Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3](/[C:7](/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:8]\[OH:9])=[N:2]1.[C:17](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.Cl>CN(C)C=O>[CH3:17][O:9]/[N:8]=[C:7](/[C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: O=C([O-])[O-]
Reactant: O/N=C(\C1=NOCCO1)c1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CO/N=C(/C1=NOCCO1)c1ccccc1O
Reaction time: 16 h
Yield: 62.7 %

Procedure:
1.2 g (0.0054 mol) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) in 5 ml of dimethylformamide are stirred at 20° C. together with 0.66 g (0.0062 mol) of sodium carbonate initially for 30 minutes. 0.83 g (0.00658 mol) of dimethyl sulphate is then added and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is adjusted to a slightly acidic pH using 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 0.8 g (50.35% of theory) of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) of a purity of 80.3% (HPLC) is obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C@H:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C@@H:23]2[CH3:35])[CH3:21])=[CH:16][CH:15]=1.[B:36](OC(C)C)([O:41]C(C)C)[O:37]C(C)C.[OH-].[Na+]>C1COCC1>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C@@H:20]([C:17]2[CH:16]=[C:15]([B:36]([OH:41])[OH:37])[C:14]([F:13])=[N:19][CH:18]=2)[CH3:21])[C@@H:23]([CH3:35])[CH2:24]1)=[O:29])([CH3:33])([CH3:32])[CH3:34]
Reactant: C[C@H](c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
n-Butyllithium (2.5 M in hexanes; 7.23 mL, 18.07 mmol) was added dropwise to a solution of diisopropylamine (2.55 mL, 18.07 mmol) in 8 mL of THF at −40° C. The mixture was stirred for 1 h at −40° C. This solution was cannulated into a 3-necked 250-mL round-bottomed flask that contained a solution of tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (4.87 g, 15.06 mmol) in 60 mL of THF at −78° C. After 15 min at −78° C., triisopropyl borate (Aldrich; 6.92 mL, 30.1 mmol) was added, and the resulting mixture was stirred at −78° C. for 15 min and then allowed to warm to ambient temperature. The reaction mixture was subsequently treated with 1 M NaOH (80 mL) and allowed to stir for 20 min. The aqueous layer was separated and the organic layer was discarded. The aqueous layer was treated with 10% HCl (aq) until a pH of about 5 to 6 was achieved. The resulting mixture was diluted with EtOAc (20 mL) and the mixture was extracted with 8:2 EtOAc/MeOH (200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (5.01 g, 13.64 mmol, 91% yield) as an off-white solid. m/z (ESI, +ve) 368.1 (M+H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[S:5][C:4]=1[C:11]([OH:13])=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:21]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([C:4]1[S:5][C:6]([C:8]([OH:10])=[O:9])=[CH:7][C:3]=1[O:2][CH3:1])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C(=O)O)sc1C(=O)O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)sc1C(=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 3-methoxy-thiophene-2,5-dicarboxylic acid (0.382 g), benzylamine (0.41 mL), N,N′-carboxyl≈diimidazole (0.66 g), and DMF was heated at 60° C. to yield 0.39 g of 3-methoxy-thiophene-2,5-dicarboxylic acid bis benzylamide; MI-APCI+ 381.1; Elem. Anal. (C21H20N2O3S); Calc'd: C, 66.30; H, 5.30; N, 7.36. Found: C, 66.52; H, 5.06; N, 7.41.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@:47]2([OH:55])[CH2:52][CH2:51][NH:50][CH2:49][C:48]2([CH3:54])[CH3:53])=[CH:43][CH:42]=1>C(Cl)(Cl)Cl.ClCCl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@:47]2([OH:55])[CH2:52][CH2:51][N:50]([C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:49][C:48]2([CH3:53])[CH3:54])=[CH:43][CH:42]=1
Reactant: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
(2R,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanoic acid (197 mg, 0.85 mmol), EDC (162 mg, 0.85 mmol), HOBt (115 mg, 0.85 mmol) was dissolved in chloroform (10 mL). DIPEA (0.15 mL, 0.85 mmol) and (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (200 mg, 0.834 mmol) were added. The mixture was stirred at rt for 2 h, diluted with dichloromethane and washed with aq NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give tert-butyl (2R,3S)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate (327 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][C:5](C(O)=O)=[C:4]([OH:13])[C:3]=1[CH3:14].[OH-].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([OH:13])[CH:5]=[CH:9][C:10]=1[C:11]#[N:12]
Reactant: Cc1c(N)c(C#N)cc(C(=O)O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Product: Cc1c(O)ccc(C#N)c1N
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A mixture of compound 75 (19 g, 0.1 mol) in quinoline (50 mL) was heated to 170° C. for 2 h (until effervescence ceased). The reaction mixture was cooled to RT and aqueous NaOH solution was added (1M, 500 mL) followed by pet. ether (500 mL). The reaction mixture was stirred for 15 min and the aqueous layer was separated. The aqueous layer was further washed with pet. ether (2×300 mL) to remove quinoline completely. The aqueous layer was acidified with 1.5N HCl to pH=5, the solid was filtered off and dried under vacuum. The obtained solid was further washed with 5% ethyl acetate in pet. ether to give pure title compound (12 g, 82%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:21]2[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:24].[CH:21]1([C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCNCC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), bis(tricyclohexylphosphine)palladium (II) dichloride (132 mg), tripotassium phosphate (3.8 g) and cyclopropylboronic acid (688 mg) were added toluene (10 mL) and water (500 μL) and the mixture was refluxed for 5 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g). 4-(2-Cyclopropyl-4-methylphenyl)piperazine-1carboxylic acid tert-butyl ester (1 g) was dissolved in chloroform (1 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg). To tetrahydrofuran (2 mL) were added 4-iodobenzoyl chloride (169 mg), 1-(2-cyclopropyl-4-methylphenyl)piperazine hydrochloride (160 mg) and 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (280 mg).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[C:13]3([CH2:19][C:18](=[O:20])[NH:17][CH2:16][CH2:15]S3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:32]([O-:35])([O-])=[O:33].[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH2:7][CH:8]2[C:13]3([CH2:19][C:18](=[O:20])[NH:17][CH2:16][CH2:15][S:32]3(=[O:35])=[O:33])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC2(CCCCC2Cc2ccccc2)SCCN1
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1
Reaction time: 1 h

Procedure:
To a solution of 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane (2.5 g) in methylene chloride (80 ml) was added 80% m-chloroperbenzoic acid (3.8 g) at 0° C. After one hour, a saturated aqueous solution (50 ml) of sodium sulfite was added to the solution. The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 1-phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (2.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH2:12]([C:3]1[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[CH:5][C:4]=1[OH:9])[CH:11]=[CH2:10]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCc1c(O)ccc(Cl)c1Cl
Temperature: 200 °C

Procedure:
A solution of 100 g. of 3,4-dichlorophenol, 50 ml. of allyl bromide, 84 g. of potassium carbonate, and 1.0 g. of potassium iodide in 500 ml. of methyl ethyl ketone was allowed to reflux overnight. The solution was then cooled, filtered, and evaporated to dryness. The residue was then heated at 200° C. for approximately four hours. NMR analysis indicated that the 113.6 g. of remaining material was primarily the desired 2-allyl-3,4-dichlorophenol.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:42]([NH:46][C:47](=[O:50])[CH2:48]Cl)([CH3:45])([CH3:44])[CH3:43]>C1COCC1.C(Cl)Cl.O>[C:42]([NH:46][C:47](=[O:50])[CH2:48][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:25]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: CC(C)(C)NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CC(=O)NC(C)(C)C)CC3)ccc1-2
Reaction time: 65 h
Yield: 63.4 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 TFA salt (250 mg, 0.49 mmol) in THF (5 mL) was added potassium carbonate (136 mg, 0.98 mmol) followed by N-tert-butyl-2-chloroacetamide (81 mg, 0.54 mmol). The reaction mixture was stirred for 65 hours before being diluted with DCM and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (SiO2, gradient 0-3% methanol in DCM) then freeze-dried from methanol and water to give 510 as a beige solid (158 mg, 63%). LCMS: RT=3.67 min, [M+H]+=509. 1H NMR δ (ppm) (CDCl3): 8.34 (1H, d, J=8.18 Hz), 7.93 (1H, s), 7.10-7.06 (2H, m), 6.96 (1H, d, J=1.81 Hz), 5.92-5.91 (1H, m), 4.42 (2H, t, J=5.03 Hz), 3.42 (2H, t, J=5.05 Hz), 3.00-2.91 (4H, m), 2.61-2.48 (1H, m), 2.35-2.24 (2H, m), 1.96-1.87 (3H, m), 1.83-1.71 (1H, m), 1.64 (6H, d, J=6.63 Hz), 1.39 (9H, s)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:15]=[C:16]=[S:17])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH3:18]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:4]=1
Reactant: CSc1ccc(-c2ccccc2)c(N=C=S)c1
Reactant: N
Solvent: CCO
Product: CSc1ccc(-c2ccccc2)c(NC(N)=S)c1

Procedure:
Reaction of 4-methylthio-2-biphenylylisothiocyanate (11.5 g), ethanol (100 ml) and 25% aqueous ammonia solution (20 ml) at ambient temperature for 15 hours gave N-(4-methylthio-2-biphenylyl)thiourea as a colourless solid (m.p. 166°-167° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[S:13][C:12]2[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[C:10]=1[C:18](OCC)=[O:19]>>[CH2:17]1[C:11]2[C:10]3[C:18](=[O:19])[N:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]4=[N:8][C:9]=3[S:13][C:12]=2[CH2:14][CH2:15][CH2:16]1
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Product: O=c1c2c3c(sc2nc2ccccn12)CCCC3

Procedure:
2-Bromopyridine and ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylate 1b were heated to 165° C. for three and half hours under argon. After cooling the solid material was crystallized from EtOH. The crystallised product was purified by flash chromatography using CH2Cl2/EtOAc 9:1 as an eluent.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:48]1[CH:53]=[CH:52][C:51](Cl)=[CH:50][CH:49]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:48]1[CH:53]=[CH:52][C:51]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:50][CH:49]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(C)c1
Temperature: 150 °C
Yield: 92 %

Procedure:
Toluene (2.0 mL) and water (0.20 mL) were added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 50.0 mg, 0.0824 mmol), (S)-t-butoxycarbonylamino-(4-chloro-phenyl)-acetic acid methyl ester (Example 166-(1); 37.0 mg, 0.123 mmol), palladium (II) acetate (1.9 mg, 0.00846 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (6.8 mg, 0.0166 mmol) and potassium phosphate (52.0 mg, 0.245 mmol). After replacement with nitrogen, the mixture was stirred with microwave heating at 150° C. for five minutes. The reaction mixture was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target compound as a colorless oil (56.4 mg, 92%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]1[CH2:13]CC[CH2:10][CH2:9]1.O>C(C(C)=O)C>[CH2:8]([C:9]1([CH3:10])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1)[CH3:13]
Reactant: OCCNCCO
Reactant: C1CCCCC1
Solvent: CCC(C)=O
Solvent: O
Product: CCC1(C)OCCN1CCO
Yield: 78 %

Procedure:
A mixture of 315 g (3 mols) of diethanolamine, 432 g (6 mols) of methylethylketone, and 100 ml of cyclohexane is stirred and heated to reflux using a Dean-Stark trap to separate the water formed. The mixture is stirred and refluxed for a total of 311/2 hours during which 54 ml of aqueous layer, 85% water and 15% methyl ethyl ketone by NMR, is collected (85% of the theoretical amount of water of reaction). The mixture is then concentrated and the residue distilled to give 373 g (78% yield) of product (MEHEOX), b.p. 85°-88° C./2.5-3.0 mm Hg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([CH3:40])[CH:33]=2)[C:17]2[S:18][C:19]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.NCCC1C=CC(C#N)=C(C)C=1.CC(OC(N1CCC(CC=O)CC1)=O)(C)C.ClC1SC2C=C(C(F)(F)F)C=CC=2N=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:40][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][N:16]([CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:17]2[S:18][C:19]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:37]=[CH:36][C:35]=1[C:38]#[N:39]
Reactant: Cc1cc(CCN(CCC2CCN(C(=O)OC(C)(C)C)CC2)c2nc3ccc(C(F)(F)F)cc3s2)ccc1C#N
Agent: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: Cc1cc(CCN)ccc1C#N
Agent: FC(F)(F)c1ccc2nc(Cl)sc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(CCN(CCC2CCNCC2)c2nc3ccc(C(F)(F)F)cc3s2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
1.1 g 4-{2-[[2-(4-Cyano-3-methyl-phenyl)-ethyl]-(6-trifluoromethyl-benzothiazol-2-yl)-amino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester [prepared according to the method described in Example 1 and 5 from 4-(2-Amino-ethyl)-2-methyl-benzonitrile trifluoro acetate, N-boc-piperidinyl-4-acetaldehyde and 2-Chloro-6-trifluoromethyl-benzothiazole] were dissolved in 50 ml dichloromethane. 5 ml trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for one hour. 150 ml ethyl acetate were added and the mixture was washed three times with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 325 mg 2-Methyl-4-{2-[(2-piperidin-4-yl-ethyl)-(6-trifluoromethyl-benzothiazol-2-yl)-amino]-ethyl}-benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](Cl)[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl.[C:74]1([CH3:86])[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[N:80]1[CH2:85][CH2:84][NH:83][CH2:82][CH2:81]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:83]3[CH2:84][CH2:85][N:80]([C:75]4[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=4[CH3:86])[CH2:81][CH2:82]3)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: Cc1ccccc1N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Temperature: 120 °C
Reaction time: 12 h
Yield: 21.3 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (410 mg, 1 mmol), palladium acetate (6.73 mg, 0.03 mmol), cesium carbonate (0.65 g, 2 mmol), xantphos (23 mg, 0.04 mmol) and 1-(ortho-tolyl)piperazine hydrochloride (320 mg, 1.5 mmol) in toluene (10 mL) was stirred at 120° C. for 12 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(20% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.10 g, 21%) as a white solid: LC/MS m/e calcd for C30H35N3O2 (M+H)+: 470.6, observed: 470.6.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:48][C:49]([C:51]1[C:52]2[CH:53]=[CH:54][N:55]=[CH:56][C:57]=2[CH:58]=[CH:59][CH:60]=1)=[NH:50]>CN(C=O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:50]=[C:49]([C:51]3[CH:60]=[CH:59][CH:58]=[C:57]4[C:52]=3[CH:53]=[CH:54][N:55]=[CH:56]4)[N:48]=2)=[CH:11][CH:12]=1
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1
Temperature: 110 °C
Yield: 26.4 %

Procedure:
4-[(Difluoromethyl)oxy]benzoic acid (Aldrich; 121 mg, 0.642 mmol) was stirred in DMF (1 ml) with HATU (244 mg, 0.642 mmol) and DIPEA (0.28 ml, 1.605 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 100 mg, 0.535 mmol) in DMF (1 ml). The resulting mixture was heated to 110° C. for 2 hrs in a Biotage Initiator microwave. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-100% ethyl acetate in cyclohexane. The relevant fractions were combined and concentrated under vacuum to provide a crude material, which was further purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)) to give the title compound as a white solid (48 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[F:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:21][C:22]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[F:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:22]=2[CH3:21])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1F
Product: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1F

Procedure:
The product from Example 305D and 2-methyl-3-nitroaniline were processed as in Example 6A to provide the title compound. MS (ESI−) m/z 407 (M−H)+.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:15])[O:13][CH:14]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:15])[O:13][CH:14]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(-c2coc(C)n2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)co1

Procedure:
3-(2-Methyl-oxazol-4-yl)-benzoic acid methyl ester (1.02 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-(3-(2-methyl-oxazol-4-yl)-phenyl]-propionic acid tert -butyl ester (1.50 g) as a pale-yellow oil.