Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=O)[CH3:23])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CSC.B.CO>C1COCC1>[CH2:22]([NH:21][CH2:20][CH:17]1[CH2:16][CH2:15][CH:14]([C:11]2[NH:12][CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:25])([F:26])[F:1])[CH:4]=3)[N:10]=2)[CH2:19][CH2:18]1)[CH3:23]
Reactant: CC(=O)NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CCNCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-acetamide (207 mg, 0.57 mmol, from Example 2A) in THF, 3 equivalents of borane dimethylsulfide (2M in THF) was added, and the solution stirred overnight at room temperature. One volume of MeOH was added to the reaction mixture, and the mixture was concentrated under reduced pressure. 50 mL of 3N HCl was added, and the mixture was warmed for 5 minutes. After washing the solution with ether, the solution was made basic with NaOH and extracted with ethyl acetate. The solution was dried (Na2SO4), concentrated under reduced pressure, and purified using preparative plate chromatography to give Ethyl-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazole-2-yl]cyclohexylmethyl}-amine.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:15]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[F:35])[CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[O:16])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](=[O:45])[C:42](O)=[O:43].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:42](=[O:43])[C:41]([C:37]2[O:36][CH:40]=[CH:39][CH:38]=2)=[O:45])[CH2:10][CH2:9]1)=[O:16]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 60 h
Yield: 34 %

Procedure:
4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 2-(furan-2-yl)-2-oxoacetic acid (563 mg, 4 mmol), DIPEA (1 ml, 6 mmol), and HATU (510 mg, 1.34 mmol) were mixed in DMF (30 ml). After the resulting reaction mixture was stirred at room temperature for 60 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford the desired product (111 mg, 31%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:17])[CH3:16]
Reactant: Cc1ccncc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnccc1C

Procedure:
To solution of 3-amino-4-methylpyridine (540.2 Mg, 5.0 Mmol, 1 equiv) in dichloromethane (20 mL) was added pyridine (0.8 mL, 10.0 Mmol, 2 equiv) and acetic anhydride (0.57 mL, 6.0 Mmol, 1.2 equiv). The resultant solution was stirred at room temperature for 16 h and concentrated in vacuo to provide a crude residue. The residue was diluted with dichloromethane (200 mL), and washed with saturated sodium bicarbonate aqueous solution (50 mL) and brine (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to yield 3-acetylamino-4-methylpyridine (400.2 Mg) as yellow solid which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[C:5]([N:9]([CH3:11])[CH3:10])[N:4]=1)#[N:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[C:5]1[N:4]=[C:3]([C:1]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:2]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CN(C)c1cncc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Yield: 32.4 %

Procedure:
2-Cyano-6-dimethylaminopyrazine (0.50 g, 3.37 mmol) and methyl thiosalicylate (1.14 g, 6.75 mmol) was dissolved in toluene (100 ml), and triethylamine (1.42 ml, 10.1 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.31 g, 32%) as pale yellow crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:28]=[CH:27][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([N+:24]([O-])=O)[CH:18]=4)=[N:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:28]=[CH:27][C:13]3[NH:14][C:15]([C:17]4[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=4)=[N:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[5-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-2-nitro-phenylamine (500 mg, 1.3 mmol) in 4:1 ethyl acetate/methanol (50 ml) was added 5% palladium on carbon (120 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was filtered through Celite, washed with methanol, and the combined filtrate and washings were concentrated to give the crude 4-[5-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine as an orange solid that was used in the next step without any purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([NH:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[N:13]=[CH:12][CH:11]=2)(=O)=O.[CH3:24][O:25][C:26]1[CH:32]=[C:31]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)[CH:30]=[CH:29][C:27]=1[NH2:28]>>[CH:19]1([CH2:18][NH:17][C:14]2[C:15]3[C:10](=[CH:9][N:8]=[C:7]([NH:28][C:27]4[CH:29]=[CH:30][C:31]([C:33]5[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=5)=[CH:32][C:26]=4[O:25][CH3:24])[CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:21][CH2:20]1
Reactant: O=S(=O)(Oc1cc2c(NCC3CC3)nccc2cn1)C(F)(F)F
Reactant: COc1cc(-c2cnn(C)c2)ccc1N
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1cc2c(NCC3CC3)nccc2cn1

Procedure:
The title compound was prepared according to Method 6 (Example 103) using 5-((cyclopropylmethyl)amino)-2,6-naphthyridin-3-yl trifluoromethanesulfonate (Preparation 96) and 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19) for 3 hours. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:9]([N:12]([CH:38]([CH3:40])[CH3:39])[CH2:13][CH2:14][C@@H:15]([C:22]1[CH:27]=[C:26]([N:28]=NC2C=CC(C)=CC=2)[CH:25]=[CH:24][C:23]=1[OH:37])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:11])[CH3:10].Cl>O.C(O)C.C(OCC)C>[CH:38]([N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14][C@@H:15]([C:22]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:23]=1[OH:37])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:40])[CH3:39]
Reactant: Cc1ccc(N=Nc2ccc(O)c([C@H](CCN(C(C)C)C(C)C)c3ccccc3)c2)cc1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(N)ccc1O)C(C)C

Procedure:
A solution of Na2S2O4 (1.23 g, 12.8 mmol) in water (10 mL) was added to a solution of (R)-N,N-diisopropyl-3-[2-hydroxy-5-(4-methylphenylazo)phenyl]-3-phenylpropanamine (0.55 g, 1.28 mmol) in ethanol (50 mL) at 75° C. during 15 min. More dry Na2S2O4 (1.23 g, 12.8 mmol) was added in 10 portions. Water was added to the solution which was then extracted with diethyl ether. The organic layer was dried (MgSO4) and evaporated to give an oil, which was chromatographed on silica (n-hexane-ethanol-triethylamine 7:3:1) to give an oil. The product was dissolved in ethanol and hydrogen chloride in diethyl ether was added. The solvent was evaporated, redissolved in water and vacuum-dried wich yielded 0.25 g (60%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10](Br)=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:44]([OH:46])[CH3:45].CN([CH:50]=[O:51])C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:44]([O:46][C:50]([C:10]1[O:9][C:8]([C:6]2[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:11]=1)=[O:51])[CH3:45]
Reactant: CSc1nc(N)nc(-c2ccc(Br)o2)c1C#N
Reactant: CCO
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2nc(N)nc(SC)c2C#N)o1
Temperature: 90 °C
Yield: 6 %

Procedure:
To a stirred solution of 1.17 g (3.74 mmol) 2-amino-4-(5-bromo-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 15 ml DMF at room temperature were added 343 mg (0.37 mmol) tris(dibenzylideneacetone)dipalladium(O) and 287 mg (0.94 mmol) triphenylarsine. Carbon monoxide was bubbled through the reaction mixture for 10 min, then 2.61 ml (18.7 mmol) triethylamine and 10.9 ml (187 mmol) ethanol were added. The reaction mixture was then heated at 90° C. for 16 hours under a carbon monoxide atmosphere (balloon). The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane then ethyl acetate) afforded 70 mg (6%) 5-(2-amino-5-cyano-6-methylsulfanyl-pyrimidin-4-yl)-furan-2-carboxylic acid ethyl ester as a yellow crystalline solid. EI-MS m/e (%): 304 (M+, 95), 303 ([M—H]+, 100), 275 (32), 259 (93), 231 (72), 202 (32).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:15]Br>>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:14][CH2:15][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1cccc(CCBr)c1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCc1cccc(Cl)c1
Yield: 50.6 %

Procedure:
1.13 g (9.35 mmol) of 3-ethyl-4-methylpyridine and 2.05 g (9.35 mmol) of m-chlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.23 g of the desired compound (yield: 50.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18](C)[CH:17]=[CH:16]2.[NH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][CH2:6][CH2:7][CH2:2][CH:3]([CH3:4])[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH2:22])[CH:17]=[CH:16]2
Reactant: N
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc2cccc(O)c2n1
Product: CC(CCCOc1cc(Cl)cc(Cl)c1)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 86 substituting 3,5-dichlorophenol for 8-hydroxyquinaldine. 1H NMR (500 MHz, CDCl3) δ ppm 7.96 (d, 1H), 7.32 (t, 1H), 7.21 (dd, 1H), 7.12 (m, 1H), 6.99 (d, 1H), 6.84 (m, 1H), 6.64 (m, 2H), 4.68 (m, 1H), 4.05 (m, 1H), 3.95 (m, 1H), 2.18 (m, 1H), 2.00 (m, 3H), 1.47 (d, 3H); MS (DCI/NH3) m/z 391 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](OS(C(F)(F)F)(=O)=O)=[CH:24][C:17]=3[C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=1.[C:39]([O:43][C:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].O1CCOCC1>CCOC(C)=O.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.O>[C:39]([O:43][C:44]([C:46]1[CH:51]=[C:50]([C:25]2[C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:16]3[O:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]=3[CH:24]=2)[CH:49]=[CH:48][CH:47]=1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 90 °C
Yield: 69.3 %

Procedure:
Cesium carbonate (1.54 g, 4.71 mmol) was added to Pd(Ph3P)4 (182 mg, 0.157 mmol), ethyl 2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (1500 mg, 3.14 mmol), 3-(tert-butoxycarbonyl)phenylboronic acid (768 mg, 3.46 mmol). Dioxane (26 mL) and water (5 mL) was added at rt. The reaction was heated to 90° C. overnight. The reaction was allowed to cool was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give to give the titled compound (1.10 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.60 (1H, s), 8.08-8.18 (2H, m), 8.02 (1H, s), 7.95-8.01 (1H, m), 7.88 (1H, s), 7.58-7.70 (2H, m), 7.46 (2H, t, J=8.78 Hz), 4.34 (2H, q, J=7.20 Hz), 1.56 (9H, s), 1.27 (3H, t, J=7.14 Hz). LC-MS retention time: 2.13 min; m/z (MH+): parent does not ionize. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:8]=[N:7][C:6]=2[N:5]([CH3:19])[C:3]1=[O:4].ClC1C=CC=C(C(OO)=[O:28])C=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]3[O:28][CH2:18]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:19])[C:3]1=[O:4]
Reactant: C=CCCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c2c(ncn2CCCCC2CO2)n(C)c1=O

Procedure:
A solution of 31 g of 1,3-dimethyl-7-(5-hexenyl)xanthine and 34.9 g of m-chloroperbenzoic acid (70% pure) in 700 ml of chloroform was stirred at room temperature for 48 hours. The mixture was shaken with 10% strength sodium dithionite solution until the test with starch-iodide paper was negative, and washed with sodium bicarbonate solution and then with water to neutrality, dried and evaporated under reduced pressure.
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH3:15]S(C)=O>C(Cl)Cl.O>[CH3:15][O:12][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][CH:4]([OH:3])[CH2:5][C:6]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
A solution of 9.0 g (79 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over a 10-minute period to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 31.4 g (64.1 mmol) of ferric sulfate pentahydrate, and 200 ml of dimethyl sulfoxide at a temperature of 20° C. No temperature change is observed as the hydrogen peroxide solution is added. After the addition is complete, the reaction mixture is stirred for 10 minutes. Water (50 ml) is added, and the temperature increases to 45° C. The mixture is diluted with methylene chloride (200 ml) and water (50 ml), and the aqueous layer is extracted with methylene chloride (2×100 ml). The organic layers are concentrated at reduced pressure, and the crude product is purified by flash chromatography on silica gel (4:1 heptane/ethyl acetate) to afford 1.25 g (11% yield) of the title compound, mp 93°-94° C.
Reaction SMILES: Cl[C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.Cl.[NH2:24][OH:25].[OH-].[Na+].CCOC(C)=O>CCO.CCCCCC>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[CH2:3][C:2]([CH3:22])([CH3:21])[O:25][N:24]=2)[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(Cl)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=NO1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a 5 L round bottom flask, equipped with magnetic stirrer and Ar inlet is placed a solution of (77.1 g, 0.24 mol) 3-chloro-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methylbutan-1one and hydroxylamine hydrochloride (20.1 g, 0.28 mol) in EtOH (2.2 L). To the stirred solution is added 2 N NaOH (119 mL,0.24 mol, 1.0 eq) dropwise over 15 min. A rapidly dissipating yellow color is observed on contact of the two solutions. After addition is complete, the reaction is heated at 50° C. The reaction is followed by TLC (EtOAc:hexane, 1:4). After 3 hr, approximately 50% conversion is achieved. The crude product is precipitated by addition of H2O (750 mL), and filtered. The filtrate is set aside. A single recrystallization of the solids from hexane provides 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethylisoxazole as a faint yellow solid. The H2O/EtOH filtrate is concentrated on a rotary evaporator to remove EtOH, and the resulting suspension is extracted with CH2Cl2 (3×200 mL). The aqueous phase is discarded, and the organic phase is dried (MgSO4), filtered, combined with the hexane mother liquor from the above crystallization, and evaporated to an oily solid. Crystallization from hexane produces 3-(3,5-di-tert-butyl-4-hydroxyphenyl)4,5dihydro-5,5-dimethylisoxazole as a yellow solid slightly less pure than the first batch.
Reaction SMILES: CO[C:3]1[C:12]2C(=CC=CC=2)N=C(C2C=CC=CC=2)N=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[NH:36][C:35](=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C(I)C>>[CH2:3]([O:37][C:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[N:36]=1)[CH3:12]
Reactant: COc1nc(-c2ccccc2)nc2ccccc12
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Solvent: CCI
Product: CCOc1nc(-c2ccccc2OC)nc2ccccc12
Yield: 84.1 %

Procedure:
According to the preparation of 69, 42 (1.13 g, 4.5 mmol) and ethyl iodide (1.40 g, 9.00 mmol) was used to yield 74 (1.06 g, 84.1%) as colorless powder.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)Cl.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.[CH3:20][O-:21].[Na+].CO>CCOCC>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:1](=[O:5])[C:2]([O:21][CH3:20])=[O:3]
Reactant: C[O-]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)c1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A 2.0 M solution of oxalyl chloride in methylene chloride (4.50 mL, 9.0 mmol) was added to a solution of 5-fluoroindole (1.14 g, 8.4 mmol) in ether (19 mL) dropwise over 10 min at 4° C. under N2. The ice bath was removed and the resulting mixture was stirred for 2 h. A 25% sodium methoxide in methanol solution (4.3 mL, 18.8 mmol) was added at −78° C. over 5 min. The mixture was allowed to warm up to room temperature and stirred for 1 h. The reaction was quenched with water (50 mL), filtered and rinsed with cold ether to afford the title compound (1.34, 72%) as a yellow solid. 1H NMR (DMSO-d6) δ 12.51 (bs, 1H), 8.56 (s, 1H), 7.86 (m, 1H), 7.60 (m, 1H), 7.15 (m, 1H), 3.90 (s, 3H).
Reaction SMILES: C([S:8][C:9]([CH3:16])([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])C1C=CC=CC=1.N.CCO.Cl>CCOCC>[SH:8][C:9]([CH3:16])([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12]
Reactant: CCCC(C)(CCO)SCc1ccccc1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CCOCC
Product: CCCC(C)(S)CCO
Temperature: 25 °C
Yield: 112.6 %

Procedure:
At a temperature of −78° C. to a solution of 16.0 g (67.1 mmol) of (rac)-3-benzylsulfanyl-3-methyl-hexan-1-ol of step (c) in 200 ml of Et2O was added from a cylinder about 200 ml of NH3 Then pieces of Na (ca. 4.0 g) were added until the reaction mixture remained blue for more than 20 min. The blue colored mixture was allowed to warm up to room temperature overnight and EtOH was added until the blue color disappeared. The mixture was then acidified with about 2.7 M of HCl, and extracted three times with 150 ml of Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Distillation of the crude product at reduced pressure (40 mbar/130° C.) gave 11.2 g (73%) of (rac)-3-mercapto-3-methyl-hexan-1-ol in form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7](O)=[C:6]2O.C(N(CC)CC)C.C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Ru].C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@H:9]([CH3:15])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(C)nc(O)c(O)c2cc1OC
Agent: [Ru]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)[C@H](C)NCC2
Yield: 98.4 %

Procedure:
6,7-Dimethoxy-l-methyl-3,4-dihydroxyisoquinoline (Table 6-2a)(1.03 g, 5 mmol) and a ruthenium catalyst (Table 7)(R, R)-1a (16 mg, 0.025 mmol) were dissolved in acetonitrile (10 ml), followed by addition of a mixture of formic acid-triethylamine (5:2), for agitation at 28° C. for 3 hours. To the reaction mixture was added an aqueous sodium carbonate solution to extract the product in ethyl acetate. After evaporation of the solvent, 1H-NMR(CDCl3) of the resulting product was measured to calculate the conversion. Then, the product was purified by silica gel chromatography, to determine the optical purity and absolute configuration of the resulting optically active amine by HPLC or GLC. As collectively shown in Table 8, (S)-6,7-dimethoxy-l-methyl-1,2,3,4-tetrahydroisoquinoline (1.02 g, yield of 99%, 96% ee) was obtained.