Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O[CH2:28][CH:29]([OH:31])[CH3:30].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:28][CH:29]([OH:31])[CH3:30])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(O)CO
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(C)O)cc1
Reaction time: 8 h

Procedure:
A solution of 7.2 g. of 4-n-hexadecylaminobenzoic acid, 15.2 g. of 1,2-dihydroxypropane, and 3.9 ml. of boron trifluoride etherate are stirred together, under nitrogen, at 115° C. for 19 hours. The solution is cooled, diluted with methylene chloride, and placed in a freezer overnight. The solid is collected, washed with hexane, and oven-dried to yield a white solid. The solid is recrystallized from hexane and chromatographed on alumina with chloroform. This process yields 2-hydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid, m.p. 91°-93° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:9]1[CH:27]=[CH:26][C:12]([NH:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:16][S:17][CH2:18][CH3:19])=[CH:11][C:10]=1[C:28]([F:31])([F:30])[F:29])#[N:8]>O.CO>[C:7]([C:9]1[CH:27]=[CH:26][C:12]([NH:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:21])([F:22])[F:23])[CH2:16][S:17]([CH2:18][CH3:19])=[O:2])=[CH:11][C:10]=1[C:28]([F:30])([F:31])[F:29])#[N:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSCC(O)(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCS(=O)CC(O)(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Reaction time: 48 h

Procedure:
A solution of sodium metaperiodate (0.407 g.) in water (15 ml.) was added dropwise to a stirred solution of 4-cyano-3-trifluoromethyl-N-(3-ethylthio-2-hydroxy-2-trifluoromethylpropionyl)aniline (0.6 g.) in methanol (25 ml.) and the mixture was stirred at laboratory temperature for 48 hours and then filtered. The solid was washed with methanol (25 ml.) and the mixture was filtered, and the combined filtrates were evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (150 ml.) and the solution was washed successively with water (15 ml.), saturated aqueous sodium sulphite solution (25 ml.) and saturated aqueous sodium chloride solution (25 ml.), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (Merck 7734) using a 1:1 v/v mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) as eluant, and the two diastereoisomers of 4-cyano-3-trifluoromethyl-N-(3-ethylsulphinyl-2-hydroxy-2-trifluoromethylpropionyl)aniline were obtained by evaporation of the appropriate fractions of the eluate. These had m.p. 141°-143° C. (more polar isomer) and 160°-162° C. (less polar isomer).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:21][CH2:20]1)=[O:4].[C:32](Cl)(=[O:35])[CH2:33][CH3:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:32](=[O:35])[CH2:33][CH3:34])[C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:21][CH2:20]1)=[O:4]
Reactant: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reactant: CCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)N(C)C(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Yield: 12 %

Procedure:
A mixture of 2.22 g of N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide, 1.39 g of propionyl chloride, 2.53 g of triethylamine and 50 ml of toluene is refluxed for 2.5 days with stirring. The mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, successively. The ethyl acetate solution is dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:ethyl acetate=3:1). 0.30 g of N-methyl-N-propionyl-2-{2-[2-(4-(3-fluorophenyl)piperazine-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained as an oil.
Reaction SMILES: O[C@H:2]([CH:22]([CH3:24])[CH3:23])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH:22]([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 37.9 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2S*,3R*)-3-hydroxy-4-methyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.14 g, 0.43 mmol) in dry CH2Cl2 (20 mL), at 0° C., Et3N (0.18 mL, 1.3 mmol) and subsequently TBTU (0.17 g, 0.55 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the pure title compound (0.052 g, 40%), as pure syn diastereoisomer, as a white solid. MS (ESI) m/z: 337 [M−NH4]+; (ESI) m/z: 318 [M−H]−. 1H NMR (DMSO-d6) δ 0.75 (d, J=6.57 Hz, 3H), 0.96 (d, J=6.51 Hz, 3H), 1.25-1.39 (m, 2H), 1.52-1.65 (m, 4H), 2.03 (dt, J=6.53, 10.83 Hz, 1H), 2.57 (t, J=7.67 Hz, 2H), 4.01 (t, J=6.58 Hz, 2H), 4.24 (dd, J=5.92, 10.84 Hz, 1H), 5.44 (dd, J=5.92, 9.53 Hz, 1H), 7.13-7.34 (m, 5H), 8.27 (d, J=9.52 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]([O-])=O.[Na+].C([O-])(O)=O.[Na+].[ClH:34]>O>[ClH:34].[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:13]2[N:12]=[C:11]3[C:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])=[N:25][NH:17][C:16]3=[CH:15][CH:14]=2)[CH2:19][CH2:20]1
Reactant: O=N[O-]
Reactant: CN1CCN(c2ccc(N)c(CS(=O)(=O)c3ccccc3)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3n2)CC1

Procedure:
A stirred solution of 2-[(phenylsulfonyl)methyl]-6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (1.20 g, 3.50 mmol) in 1.0 M aqueous hydrochloric acid (20 mL) is cooled in an ice bath, treated dropwise with NaNO2 (358 mg, 5.2 mmol) in water, stirred for 1h, treated with aqueous saturated NaHCO3 and filtered. The brown solid filtercake is washed with water, dried in vacuo, triturated with acetone and filtered. The filtercake is washed with ether and air-dried to afford the free amine of the title compound as a tan solid, 0.50 g. This solid is dissolved in a mixture of ethanol and 4.0 M HCl in dioxane and concentrated in vacuo. The resultant residue is triturated with ether to afford the title compound as an off-white solid, mp >250° C., identified by mass spectral and NMR analyses.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([Cl:33])=[C:24]([C:26]2[N:30]([CH2:31][CH3:32])[N:29]=[CH:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([Cl:33])=[C:24]([C:26]2[N:30]([CH2:31][CH3:32])[N:29]=[CH:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCn1nccc1-c1cc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)sc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1-c1cc(C(=O)NC(CN)Cc2ccccc2)sc1Cl
Reaction time: 0.5 h
Yield: 53 %

Procedure:
1,1-dimethylethyl[2-({[5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (61 mg, 0.12 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). After 0.5 h, the solution was concentrated and neutralized through silica using 4% MeOH in DCM (1% NH4OH). The title compound was further purified using reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) affording the bis-TFA salt of the title compound (41 mg, 53%) as a white solid. LC-MS (ES) m/z=389 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.61 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.33-7.21 (m, 5H), 6.41 (d, J=2.0 Hz, 1H), 4.52 (m, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.22 (dd, J=12.9, 3.5 Hz, 1H), 3.12 (dd, J=12.6, 10.1 Hz, 1H), 2.98 (m, 2H), and 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11]([Cl:18])=[C:10]([C:19]#[N:20])[C:9]2=[O:21])=CC=1>C(O)(C(F)(F)F)=O>[Cl:18][C:11]1[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[NH:8][C:9](=[O:21])[C:10]=1[C:19]#[N:20]
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Cl)c2cccnc2[nH]c1=O
Yield: 95.8 %

Procedure:
A solution of 1-(4-methoxybenzyl)-4-chloro-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carbonitrile (32) (326 mg, 1 mmol) in TFA was refluxed for 24 h. The solution was cooled and excess TFA was distilled off under reduced pressure. The residue was taken in water, basified by solid NaHCO3 and filtered. The solids were washed with excess water and dried to yield 197 mg (95%) of 4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (31) as white solids. MP: 310° C.; 1H-NMR (DMSO-d6): δ 7.58 (dd, J=4.4, 8.0 Hz, 1H), 8.50 (d, J=2.0, 8.0 Hz, 1H), 8.83 (dd, J=4.4, 1.6 Hz, 1H), 13.03 (s, 1H); EIMS: 206 (M+1).
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[NH2:10][C:11](N)=[O:12].[Cl-].[NH4+].N>C1(C)C=CC=CC=1>[CH3:5][Si:4]([NH:10][C:11](=[O:12])[NH:3][Si:4]([CH3:5])([CH3:6])[CH3:7])([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NC(N)=O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture containing 750 parts by volume of hexamethyldisilazane, 750 parts by volume of toluene, 180 parts urea and 0.5 part of ammonium chloride is heated to reflux temperature (approx. 110° C.). After refluxing for 1.25 hours the evolution of ammonia has stopped and the reaction is considered to be complete. The product is cooled, filtered andthe filtered residue dried at 12 mm Hg (abs.). Approximately 603 parts (98.4 percent of theoretical) of bis-(trimethylsilyl-)urea having a purityin excess of 99 percent by weight are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[OH:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([O:28][CH2:29][CH3:30])=[N:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:16][C:13]1[N:12]=[N:11][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][O:17][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([O:28][CH2:29][CH3:30])=[N:23][CH:24]=[N:25]4)=[CH:20][CH:19]=3)[CH2:5][CH2:6]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reactant: CCOc1ncnc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ncnc2cc(OCCC3CCN(c4ccc(C)nn4)CC3)ccc12
Temperature: 90 °C
Yield: 17.6 %

Procedure:
A mixture of 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine (76 mg, 318 μmol), 7-hydroxy-4-ethoxyquinazoline (100 mg, 526 mmol), potassium carbonate (109 mg, 789 mmol) and potassium iodide (53 mg, 319 mmol) in DMF (5 mL) was heated at 90° C. overnight in an argon atmosphere. The mixture was concentrated, and the residue partitioned between ethyl acetate (100 mL), and water (20 mL). The organic phase was dried (MgSO4), filtered, concentrated and purified by column chromatography (silica), using gradient elution (ethyl acetate-methanol/EA). The combined fractions gave a white solid (22 mg, 18%). The 1H nmr data are recorded in Table 6 below.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][C:6]([O:9][CH3:10])([CH3:8])[CH3:7].O1CCCC1.C(O)(=O)C(O)=O>O>[CH3:10][O:9][C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CCC(C)(C)OC)OC
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(C)CCC=O
Yield: 85.3 %

Procedure:
A mixture of 1,1,4-trimethoxy-4-methylpentane (3.2 g, 0.018 mol), tetrahydrofuran (100 mL), water (10 mL) and oxalic acid (1.0 g, 0.022 mol) was heated at reflux for 40 hours. Workup provided 4-methoxy-4-methylpentanal (2.0 g).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[F:9][C:7]1[CH:8]=[C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[CH:3]=[CH:4][C:5]=1[NH2:6]
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 75.3 %

Procedure:
The title compound (430 mg) was prepared from 4-bromo-6-fluoroaniline (500 mg, 2.63 mmol) and 3-Methoxyphenylboronic acid (519 mg, 3.42 mmol) as a red liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.34 (dd, J 2, 13.1, 1H), 7.27 (t, J 7.9, 1H), 7.22 (dd, J 2, 8.3, 1H), 7.12 (d, J 7.9, 1H), 7.09-7.07 (m, 1H), 6.84-6.78 (m, 2H), 5.29 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([CH2:26][CH3:27])=[CH:4][CH2:5][C:6]1[C:14]([O:15]CC[Si](C)(C)C)=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:22])=[C:8]([CH3:23])[C:7]=1[O:24][CH3:25].C[O:29][P:30]([O:33]C)[O:31]C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>>[CH2:26]([C:3](=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:23])[C:7]=1[O:24][CH3:25])[CH2:10][O:11][C:12]2=[O:22])[CH2:2][P:30](=[O:29])([OH:33])[OH:31])[CH3:27]
Reactant: COP(OC)OC
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Product: CCC(=CCc1c(O)c2c(c(C)c1OC)COC2=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
A solution of 6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (230 mg, 0.5 mmol) in trimethylphosphite (1.5 mL, 12.75 mmol) was heated to 100° C. for 4 hours. The reaction was worked up by removal of excess trimethylphosphite under reduced pressure. The residue was dissolved in acetonitrile (1 mL) and TMSBr (646 μL, 5.0 mmol) and 2,6-lutidine (580 μL, 5.0 mmol) were added at 0° C. The reaction solution was allowed to warm to room temperature and stirred for 4 hours. The reaction was cooled to 0° C. and quenched with addition of MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 77 mg (58%) of the product. 1H NMR (300 MHz, CD3OD) δ 1.08 (t, 3H), 2.16 (s, 3H), 2.43 (m, 2H), 2.48 (d, 2H, J=22 Hz), 3.46 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.25 (s, 2H), 5.38 (q, 1H, J=7 Hz) ppm.; 31P (121.4 MHz, CD3OD) δ 25.65 ppm.; MS (m/z) 355 [M−H]−, 357 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:14][C:15]([C@H:17]2[N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][S:18]2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:33][C:32]([S:35]([N:21]2[CH2:20][CH2:19][S:18][C@H:17]2[C:15]([NH:14][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:16])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)N[C@H](c1ccccc1)c1ccccn1
Product: O=C(N[C@H](c1ccccc1)c1ccccn1)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from tert-butyl (2S)-2-({[(R)-phenyl(pyridin-2-yl)methyl]amino}-carbonyl)-1,3-thiazolidine-3-carboxylate (Intermediate 6) and [1,1′-biphenyl]-4-sulfonyl chloride, the title compound was obtained in 99% purity by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@H:25]5[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]5)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@H]1CC[C@H](Nc2nc3ccc(Cn4cnc5cc(F)cnc54)cc3s2)CC1
Temperature: 110 °C

Procedure:
To a stirred suspension of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (119 g, 0.3 mmol) from Step 4 of Example 162 and trans-4-aminocyclohexanol (119 mg, 1.0 mmol) in anhydrous DMA (1 mL) was added DIEA (180 μL, 1.0 mmol). The mixture was heated in a sealed tube at 110° C. for 15 h. The mixture was cooled to rt and was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford trans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 37%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J=2.6, 9.3 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.48 (s, 2H), 4.55 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 1.93-2.03 (m, 2H), 1.78-1.87 (m, 2H), 1.19-1.30 (m, 4H); LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [CH:1]1(CCCCCCCCCCCCN)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:25]([N:39]=[C:40]=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH:1]1([N:39]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:40]([NH:39][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:41])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCCCCCCCCCCCCN=C=O
Reactant: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCNC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 42, starting from 7.0 g of the compound of Example 1 and 4.8 g of tetradecyl isocyanate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]1[CH2:20][O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][N:16]1[CH2:17][CH2:18][C:13]2([O:19][CH2:20][CH2:11][O:12]2)[CH2:14][CH2:15]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(CN2CCC3(CC2)OCCO3)cc1F
Yield: 94.9 %

Procedure:
A solution of 3,4-difluorobenzaldehyde (4.40 g, 30.9 mmol), 4,4-ethylenedioxy-piperidine (4.40 g, 30.9 mmol), sodium triacetoxyborohydride (6.40 g, 30.2 mmol) and acetic acid (1.8 g, 30.0 mmol) in dichloroethane (200 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was washed with 1N sodium hydroxide. The organic layer separated, dried (MgSO4) and the solvents evaporated in vacuo to give D3 (7.9 g, 98%). C14H17F2NO2 requires 269; Found 270 (MH+)
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:21][C@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][N:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[C:3]([C:1]([NH2:2])=[O:36])=[N:4][CH:5]=1)[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(=O)O
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3ccno3)cc2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3ccno3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(4-(isoxazol-5-yl)phenylamino)pyrazin-2-ylamino)-4-methylpentanamide (5 mg, 0.012 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.2 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 410.3 (M+H); UV 202.3, 235.2, 276.9, 331.2 nm; t 0.627 min.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4]/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].[SH:22][C@@H:23]([CH2:27][C:28]([OH:30])=[O:29])[C:24](O)=[O:25]>C1(C)C=CC=CC=1>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][NH:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[CH:6]1[N:5]([CH2:4][CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:24](=[O:25])[CH:23]([CH2:27][C:28]([OH:30])=[O:29])[S:22]1
Reactant: CN(C)CCNc1c(F)cccc1/C=N/CCC(C)(C)C
Reactant: O=C(O)C[C@H](S)C(=O)O
Solvent: Cc1ccccc1
Product: CN(C)CCNc1c(F)cccc1C1SC(CC(=O)O)C(=O)N1CCC(C)(C)C

Procedure:
2-((E)-(3,3-dimethylbutylimino)methyl)-N-(2-(dimethylamino)ethyl)-6-fluorobenzenamine (175 mg, 0.5964 mmol) and (S)-2-mercaptosuccinic acid (102 mg, 0.6793 mmol) were stirred in toluene (7 mL) at 80° C. for 24 hours. Crude 2-(2-(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid was obtained as a brown oil and carried on to the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[CH3:20]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:17]2[CH:16]=[CH:15][C:14]([CH3:20])=[C:13]([Cl:12])[CH:18]=2)[CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1ccc(I)cc1Cl
Product: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1Cl

Procedure:
The title compound, m. p. 115-116° C., MS: m/e=288 (M+), was prepared from 4-chloroquinoline and 2-chloro-4-iodo-toluene.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[CH3:16][O:17][CH2:18][CH2:19]Br>CN(C=O)C.CCOC(C)=O>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:19][CH2:18][O:17][CH3:16])[C:6]1=[O:15]
Reactant: NC1Cc2ccccc2NC1=O
Reactant: COCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(N)Cc2ccccc21
Yield: 77.7 %

Procedure:
Sodium hydride (60% in oil, 321 mg, 8.03 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985; 1511–16; 759 mg, 3.82 mmol) in anhydrous DMF (10 mL) at 0° C. over a period of 5 min. After 1 hour 2-bromoethyl methyl ether (0.40 mL, 4.20 mmol) was added and stirring maintained for 18 hours. The reaction was diluted with EtOAc (100 mL) and washed with sat. aqueous K2CO3 (20 mL). The aqueous was extracted with DCM (3×50 mL) and the combined organics dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (4:1)) to afford the title compound (654 mg, 78%) as a brown oil.