Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][C:54]([O:56]CC)=[O:55])[N:10]=2)[N:5]=1)[CH3:3].[OH-].[Na+]>C(O)C.O>[ClH:1].[C:54]([CH2:53][O:52][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH2:2][CH3:3])[CH:13]=[C:12]2[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:20][CH:21]=1)([OH:56])=[O:55]
Reactant: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2nc(OCC(=O)O)ccc2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (2.7 ml) was added to a solution of 2-ethyl-6-(ethoxycarbonylmethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (1.0 g) in ethanol (16 ml). The solution was heated at 50° C. for 2 hours and then cooled. 4M Sodium hydroxide solution (10 ml) was added and the solution was heated at 50° C. for 30 minutes and then diluted with water (50 ml). The solution was washed with ether (25 ml) and the aqueous phase was concentrated by evaporation. Water (10 ml) was added to the residue and the suspension was stirred for 1 hour. The insoluble solid was collected by filtration and dissolved in ethanol (7 ml). Concentrated hydrochloric acid was added and the resultant precipitate was collected by filtration to give 6-(carboxymethoxy)-2-ethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine hydrochloride, m.p. 223°-225° C.; NMR (d6 -DMSO): 1.4(t, 3H), 3.1(q, 2H), 5.0(s, 2H), 5.6(s, 2H), 7.2(d, 2H), 7.4-7.8(m, 8H), 8.7(d, 1H); mass spectrum (+ve FAB, DMSO/NBA): 527 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1])[CH:7]=[CH:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc2ccn(Cc3ccccc3)c12
Reaction time: 1 h

Procedure:
1-Benzyl-7-bromo-1H-indole was prepared from 7-bromo-1H-indole (0.500 g, 2.55 mmol), sodium hydride (0.285 g, 7.13 mmol of 60% dispersion on mineral oil), benzyl bromide (0.67 mL, 5.6 mmol) in DMF (5 mL). The reaction mixture was stirred for 1 hour after the addition of sodium hydride and for 1 hour after the addition of benzyl bromide. The compound was purified by flash chromatography (using hexane as an eluant) and dried at 60° C. for 30 minutes to yield a cream-colored solid (0.508 g, 70%), mp: 74-75° C. 1HNMR (300 MHz, DMSO-d6): δ 7.5-7.65 (m, 2H), 7.15-7.35 (m, 4H), 6.8-7.0 (m, 3H), 6.6 (s, 1H), and 5.8 ppm (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](/[C:20](/[C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[CH:29]=2)=[N:21]\[S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:18][CH:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C@@:20]([NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[CH:29]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[N:18][CH:19]=1
Reactant: CC(C)(C)[S@@](=O)/N=C(/c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@](Cc1ccccn1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Methyl pyridine (48 μL, 0.49 mmol) in THF (90 μL) was cooled at −78° C. for 10 min, followed by the addition of n-BuLi (246 μL, 0.49 mmol, 2M solution in cyclohexane). The reaction turned into maroon and was stirred at −78° C. for 40 min. (R,Z)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (100 mg, 0.25 mmol) in THF (1 mL) was added and the dark green colored reaction mixture was stirred at −78° C. for another 2 h. Quenched with H2O (10 mL), the reaction mixture was extracted by EtOAc (2×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC YMC ODS S5 28×100 mm Ballistic column 40-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide at a retention time of 9.66 min and was isolated as a clear oil (48 mg, yield 38%) LCMS: 1.76 min [M+1] 500.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.72 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.45 ppm, 1 H, d, J=2.64 Hz; 8.28 ppm, 1 H, d, J=4.39 Hz; 7.93 ppm, 1 H, s; 7.68 ppm, 1 H, d, J=8.79 Hz; 7.48 ppm, 1 H, dd, J=8.57, 2.42 Hz; 7.35 ppm, 1 H, t, J=6.81 Hz; 7.31 ppm, 1 H, s; 7.10 ppm, 1 H, d, J=7.91 Hz; 6.97 ppm, 2 H, m; 6.79 ppm, 1 H, d, J=7.47 Hz; 4.10 ppm, 1 H, d, J=14.06 Hz; 3.86 ppm, 1 H, d, J=14.50 Hz; 1.25 ppm, 9 H, s.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]([F:31])([F:30])[C:15](=[O:29])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][CH3:28])([CH3:19])[CH3:18]>C1COCC1>[F:31][C:14]([F:13])([F:30])[C:15]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)([OH:29])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][CH3:28])([CH3:19])[CH3:18]
Reactant: Cc1ccccn1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccccn1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
tert-Butyl lithium (1.7 M in pentane, 0.5 mL) was added dropwise to a solution of 2-methylpyridine (0.050 g) in THF (0.5 mL) cooled to −70° C. under argon. The mixture was stirred at −70° C. for 10 minutes and 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (0.080 g) (Example 1) in THF (0.5 mL) was added over 1 minute. The reaction mixture was stirred for 5 minutes and then quenched with MeOH. The reaction mixture was concentrated in vacuo and the residue fractionated directly by preparative layer chromatography on silica gel (methylene chloride-hexanes (1:1)) to give the 57 mg of the title compound, m.p. 94° C.-96° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:19]=1[CH:26]=[O:27]>O1CCCC1>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH:26]([C:19]3[C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]=3[CH3:17])[OH:27])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: Brc1ccc2ccncc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C(O)c2ccc3ccncc3c2)C(C)(C)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 122.7 %

Procedure:
A solution of 7-bromoisoquinoline (958 mg, 4.6 mmol) in tetrahydrofuran (15 mL) was added dropwise into n-butyl lithium (1.6 M in hexane, 2.87 mL, 4.6 mmol) at −78° C. and stirred at −78° C. for 30 minutes. Then 2,6,6-trimethylcyclohex-1-enecarbaldehyde (350 mg, 2.3 mmol) in tetrahydrofuran (2 mL) was added and the reaction was stirred at −78° C. for 1 hour and then allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride and the organics were extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (794 mg, Yield: 100%). Rf 0.5 (2:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.04 (s, 1H), 7.78 (s, 2H), 7.64 (d, J=5.6 Hz, 1H), 5.56 (s, 1H), 2.05-2.00 (m, 2H), 1.70-1.56 (m, 4H), 1.35 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H) ppm; Mass spectrum (ESI +ve) m/z 282 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:20].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:23][N:24]([CH3:26])[CH3:25])[N:6]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:20]
Reactant: Cc1ncccc1-n1c(C)nc2ccc(F)cc2c1=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1ncccc1-n1c(C=CN(C)C)nc2ccc(F)cc2c1=O
Temperature: 140 °C
Yield: 56.1 %

Procedure:
A mixture of 6-fluoro-3,4-dihydro-2-methyl-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one (1.02 g, 3.79 mmol) and dimethylformamide dimethyl acetal (1.01 mL, 7.58 mmol) in dimethylformamide (5 mL) was heated to 140° C. for 24 hours. Additional dimethylformamide dimethyl acetal (2 mL) was added and the reaction was heated at 140° C. for 16 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure. The dark residue was triturated with ether and the dark purple crystalline solid which formed was collected and dried to give 0.69 g (56%) of 6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one which had: 1H NMR δ 8.61 (dd, J=1.5, 5 Hz, 1H), 7.87 (d, J=12.3 Hz, 1H), 7.78 (dd, J=3, 8.5 Hz, 1H), 7.50-7.45 (m, 2H), 7.39-7.29 (m, 2H), 3.97 (d, J=12.3 Hz, 1H), 2.86 (br s, 6H), 2.35 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][N:16]1[CH2:21]CNCC1)#N>C(O)(C)C>[N:1]1([C:21]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=3[S:15][N:16]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccccc1SN1CCNCC1
Solvent: CC(C)O
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 90 °C
Yield: 55 %

Procedure:
Anhydrous piperazine (17.2 g, 0.20 mol) and isopropanol (3.0 mL) were charged to a round bottom flask equipped with a mechanical stirrer, thermometer, condenser topped with a nitrogen inlet, and an addition tunnel. Once the flask was purged and then maintained under nitrogen, the mixture was heated to 90° C. to afford a solution. A solution of 1-(2-cyanophenylthio)piperazine (4.38 g, 20.0 mmol) in isopropanol (2.0 mL) was slowly added to the warm piperazine solution over 1 hour. Once the addition was complete, the solution was heated to reflux (118° C.) for 24 hours. The reddish solution was cooled to room temperature and then analyzed by HPLC. 3-(1-Piperazinyl)-1,2-benzisothiazole was formed in 55% yield by HPLC assay.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)[C:6]=2[N:7]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CN(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([NH:23][CH:20]3[CH2:22][CH2:21]3)=[O:16])[C:6]=2[N:7]=1
Reactant: O=C(O)c1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1cccc(-c2csc3cnc(Cl)nc23)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)benzoic acid (600 mg, 2.06 mmol) was dissolved in N,N-dimethylformamide (20 mL) and then cyclopropylamine (234 mg, 4.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (589 mg, 3.09 mmol), hydroxybenzotriazole (417 mg, 3.09 mmol) and trimethylamine (574 mL, 4.12 mmol) were added. The reaction mixture was stirred at room temperature for a day, diluted with ethyl acetate, and washed with ammonium chloride aqueous solution. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (20% ethyl acetate/hexane) yielded the target compound (580 mg, 85% yield).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([C:17](O)([CH3:19])[CH3:18])[CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]([F:7])([CH3:19])[CH3:18])[N:14]=[CH:15][N:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1cc(Cl)ncn1
Solvent: ClCCl
Product: CC(C)(F)c1cc(Cl)ncn1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of DAST (0.153 mL, 1.159 mmol) in DCM (5 mL) was added 2-(6-chloro-4-pyrimidinyl)-2-propanol (Intermediate 28, 100 mg, 0.579 mmol) dissolved in DCM (5 mL) dropwise, and the resulting mixture stirred under argon at −78° C. for 4 hrs. The reaction mixture was quenched with excess saturated sodium bicarbonate solution (50 mL) and extracted with DCM (2×20 mL). The organic layers were collected and solvent was removed gently in vacuo. Crude product in DCM was taken into the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.Cl[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH2:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[N:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)n2)CC1
Temperature: -10 °C
Yield: 85 %

Procedure:
A stirred solution of 1-methyl-4-(5-nitropyridin-2-yl)piperazine (1.10 g, 5.00 mmol) and chloromethylphenylsulfone (0.950 g, 5.00 mmol) in dry THF, under nitrogen, is cooled to −60° C., treated with 1.0 M KOtBu in THF (10.0 mL, 10.0 mmol), allowed to warm to −10° C. over a 1 h period, quenched with acetic acid, treated sequentially with water and saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from EtOAc to give the title compound as a yellow solid, 1.60 g (85% yield), mp: 170°-172° C., identified by mass spectral and NMR analyses.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9])(=[O:18])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(CN)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,2-dimethoxyethylamine (2.61 g) in methylene chloride (100 ml) were added 2-nitrophenylsulfonylchloride (5.0 g) and diisopropylethylamine (5 ml) dropwise at −78° C. and the mixture was stirred for 10 minutes at room temperature. To the reaction mixture was added 1N hydrochloric acid and was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and was concentrated to give the title compound having the following physical data.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])=[N:8][CH:9]=1.[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:15][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:11]([F:12])([F:13])[F:14])=[N:8][CH:9]=1
Reactant: OC(c1ccc(Br)cn1)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(Br)cn1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred suspension of sodium hydride (765 mg, 60% dispersion in mineral oil) in dry diethyl ether (20 ml) under an argon atmosphere at 0° C. was added dropwise a solution of (RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanol (3.06 g) in diethyl ether (10 ml) and the resulting mixture was stirred at room temperature for 30 min. Trifluoromethanesulfonyl chloride (1.4 ml) was added and stirring was continued for a further 15 min at room temperature. The reaction mixture was quenched by addition of 10% aq. sodium bicarbonate solution and the mixture was extracted with diethyl ether. The phases were separated and the organic phase was washed with saturared brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by Kugelrohr distillation (60° C. oven temperature, 0.3 mbar) to give trifluoro-methanesulfonic acid (RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (3.6 g, 78%) as a white solid. MS (EI): 389 ([{81Br}M]+), 387 ([{79Br}M]+), 320 ([{81Br}M-CF3]+), 318 ([{79Br}M-CF3]+), 256 ([{81Br}M-CF3—SO2]+), 254 ([{79Br}M-CF3—SO2]+), 240 ([{81Br}M-OSO2CF3]+), 238 ([{79Br}M-OSO2CF3]).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCc1ccccn1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.00 g, 5.50 mmol), 2-(aminomethyl)pyridine (0.710 g, 6.57 mmol), triethylamine (0.610 g, 6.03 mmol) and benzene (40 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-pyridyl)methyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.410 g, 54.2% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([CH3:18])=[C:14]([CH3:17])[N+:15]=2[O-])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.P(Cl)(Cl)([Cl:22])=O.N>C(Cl)(Cl)Cl>[Cl:22][CH2:17][C:14]1[N:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][C:13]=1[CH3:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)[n+]([O-])c1C
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Temperature: 0 °C
Yield: 60 %

Procedure:
To a solution of 2-(4-isopropoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide; hydrochloride (2.5 g, 8.8 mmol) in chloroform (12 ml) was added a solution of phosphorous oxychloride (1 ml, 11 mmol) in chloroform (12 ml) within 5 min. The reaction mixture was heated under reflux for 45 min, cooled to 0° C. and made basic (pH 10) by carefully adding concentrated aqueous NH3 solution. The suspension was poured onto ice water and extracted two times with dichloromethane. The combined extracts were washed with ice water/brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, dichloromethane) to yield 1.6 g (6 mmol, 60%) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:38]>O.C(OCC)(=O)C>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Yield: 81 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (450 mg, 0.811 mmol) and saturated aqueous ammonium hydroxide (6.0 mL) were heated in a microwave reactor to 90° C. for 90 minutes. The reaction mixture was diluted with water, solution layered with ethyl acetate and pH of the mixture adjusted to 7 giving a gummy residue. The liquors were decanted and set aside; the gum was dissolved in mixture of warm ethyl acetate, dichloromethane and methanol and the solution added to the earlier liquors. The pH of this mixture was re-adjusted to 7.0. Organic phase was separated, dried (MgSO4), filtered and evaporated to give an orange colored foam which was dissolved in ethyl acetate (5 mL). Drop-wise addition of this solution to rapidly stirring hexanes (100 mL) gave a creamy white suspension which was filtered, filter pad washed with fresh hexanes, then air-dried to afford the title compound as a light yellow solid (370 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.88 (s, 1H) 7.97 (d, J=5.05 Hz, 1H) 7.64-7.77 (m, 1H) 7.40-7.48 (m, 1H) 7.33-7.39 (m, 1H) 7.18-7.32 (m, 4H) 6.75 (s, 2H) 5.84 (d, J=5.05 Hz, 1H) 5.09 (t, J=5.43 Hz, 1H) 3.51 (d, J=5.31 Hz, 2H) 1.33 (s, 6H). MS (ESI): 536.0 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[Na+].C([Li])CCC.[C:12]1([CH:18]2[S:23][CH2:22][CH2:21][CH2:20][S:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:25][C:26]1[CH:30]=[CH:29][O:28][CH:27]=1>CCCCCC.C1COCC1>[C:12]1([C:18]2([CH2:25][C:26]3[CH:30]=[CH:29][O:28][CH:27]=3)[S:19][CH2:20][CH2:21][CH2:22][S:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1ccoc1
Reactant: c1ccc(C2SCCCS2)cc1
Agent: CC(C)(C)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(C2(Cc3ccoc3)SCCCS2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of sodium tert-butoxide (5.16 g, 54 mmol) in dry hexane (120 mL) was added n-butyl lithium (34 mL, 51 mmol) at 0° C. and stirred for 1 h at 0° C., and then for 1 h at room temperature. The mixture was cooled to −78° C., and transferred to a preformed mixture of 2-phenyl-[1,3]dithiane (10.0 g, 51 mmol) dissolved in dry THF (120 mL) at −78° C., and n-butyl lithium (34 mL, 51 mmol) and kept for 15 min. A dark brown colored solution was observed. After stirring for 1 h at −78° C., 3-bromomethyl-furan (Danso-Danquah R. E. and Scott A. I. Tetrahedron, 1993, 49, 8195-8210; New D. G. et al, J. Org. Chem., 1996, 61, 1578-1598) (10.7 g, 66 mmol) was added via canula. After 30 min., the reaction mixture was quenched with water and warmed to ambient temperature. The reaction mixture was extracted with diethyl ether, and the organic extracts were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography using 0.2-0.5% ethyl acetate in hexane as eluent. Yield: 5.6 g, 32%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][NH2:11])[CH:8]=[CH:9][C:2]1=2.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]=O>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][N:11]3[CH:16]([C:15]4[C:14]([O:13][CH3:12])=[CH:21][CH:20]=[CH:19][C:18]=4[O:22][CH3:23])[CH2:19][CH2:18][CH2:15][C:14]3=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: COc1cccc(OC)c1C=O
Reactant: NCc1ccc2sccc2c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2sccc2c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available benzo[b]thiophen-5-ylmethanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.79 min.; [M+H]+: 382.09 g/mol.