29]=[C:28]([C:33]([O:35][CH3:36])=[O:34])[C:27]=1[Cl:37])(=[O:24])[CH3:23]
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Reactant: CC1(C)OB(c2cc(F)c([Si](C)(C)C)cc2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)cc(NC(C)=O)c1Cl
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 54.6 %

Procedure:
In a microwave vessel, a suspension of (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (see, e.g., WO 2013003740 A1) (1 g, 2.56 mmol), methyl 4-acetamido-3,6-dichloropicolinate (Head L) (0.562 g, 2.135 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.150 g, 0.214 mmol) and sodium carbonate (0.272 g, 2.56 mmol) in a 3:1 mixture of acetonitrile (5.34 mL) and water (1.779 mL) was stirred under microwave irradiation (120° C., 20 min). The reaction mixture was poured into an half saturated brine solution and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a white solid (0.481 g, 1.165 mmol, 54.6%): mp 135-137° C.; 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=0.8 Hz, 1H), 7.96 (s, 1H), 7.62 (dd, J=8.5, 5.7 Hz, 1H), 7.13 (dd, J=10.5, 4.1 Hz, 1H), 4.02 (s, 3H), 2.33 (s, 3H), 0.33 (d, J=0.8 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −106.66, −106.72, −123.42, −123.48; ESIMS m/z 411 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[N:8][NH2:9].[OH-].[K+]>C(OC(O)C)C.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[NH:9][N:8]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=NN)c2sccc2Br)cc1
Agent: CCOC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2n[nH]c3ccsc23)cc1
Yield: 702.7 %

Procedure:
A solution of 1.0 g of (3-bromothien-2-yl) (4-methoxyphenyl)methanone hydrazone in 60 ml of ethoxyethanol was treated with an alkaline solution prepared by dissolving 6.0 g of 85% potassium hydroxide pellets in 20 ml of water. The resultant solution was stirred at 105°-110° for 30 minutes and to it under nitrogen was added 250 ml of finely powdered cuprous chloride. The darkened mixture was maintained at 105°-110° C. for an additional 90 minutes and quenched with water. The organic materials were extracted exhaustively with ethyl acetate/ether (1:1) and the combined organic solution was washed (four times) with water and dried. Evaporation of the solvents afforded a thick oil which was purified by passage through an alumina column. Elution with ether removed most of the dark impurities and further elution with 5% methanol/ether gave 5.2 g of an oil which solidified on scratching, m.p. 143°-144° C. For analysis, a small sample was recrystallized from ether/hexane without any change in the melting range.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: CC(=O)c1ccc2c(c1)N(CCCCCCO[Si](C)(C)C(C)(C)C)c1ccccc1S2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)N(CCCCCCO)c1ccccc1S2
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
A solution of 150 mg (0.33 mmol) of 1-[10-[6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]hexyl]-10H-phenothiazin-2-yl]ethanone in 0.6 mL of tetrahydrofuran is treated with 0.41 mL (0.41 mmol) of 1M tetrabutylammonium fluoride in tetrahydrofuran. The reaction is stirred for 3 hours at room temperature, then diluted with 20 mL of ethyl acetate. The organic layer is washed successively with 10% sodium bisulfate solution and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated in vacuo to give 114 mg of 1-[10-(6-hydroxyhexyl)-10H-phenothiazin-2-yl]ethanone as a dark oil. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1680, 1590, 1560 cm-1 ; MS m/e calculated for C20H23NO2S: 341.1449, found 341.1456.
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Product: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
The (E)-2-pivaloylthiomethyl -3-phenylpropenoic acid above is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.[I:40]I>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][C:10]=1[I:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)cc1
Reactant: II
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 88 h
Yield: 158.2 %

Procedure:
A solution of 4(benzyloxy)benzotrifluoride (12.71 g, 50.4 mmol) in acetonitrile (300 ml) was stirred under nitrogen and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (17.75 g, 50.4 mmol) and iodine (6.4 g, 25.2 mmol) added. The mixture was stirred at room temperature for 88 h. The solvent was evaporated and the residue partitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was washed with water, dried (MgSO4) and evaporated to an orange oil which was purified by flash chromatography (silica gel, 5% ethyl acetate:isohexane) to give the title compound as an orange oil (15.07 g, 79%)