Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH2:18][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:16][N:15]=3)[S:13][C:6]=12
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
A mixture of 400 (451 mg, 1.14 mmol) and 1-methylpiperazine (152 μL, 137 mg, 1.37 mmol) in DCM (7 mL) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (340 mg, 1.60 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (20 mL) The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 30-50% MeOH (with 2% Et3N) in EtOAc to afford 401 (308 mg, 52% yield). MS (m/z): (M+1) 480.0 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1.C(Cl)(Cl)Cl.C(O)C>[NH2:8][CH2:9][C:10]([N:11]([CH3:12])[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:21][C:6]=1[C:7](=[N:23][OH:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:13]
Reactant: NO
Reactant: CN1C(=O)CN=C(c2ccccc2Cl)c2cc(N)ccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN(C(=O)CN)c1ccc(N)cc1C(=NO)c1ccccc1Cl

Procedure:
A solution of 5.0 g (16.68 mmol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one and 1.74 g (22.02 mmol) of hydroxylamine hydrochloride in 50 ml of pyridine is heated to reflux for 2 hours under argon. After cooling, the mixture is taken up in 600 ml chloroform/ethanol (4:1) and washed with 250 ml of water. The aqueous phase is adjusted to pH 8, saturated with sodium chloride and extracted with chloroform overnight in a perforator. After drying and evaporating the solvent, the residue is suspended in hot tert.-butyl methyl ether and filtered off. There is obtained 2,4'-diamino-2'-[o-chloro-α-(hydroxyimino)benzyl]-N-methylacetanilide of melting point 150° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.O.Cl>C(O)C.[Fe]>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnc(Cl)c(N)c1
Reaction time: 1 h

Procedure:
A solution of 1.08 g (5.00 mMol) of methyl 6-chloro-5-nitro-nicotinate (see A. H. Berrie, G. T. Newbold, F. S. Spring in J. Chem. Soc., 2590, 1951) in 25 ml of absolute ethanol was mixed successively with 0.53 ml (29 mmol) of water, 3.2 g (57 mMol) of iron powder and 0.030 ml of concentrated hydrochloric acid and heated to boiling for one hour. Then equal quantities of water, iron powder and hydrochloric acid were added and the mixture was heated to boiling for 30 minutes. The precipitate formed on cooling was filtered off and washed with ethanol and the solvent was distilled off in vacuo. Yield: 0.75 g (81% of theory) of greenish-yellow solid, Rf value: 0.31 (silica gel;ethyl acetate/petroleum ether=1:4) C7H7ClN2O2 (186.60) YEF- Mass spectrum: M+ =186 and 188 (chlorine isotopes).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41][CH2:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1.ON1C2C=CC=CC=2N=N1.[Cl-].C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:47][C:46]4[CH:45]=[CH:44][C:43]([CH2:42][S:41][C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=5)=[CH:49][CH:48]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: Nc1ccc(CSc2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.50 g) was dissolved in DMF (10 ml), 4-[(2-pyridinylsulfanyl)methyl]aniline (272 mg) and 1-hydroxybenzotriazole (321 mg) were added to the mixture, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chloride (401 mg) and triethylamine (0.44 ml) were added to the mixture, and the mixture was stirred for 16 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 199) (0.36 g).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([O:26]CC)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Temperature: 70 °C
Yield: 101.2 %

Procedure:
To ethyl 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylate (430 mg, 0.891 mmol; prepared as in Example 23) in THF/H2O (6 mL/1 mL) was added lithium hydroxide (21.3 mg, 0.891 mmol). The reaction mixture was sealed and heated to 70° C. for 2 hours. The mixture was cooled to ambient temperature and HCl (0.45 mL, 4M in dioxane) was added. The mixture was concentrated under reduced pressure to give crude product (410 mg, mixed with LiCl).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])=[O:35].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[C:34](=[O:35])[CH2:33][N:3]1[C:4](=[O:31])[C:5]2[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=2[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:2]1=[O:1]
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3F)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(2,4-difluorophenyl)ethanone (0.88 g) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.98 g, 49%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:12])=[NH:11])=[CH:5][CH:4]=1.O.[NH2:14]N.[C:16]([NH:19][CH:20]([CH3:28])[C:21](=O)[C:22](OCC)=[O:23])(=[O:18])[CH3:17]>C(O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[NH:12][C:22](=[O:23])[C:21]([CH:20]([NH:19][C:16](=[O:18])[CH3:17])[CH3:28])=[N:14][N:11]=2)=[CH:7][CH:8]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: Cc1ccc(CC(=N)N)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Reaction time: 0.75 h

Procedure:
10 g (54.2 mmol) of 2-(4-methylphenyl)ethanamidine hydrochloride (Example 3A) are taken up in 100 ml of ethanol and treated with 3.25 g (65.0 mmol) of hydrazine hydrate. The mixture is stirred for 45 min, then the compound of Example 6A is added. It is then stirred for 4 h at 80° C. (bath) and overnight at room temperature. The substance is purified by flash chromatography, preliminary fractions first being separated off using ethyl acetate. The product is eluted with dichloromethane/methanol 30/1.
Reaction SMILES: Cl.CO[C:4](=[O:13])[CH:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][NH:6]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:4]([CH:5]2[CH2:10][CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7][NH:6]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(=O)C1CCC(C)(C)CN1
Agent: Cl
Product: CC1(C)CCC(C(=O)N2CCCC2)NC1
Reaction time: 8 h

Procedure:
4.2 g (23.5 mmoles) of 5,5-dimethyl pipecolic acid methyl ester hydrochloride were added to 40 ml of pyrrolidine kept at 0° C. After the addition, the solution was allowed to reach room temperature and stirring was continued overnight. The reaction mixture was evaporated in vacuo and the residue treated with 30 ml of 40% NaOH, extracted with diethyl ether, dried over sodium sulphate and evaporated in vacuo to dryness to give 3.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:9][C:10]=1[C:11]([NH:13][O:14]C1CCCCO1)=[O:12].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[S:9][C:10]=1[C:11]([NH:13][OH:14])=[O:12]
Reactant: O=C(NOC1CCCCO1)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
To a solution of 4-(3,4-dichlorobenzyl)-2-(morpholin-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,3-thiazole-5-carboxamide (153 mg, 0.324 mmol) in methylene chloride (1.50 mL) was added trifluoroacetic Acid (1.50 mL, 19.5 mmol). The reaction was stirred at rt for 12 hrs. The resulting solution was concentrated and distributed between NaHCO3(aq) saturated solution and CH2Cl2. The aqueous layer was extracted with CH2Cl2(×2). The combined org layer was washed with water, dried, and concentrated. Purification on a silica gel column (gradient elution, 0-8% MeOH/CH2Cl2) provided 4-(3,4-dichlorobenzyl)-N-hydroxy-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide as a yellow solid (53 mg, 42.1% yield). LCMS: (AA) ES+ 388, 390, 392; 1H NMR (400 MHz, MeOD) δ 7.47-7.41 (d, J=1.8 Hz, 1H), 7.38-7.29 (d, J=8.3 Hz, 1H), 7.25-7.14 (dd, J=8.3, 1.9 Hz, 1H), 4.28-4.21 (s, 2H), 3.79-3.71 (t, J=4.9 Hz, 4H), 3.50-3.43 (t, J=4.9 Hz, 4H), 3.33-3.27 (t, J=1.6 Hz, 1H).
Reaction SMILES: CC1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1.Br[C:35]1[C:36]([C:42]#[N:43])=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:35]2[C:36]([C:42]#[N:43])=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(Br)c(C#N)n1
Reactant: CC1(C)OB(c2ccc(F)cc2)OC1(C)C
Agent: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Product: Cc1ccc(-c2ccc(F)cc2)c(C#N)n1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3-bromo-6-methylpicolinonitrile. ESI-MS (m/z): 213 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>O1CCCC1>[Cl:28][CH:29]([Cl:33])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[O:10][N:9]=2)[CH:3]=1)=[O:31]
Reactant: Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(3-Aminophenyl)-5-(2,6-dichlorophenyl)isoxazole (60 mg, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) with triethylamine (33 mL, 0.24 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (23 mL, 0.24 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give the title compound as a tan solid, 74 mg.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)#[N:2].Cl.[OH-].[Na+].CCOCC>C1COCC1.C(Cl)Cl>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1
Reactant: COc1cc2c(cc1OC)CN(CCC#N)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CN(CCCN)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-(2-cyanoethyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (5.70 go 23.1 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0 M, 81 mL, 81 mmol, 3.5 equiv) at room temperature. The mixture was stirred at reflux for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 130 mL) was added cautiously at room temperature and stirring was continued for 2.5 hours at 55-60° C. The mixture was cooled to 0° C., basified to pH 10-11 by addition of 6 N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (20 mL) was added HCl in ether (1.0 N, 40 mL, 1.7 equiv). The resulting solution was added dropwise into ether (250 mL) with swirling. The precipitate was filtered and washed with ether (3×100 mL). This solid was taken up in water (50 mL), which was basified to pH 10 by addition of 1 M aqueous NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 5.10 g (88%) of white solid, which was characterized spectroscopically.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][OH:9])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1ccc(CO)cc1
Yield: 45.9 %

Procedure:
A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol), 4-(hydroxymethyl)phenylboronic acid (25 g, 0.164 mol), Pd(PPh3)4 (9.5 g, 0.0082 mol), and sodium carbonate (200 g in 500 ml of water) in toluene (750 ml) were refluxed under nitrogen atmosphere for 15 h. Separated the toluene layer and distilled under reduced pressure to give a residue. The residue was then purified by column chromatography to yield [4-(3-methyl-2-pyridinyl)-phenyl]methanol (12 g, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](=[O:16])[NH:17][C:18]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2cc(C(C)(C)C)on2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.) solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (1 g; 4.424 mmol) and 3-amino-5-t-butylisoxazole (606 mg; 4.324 mmol) and N,N-diisopropylethylamine (1.521 mL; 8.732 mmol) in anhydrous acetonitrile (12 mL) is added phosphorous oxychloride (0.39 mL; 4.424 mmol). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 354 [M+H+].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][S:14][C:15]1[C:16]2[CH:23]=[CH:22][S:21][C:17]=2[N:18]=[CH:19][N:20]=1.[I:24]I.[NH4+].[Cl-]>C1COCC1.O>[CH3:13][S:14][C:15]1[C:16]2[CH:23]=[C:22]([I:24])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: II
Reactant: CSc1ncnc2sccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CSc1ncnc2sc(I)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
Butyllithium (1.6 M in hexane, 32.8 mL) was added dropwise to a stirred solution of diisopropylamine (7.36 mL) in THF (170 mL) at −78° C. under an inert atmosphere. The reaction mixture was warmed to 0° C., stirred for 20 min, recooled to −78° C. and 4-(methylthio)thieno[2,3-d]pyrimidine (J. Heterocycl. Chem. 1975, 12, 921-924) (9.11 g) in THF (17 mL) added. A purple solution resulted and then iodine (19.0 g) in THF (20 mL) was added and stirring at −78° C. continued for 1 hours before warming to ambient temperature and stirring for a further 1.5 hr. Saturated aqueous NH4Cl (3 mL), then water (500 mL) were added and the reaction mixture extracted with DCM (500 mL), the organic layer was washed with Na2S2O3 (2M, aq) (2×50 mL), water (2×200 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was triturated with DCM (50 mL) to afford the title compound as a brown solid (11.8 g, 77%);
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3OCC(C)(C)C[O:39]3)[CH2:32][CH3:33])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O.CCOC(C)=O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCN(CCCCC1OCC(C)(C)CO1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CCCCC=O)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl](ethyl)amino]-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (20 mg, 0.0286 mmol) in THF (3 mL) and water (1 mL) was added p-toluene sulfonic acid (excess). The reaction was stirred at room temperature for 16 hours, and then brought to reflux and stirred for 24 hours. The mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO3 solution and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (35% EtOAc/hexanes) afforded 5-[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]pentanal. Rf=0.24 (35% EtOAc/hexanes). LCMS=615.2 (M+1)+. 1H NMR (CDCl3, 500 MHz), 9.72 (s, 1H), 7.89 (s, 1H), 7.79 (s, 2H), 7.19-7.12 (m, 3H), 5.73 (d, J=8.2 Hz, 1H), 4.73 (d, J=16.3 Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 4.04-4.00 (m, 1H), 2.95-2.85 (m, 4H), 2.42 (t, J=7.1 Hz, 2H), 1.61-1.37 (m, 4H), 0.98 (t, J=7.1 Hz, 3H), 0.67 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:20]=[C:19]([CH2:21]Cl)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([N:7]2[C:8]([NH2:10])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:20]=1)=[N+:24]=[N-:25]
Reactant: CC(C)(C)c1cc(N)n(-c2cc(CCl)c3ccccc3c2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(N)n(-c2cc(CN=[N+]=[N-])c3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 3-t-butyl-1-[4-(chloromethyl)naphthalen-2-yl]-1H-pyrazol-5-amine (1.5 g, 4.8 mmol) in DMF (8 mL) was added NaN3 (325 mg, 5.0 mmol). The mixture was stirred at RT overnight, then poured into ice-H2O and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to afford 1-[4-(azidomethyl)naphthalen-2-yl]-3-t-butyl-1H-pyrazol-5-amine (1.35 g, 88% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.06 (m, 2H), 8.04 (m, 1H), 7.85 (s, 1H), 7.54-7.57 (m, 2H), 5.41 (s, 1H), 5.35 (brs, 2H), 4.96 (s, 2H), 1.21 (s, 9H); MS (ESI) m/z: 321 (M+H+).