Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[OH:40].[OH-].[Na+]>C(Cl)Cl.O>[OH:40][C:33]1[CH:34]=[C:35](/[CH:36]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:29][CH:28]=2)[CH:38]=[CH:39][C:32]=1[O:31][CH3:30]
Reactant: COc1ccc(C=O)cc1O
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C/c2ccc(OC)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.3 %

Procedure:
To a stirred mixture of 4-methoxybenzyltriphenylphosphonium chloride (5.51 g, 13mmol) and 4-methoxy-3-hydroxybenzaldehyde (2 g, 13 mmol) in CH2Cl2 was added a cooled aqueous solution of NaOH(62.5 eq) in H2O. The mixture was stirred at room temperature for 48 h. The aqueous layer was then acidified to pH 5 and the precipitated solid was filtered and dried. Purification by silica gel chromatography using hexane/ethyl acetate (1:1) gave the title E-trans product as a colourless solid 0.11 g (3%): 1H NMR (DMSO) δ 9.3 (1H, bs). 7.6 (2H, d), 7.2 (7H, m), 3.5 (6H, s): Mass Spectrum (FAB) 257 (M+1).
Reaction SMILES: [Cl-].[NH4+].[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])=[CH:5][CH:4]=1.C(O)C>O.[Fe]>[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][C:10]=2[Cl:19])=[CH:5][CH:4]=1
Reactant: Nc1nc(-c2ccc(-c3ccccc3)cc2)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(-c2ccc(-c3ccccc3)cc2)nc1N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Ammonium chloride (632 mg, 11.82 mmol) and iron (1320 mg, 23.64 mmol) were added to a stirred mixture of 6-([1,1′-biphenyl]-4-yl)-5-chloro-3-nitropyridin-2-amine (550 mg, 1.688 mmol) in water (2 ml)/Ethanol (2 mL) and the mixture was stirred at 60° C. for 3 h. The mixture was filtered through Celite™, rinsing with ethyl acetate (100 mL). Water (80 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (saturated, 80 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel Biotage™ 40S, eluting with 0-60% EtOAc/hexane to give title compound. LC-MS: calculated for C17H14ClN3 295.09 observed m/e: 296.12 (M+H)+ (Rt 1.09/2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.Cl.Cl.[N:15]1([CH2:21][CH2:22][CH2:23][N:24]2[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:27]2[CH2:28][CH2:29][C:30](=[O:31])[N:24]([CH2:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:25][CH2:26]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension of (E)-3-(3-Chloro-phenyl)-acrylic acid acid (26 mg, 0.12 mmol), 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4) (24 mg, 0.1 mmol), O-(7-azabenotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in DMF (1 ml) was added Et3N (21 ul, 0.15 mmol) and the mixture shaken for 1 h. The reaction was then directly purified by preparative HPLC affording the title product (28 mg, 69%) as a white powder. MS: 404.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:6]1)=[O:4].[CH:21](NC(C)C)(C)C.[Li].IC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:9][CH2:8][N:7]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:6]1)=[O:4]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCN(CC2COc3ccccc3O2)C1
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(CC2COc3ccccc3O2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution containing 80 mg (0.29 mmol) of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidine-3-carboxylic acid methyl ester in dry tetrahydrofuran (4.5 mL) at −78° C. under nitrogen was added 0.3 mL (0.58 mmol) of lithium diisopropylamine (2.0 M solution in heptane/tetrahydrofuran/ethylbenzene). The reaction mixture was stirred at −78° C. for 1 h and subsequently 0.04 mL (0.58 mmol) of iodomethane was added. The reaction mixture was allowed to warm to room temperature and the stirring was continued for 3 h. The reaction was quenched with 15 mL of saturated aqueous NH4Cl-solution and the tetrahydrofuran was evaporated off under vacuum. Water (50 mL) was added and the pH was adjusted to 10 using 1M Na2CO3. The water phase was extracted with ethyl acetate (3×25 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness, and the residue was dried under high vacuum.
Reaction SMILES: [SH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>O1CCCC1>[C:9]([O:8][C:7]1[C:2]([SH:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: Oc1cccnc1S
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1cccnc1S
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Mercapto-3-pyridinol (25) (1.27 g) was dissolved in tetrahydrofuran (50 ml) and treated with acetic anhydride (2 ml) and pyridine (1 ml). The reaction was stirred at room temperature for 48 hours, the solvent evaporated and the residue chromatographed on silica H [Merck Kieselgel 60 (>230 mesh)] to yield 3-acetoxy-2-mercaptopyridine (26) as a yellow crystalline solid from ethyl acetate (0.9 g) m.p. 178°-80°; νmax (CHCl3) 3400, 1760, 1605, 1590, 1460, 1180 cm-1 ; δ (CDCl3 +DMSO-d6) 2.36 (3H, s, COCH3) 6.80 (1H, dd, J18, 20 Hz, CS-H), 7.18 (1H, d) and 7.60 (1H, d,) C4 and C6 H's (Found: C, 49.77; H, 4.16; N, 8.36. C7H7NO2S requires C, 49.70; H, 4.14; N, 8.28%).
Reaction SMILES: Cl[C:2]1([CH2:10][CH:11]=[CH2:12])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]C1=O>C1(C)C(C)=CC=CC=1>[CH2:10]([C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]=1)[CH:11]=[CH2:12]
Reactant: C=CCC1(Cl)C(=O)CCCC1=O
Solvent: Cc1ccccc1C
Product: C=CCC1=CCCC1=O
Reaction time: 4.5 h
Yield: 49.5 %

Procedure:
Anhydrous powdered sodium carbonate (670 g) and 1300 ml of dry (alumina) xylene were placed in a 3-1., three-necked flask equipped with a Dean-Stark trap, condenser, vibra-mixer, dropping funnel and argon inlet. The flask was flushed with argon and the contents brought to reflux. A solution of 2-chloro-2-allyl-1, 3-cyclohexanedione (147 g, 0.79 mol) in 200 ml of xylene was added dropwise at such a rate that strong refluxing was maintained. After 4.5 hr. the reaction was cooled, filtered, and the sodium carbonate cake washed thoroughly with ethyl acetate. Evaporation of the solvent and careful fractionization of the residual oil gave 47.8 g (50 percent) of 2-allyl-2-cyclopenten-1-one, bp 73°-84°/4.2 mm.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].[O-]CC.[Na+].C([O:18][C:19](=O)[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)C>CN(C)C=O>[OH:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:19](=[O:18])[C:20]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccnc1N
Reactant: CCOC(=O)Cc1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncccc2c(O)c1-c1cccnc1
Temperature: 150 °C

Procedure:
To a solution of 2-amino-nicotinic acid methyl ester (200 mg) (Example 1.1) in N,N-dimethylformamide (“DMF”) (2 ml) was added sodium ethoxide (21 μl) (21% by weight in ethanol) followed by ethyl-3-pyridyl-acetate (200 μl). The reaction mixture was heated in the microwave at 150° C. for 15 minutes. The mixture was quenched by addition of aqueous hydrochloric acid (2M) (0.72 ml) and then diluted with water. The precipitate was isolated by filtration and washed with water and finally triturated with diethyl ether to give 4-hydroxy-3-pyridin-3-yl-1H-[1,8]naphthyridin-2-one as a beige solid (109 mg). 1H-NMR (400 MHz, d6-DMSO): 11.75 (bs, 1H), 8.70 (m, 1H), 8.52-8.53 (dd, 1H), 8.48-8.49 (dd, 1H), 8.35-8.37 (dd, 1H), 7.98 (d, 1H), 7.45-7.49 (dd, 1H), 7.23-7.26 (dd, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)=[O:3].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:14]1([C:2]([C:4]2[CH:13]=[CH:12][C:7]3[O:8][CH2:9][CH2:10][O:11][C:6]=3[CH:5]=2)([OH:3])[CH3:1])[CH2:16][CH2:15]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c(c1)OCCO2)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (8.42 mmol) of 1,4-benzodioxan-6-yl methyl ketone and 33.7 ml (16.84 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.12 g (59% of theory) of the title compound were obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.Cl.[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)CCCCCC(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(=O)CCCCCC(=O)N[C@@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
7-oxododecanoic acid (1000 mg, 4.67 mmoles) and L-alanine methyl ester hydrochloride (656 mg, 4.7 mmoles) were dissolved in N,N-dimethylformamide (5 ml). The solution was cooled to 0° C. and diphenylphosphoryl azide (1300 mg, 4.72 mmoles) and triethylamine (950 mg, 0.95 mmoles) were added thereto. The reaction mixture was stirred for 1 hour on an ice bath and for 24 hours at room temperature. The resulting suspension was diluted with ethyl acetate (30 ml) and washed successively with citric acid (0.52M; 3×5 ml), water (3×5 ml), saturated NaCl solution (3×5 ml), saturated NaHCO3 solution (3×5 ml), water (3×5 ml) and saturated NaCl solution (3×5 ml). The organic phase was dried with MgSO4 and filtered, the filtrate was evaporated and the compound was precipitated from n-hexane/diethyl ether.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18]([S:20][CH3:21])[C:17]([Cl:22])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18]([S:20]([CH3:21])=[O:31])[C:17]([Cl:22])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2ccc(S(=O)(=O)NC(C)(C)C)o2)ncc1Cl
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccc(S(=O)(=O)NC(C)(C)C)o2)ncc1Cl
Reaction time: 0.5 h

Procedure:
To the solution of N-tert-butyl-5-(5-chloro-4-(methylthio)pyrimidin-2-yl)furan-2-sulfonamide (150 mg, 0.42 mmol, 1.0 equiv.) in CH2Cl2 (3 mL) was added m-CPBA (124 mg, 0.54 mmol, 1.3 eq., 75% content) at 0° C. The reaction mixture was stirred for 30 minutes and then concentrated to produce N-tert-butyl-5-(5-chloro-4-(methyl sulfinyl)pyrimidin-2-yl)furan-2-sulfonamide. The residue was directly used for the next step. LC-MS (m/z)=378.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C#Cc1ccc(NCC2CC2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(NCC2CC2)nc1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a 0° C. solution of 855 mg (3.50 mmol) of cyclopropylmethyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine in 7 mL of THF, was slowly added 7.0 mL (7.0 mmol) of 1M TBAF in THF. The mixture was stirred for 2 h, then poured into water and extracted with Et2O. The Et2O was washed with brine. The washes were extracted once with Et2O, and the combined extracts were diluted with 10 mL of CH2Cl2 and left to sit for 10 min. The solution was then decanted from the water that had separated, and was dried with Na2SO4, filtered, concentrated, and chromatographed (1–20% EtOAc in hexanes) to provide 467 mg of 2-(cyclopropylmethyl)amino-5-ethynyl pyridine.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.CN(C)C=O.N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(#N)C>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])[O:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [4-(1H-tetrazol-5-yl)phenyl]amine (0.97 g, 0.006 mol, prepared in sequence by the procedures described by W. G. Finnegan et al., J. Amer. Chem. Soc, 1958, 80, 3908 and McManus and Herbst, J. Amer. Chem. Soc,, 1959, 24, 1044) in acetonitrile (30 mL), dimethylformamide (7 mL) and pyridine (0.97 mL, 0.95 g, 0.012 mol) under argon at 0° C. was treated with p-nitrophenyl chloroformate (1.21 g, 0.006 mol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 1M HCl, resulting in separation of product insoluble in either phase. This was collected, triturated with wet ether and dried in vacuo overnight to yield 1.37 g of [4-(1H-tetrazol-5-yl)phenyl]carbamic acid, 4-nitrophenyl ester, m.p. >260° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:0.2), Rf =0.63; 1H-NMR (DMSO-d6 ) δ7.6 (d, J=8.8 Hz, 2H), 7.7 (d, J=8.8 Hz, 2H), 8.1 (d, J=8.8 Hz, 2H) 8.3 (d, J=8.8 Hz, 2H); 13C-NMR (DMSO-d6) δ150.6, 144.7, 140.9, 128.0, 125.3, 123.0, 118.9, 118.2. M.S., (M+H)+ at 327, M.W. 326.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([C:33](O)=[O:34])[CH:12]=[C:13]2[C:18]=1[NH:17][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=1)[C:15]([CH3:32])([CH3:31])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:12]=[C:13]2[C:18]=1[NH:17][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:20]=1)[C:15]([CH3:31])([CH3:32])[CH2:14]2
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)cc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)cc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (118 mg, 2.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (285 mg, 3.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.3 mmol) and 1,1′-carbonyldiimidazole (98 mg, 0.6 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (43 mg, 30%) as a white solid: LC/MS m/e calcd for C23H28ClN3O4S (M+H)+: 479.05, observed: 478.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]SC)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].O[O:15][S:16]([O-:18])=O.[K+].[CH3:20]O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:16]([CH3:20])(=[O:18])=[O:15])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CSCc1ccc(O)c(C(C)=O)c1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CC(=O)c1cc(CS(C)(=O)=O)ccc1O
Reaction time: 2 h

Procedure:
To a solution of 2'-hydroxy-5'-(methylthiomethyl)acetophenone (2.20 g, 11.0 mmol) in 88 mL methanol cooled in an ice bath was added a solution of OXONE (commercial potassium peroxymonosulfate mixture, Aldrich Chemical Co.)(20.28 g, 33.0 mmol) in 88 mL water. The mixture was stirred two hours with cooling then partially concentrated in vacuo. The product was isolated in the same manner employed in the previous example to give after recrystallization from n-butylchloride 1.70 g (68%) product, as a white solid, mp 142°-144° C.:
Reaction SMILES: [Cl:1][C:2]([F:10])([C:6]([Cl:9])([F:8])[F:7])[C:3](F)=[O:4].[Cl-:11].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]([F:10])([C:6]([Cl:9])([F:8])[F:7])[C:3]([Cl:11])=[O:4]
Reactant: [Cl-]
Reactant: O=C(F)C(F)(Cl)C(F)(F)Cl
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(Cl)C(F)(Cl)C(F)(F)Cl
Reaction time: 2 h
Yield: 131.1 %

Procedure:
A 100-g sample (0.5 mole) of 2,3-dichloro-2,3,3-trifluoropropionyl fluoride, prepared as shown in Example 11, was added dropwise to a stirred suspension of 34 g (0.25 mole) of aluminum chloride in 200 ml of methylene chloride. The reaction mixture was stirred for 2 hrs, and the volatile portion was distilled under reduced pressure into a Dry-ice cooled trap. Redistillation gave 70.6 g (66%) of 2,3-dichloro-2,3,3-trifluoropropionyl chloride as a colorless liquid: bp 87.5°-88°; nd25 1,3812; ir (liquid 5.57μ (C=O); 19F nmr (CCl3F) δ 64.2 ppm (d, J = 173 Hz to d, J = 8 Hz, 1F), 65.7 ppm (d, J = 173 Hz to d, J = Hz, 1F) and 117.4 ppm (d, J = 10 Hz to d, J = 8 Hz, 1F).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:22]1[CH2:26][CH2:25][C:24]([C:27]#[N:28])=[CH:23]1>CN(C)C=O.O>[C:27]([C:24]1[CH2:25][CH2:26][C@@H:22]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:23]=1)#[N:28]
Reactant: N#CC1=CC(Br)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN([C@H]2C=C(C#N)CC2)CC1
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
To a stirred solution of tert-butyl piperazine-1-carboxylate (59.5 g, 320 mmol) in dimethyl formamide (400 ml) was added triethylamine (134 ml, 959 mmol) at 25° C. and stirred the reaction mixture for 10 minutes. To this was added 3-bromocyclopent-1-enecarbonitrile (55 g, 320 mmol) and the reaction mixture was stirred for 3 h. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue obtained was diluted with water (250 ml) and extracted with ethyl acetate (3×250 ml). The combined organic layer was dried over anhydrous sodium sulphate. The solvent in the organic layer was evaporated under reduced pressure to obtain crude product. The crude product purified by flash column chromatography over silica gel (100-200 mesh) using 40% ethyl acetated in hexane as an eluent to obtain the title compound (35 g, 126 mmol, 39.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[F-].[Cs+].I[CH:36]([CH3:38])[CH3:37]>C(#N)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH:36]([CH3:38])[CH3:37])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]=2[C:22]([F:24])([F:25])[F:23])[O:11][N:10]=1
Reactant: CC(C)I
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)OC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Yield: 79.4 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.064 mmol), cesium fluoride (12 mg, 0.077 mmol) and 2-iodopropane (0.008 mL, 0.077 mmol) were dissolved in dried acetonitrile (1 mL) and the mixture was refluxed for 20 h. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent was solvent removed under reduced pressure. The product was purified by pTLC (PE/EE 9/1) to give 26 mg of a yellow oil (yield 79%). Result of LC/MS [M+H]+: 511.8; 1H NMR (CDCl3): 1.02 (6H, d, 2×CH3), 5.02 (1H, m, CH-propyl), 7.18 (1H, t, CH-arom.), 7.28-7.61 (6H m, CH-arom.), 8.31 (1H, s, CH-pyraz.).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])[N:3]=1
Reactant: Oc1ccccc1Cl
Reactant: Clc1cncc(Cl)n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2ccccc2Cl)n1
Yield: 89 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 2-chlorophenol (193 μL, 1.86 mmol, d=1.24 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (363 mg). Yield: 89%. 1H NMR (250 MHz, DMSO-d6) δ 7.37-7.39 (m, 1H, Harom 4), 7.46-7.47 (m, 2H, Harom 5+6), 7.64 (d, 1H, Harom 3, J=8.2 Hz), 8.55 (s, 1H, HPz 5), 8.65 (s, 1H, HPz 3). m/z: 240.0 [(M)+, calcd for C10H6Cl2N2O 240.0].
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][CH2:21][CH2:22][C:23]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)=[O:24]
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCl)N1c2ccccc2-c2ccccc2-c2ccccc21
Yield: 94 %

Procedure:
9H-Tribenz[b,d,f]azepine (0.17 g, 0.70 mmol, prepared similarly as described by H. C. Axtell et al., J. Org. Chem. 56, 3906 (1991)) was suspended in dry toluene (5 ml). 3-Chloropropionyl chloride (0.13 g, 1.0 mmol) and triethylamine (0.1 ml) were added and the mixture was heated at reflux temperature for 1.5 hour. Saturated aqueous sodium bicarbonate (10 ml) was added, and the phases were separated. The organic phase was washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo, affording 220 mg, (94%) of crude 3-chloro-1-(9H-tribenz[b,d,f]azepine-9-yl)propan-1-one as a foam.