Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.CO.[CH:24]1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1>[CH3:24][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 8 h

Procedure:
800 gm (2.61 mol) of the difficulty soluble diastereoisomer of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C, were suspended in 4 liters of benzene and 125.5 gm (3.92 mol) of methanol, and a solution of 648 gm (3.14 mol) of dicyclohexyl-carbodiimide in 650 ml of benzene was added while stirring and cooling at 20°-25° C. The acid dissolved, and dicyclohexylurea precipitated out. The mixture was allowed to stand overnight at room temperature, then the excess of carbodiimide was decomposed by addition of glacial acetic acid, and then 2 liters of water were added, the dicyclohexylurea was suction-filtered off, the organic phase was separated from the filtrate and evaporated in vacuo after drying. The obtained oil (969 gm) was recrystallized from 2.9 liters of isopropanol. Yield: 736 gm (88% of theory); m.p. 75°-77° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[CH:22]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro4-trifluoromethylphenyl)-4-trimethylsilylethynylpyrazole (2.0 g, crude from example B1) in methanol (30 ml) was added potassium carbonate (1 g). After 10 minutes at room temperature the reaction mixture was partitioned between ether (100 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane folloxwed by recrystallisation from ether to provide the title compound as a white solid m.p. 215-216° C.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.Cl>C(#N)C>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:35])=[CH:29][CH:28]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Br)cc4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and 4-bromophenylisocyanate (0.20 g, 1.00 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.20 g, 2.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 2 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered, washed with water (30 mL) and dried in vacuo providing 1-(4-bromo-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.42 g, 89% yield); mp 278-280° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.00 (99.50%); 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.29-2.46 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.81-3.02 (m, 1H, CHH), 4.30 (d, 1H, CHH), 4.36-4.52 (m, 3H, CH2 and CHH), 5.11 (dd, J=4.8, 13.1 Hz, 1H, CH), 6.80 (t, J=5.7 Hz, 1H, NH), 7.31-7.47 (m, 5H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, 1H, Ar), 8.81 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.77, 47.12, 51.56, 112.42, 119.66, 121.88, 122.93, 126.89, 130.30, 131.32, 139.81, 142.38, 144.69, 155.03, 167.93, 170.99, 172.85; LCMS: MH=472; Anal. Calcd for C21H19BrN4O4: C, 53.52; H, 4.06; N, 11.89. Found: C, 53.32; H, 3.97; N, 11.77.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1O[C@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.2 mg, 0.0137 mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.70 mg, 24.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.71 (s, 3H), 2.60 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H) 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 498.8 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([OH:24])=O)[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].CCN=C=NCCCN(C)C>CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[NH:36]([C:22]([C@H:19]1[N:16]2[C:17](=[O:18])[C:12]([N:11]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)[C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][N:14]=[C:15]2[CH2:21][CH2:20]1)=[O:24])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)[C@@H]1CCc2ncc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OCc3ccccc3)c(=O)n21
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)[C@@H]1CCc2ncc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OCc3ccccc3)c(=O)n21
Temperature: 25 °C

Procedure:
To a solution of 12a (6.18 g, 12.7 mmol) and aniline (1.64 mL, 19.0 mmol) in 60 mL 5:1 CH2Cl2/DMF at 0° C., was added HOAt (1.90 g, 14.0 mmol), NaHCO3 (2.13 g, 25.4 mmol), and EDCI (3.41 g, 17.8 mmol). The mixture was stirred and allowed to warm to rt over 15 h. The reaction was diluted with EtOAc and the organic phase was washed with H2O, sat. NaHCO3, H2O, 1N HCl, H2O, and brine. The organic phase was dried (Na2SO4) and concentrated. The residue obtained was purified by flash chromatography (50 to 60 to 70% EtOAc/hexanes) to afford 4.60 g (60%, 2 steps) of 12b as an off-white solid. 1H NMR (300 MHz, CDCl3) δ9.35 (br s, 1H), 7.68 (br s, 1H), 7.52-7.21 (m, 13H), 7.07 (t, J=7.5, 1H), 5.28 (dd, J=8.7, 0.5, 1H), 5.22-5.11 (m, 2H), 4.84 (br s, 2H), 3.47-3.34 (m, 1H), 3.04-2.95 (m, 1H), 2.80 (br t, J=10.5, 1H), 2.44-2.30 (m, 1H). MS (ESI) 563.5 (M+H+), 35 585.5 (M+Na+), 561.4 (M−H+).
Reaction SMILES: C(C1NC2C(C=1)=CC=CC=2)C.[N+]([O-])([O-])=O.[Na+].S(=O)(=O)(O)O.[N+:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH2:34][CH3:35])=[CH:28]2)([O-])=O.CC(C)CCC1NC2C(C=1)=CC=CC=2>>[NH2:22][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH2:34][CH3:35])=[CH:28]2
Reactant: CCc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CC(C)CCc1cc2ccccc2[nH]1
Agent: CCc1cc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Product: CCc1cc2cc(N)ccc2[nH]1

Procedure:
This synthesis could be achieved beginning with a standard nitration of 2-ethylindole using sodium nitrate and sulfuric acid similar to that cited in Yokoyama; Tanaka; Yamane; Kurita; Chem. Lett.; 7; 1991; 1125-1128. The resultant 5-nitro-2-ethylindole could be reduced to the desired amino compound using catalytic hydrogenation as in 28b).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:7]=1)C.[Li+].[BH4-]>C1COCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[N:7]=[C:6]([CH2:5][CH2:4][OH:3])[C:11]([CH3:12])=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(OC)cc2)ccc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C)c(CCO)n2)cc1

Procedure:
Following the same procedure described for the preparation of Example 470 and starting from [6-4-methoxyphenyl)-3-methyl-2-pyridinyl]acetate (Example 479, 0.25 g, 0.88 mmol), LiBH4(0.88 mL, 2 M in THF, 1.75 mmol) in THF (4.4 mL), the title compound was obtained (0.18 g, 84%). 1H NMR (400 MHz, CD2Cl2) δ 7.87 (d, 2H), 7.55-7.45 (m, 2H), 6.98 (d, 2H), 4.18-4.08 (m, 2H), 3.85 (s, 3H), 3.06-2.95 (m, 2H), 2.29 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].O.[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[N:20]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=3[CH2:9][OH:10])[CH:25]=2)[N:20]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: OCc1cc(F)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccc(F)cc3CO)ccc2n1
Temperature: 120 °C

Procedure:
74 mg of (2-bromo-5-fluorophenyl)methanol, 100 mg of potassium carbonate, 1 ml of water and 15 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 3 ml of ethanol under argon. The mixture is heated at 120° C. for min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated in vacuo. The residue is purified by reverse-phase column chromatography.
Reaction SMILES: [CH2:1]([C:5]1(C)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].Cl.[CH3:19]O>>[CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:19])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CC1(C)Cc2ccccc2C=N1
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc2c(c1)CNC(CC(C)C)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of 24.5 mg of 3-isobutyl-3-methyl-3,4-dihydroisoquinoline in methanol (1 mL) was added 4.5 mg of sodium borohydride, followed by stirring at room temperature for 5 minutes. After completion of the reaction, to the reaction liquid was added 2N hydrochloric acid, followed by drying under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 24 mg (yield 96%) of a title compound as a light yellow oily substance.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]2[CH2:45][CH2:44]2)[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:43]1([N:41]2[C:40](=[O:46])[CH:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42]2)[CH2:45][CH2:44]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 120 °C
Yield: 73.9 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (0.729 g, 1.52 mmol) in 1,4-dioxane (16 mL) were added 5-bromo-1-cyclopropylpyridin-2(1H)-one (0.323 g, 1.51 mmol), 2 M aq Cs2CO3 (4 mL), and PdCl2(dppf).CH2Cl2 (0.079 g, 0.0964 mmol). The mixture was degassed and heated, under a nitrogen atmosphere, at 120° C. for 16 h. The mixture was diluted with CH2Cl2, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with MeOH/CH2Cl2 to afford 0.543 g (74%) of (S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.41 min, m/z 487 (MH+);
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH:4]1[CH2:5][CH2:6][CH:2]([CH:3]=[CH:12][C:11]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:9]([O:8][CH3:7])[CH:10]=2)[NH:1]1
Reactant: NC1CCNC1
Reactant: COc1ccc(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=CC2CCNN2)cc1OC
Reaction time: 12 h

Procedure:
3-Aminopyrrolidine is reacted with 3-(3,4-dimethoxybenzaldehyde, which is commercially available from Aldrich (Milwaukee, Wis.) in an inert solvent, for example methanol, in the presence of a base, for example sodium carbonate, and stirred for about 4–24 hours, preferably about 12 hours, at about room temperature. When the reaction is substantially complete, 4-(2-aza-2-pyrrolidin-3-ylvinyl)-1,2-dimethoxybenzene is isolated and purified by conventional means, and used without further purification.
Reaction SMILES: ClC1C=CC(COC2C=C(CO)C=CC=2)=CC=1C(F)(F)F.C[O:23][C:24](=[O:57])[CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:33]([S:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([C:53]([F:56])([F:55])[F:54])[CH:47]=3)[CH:39]=2)=[C:32]2[C:28]=1[CH2:29][CH2:30][CH2:31]2>>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][O:44][C:40]2[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=2)[CH2:37][S:36][C:33]2[CH:34]=[CH:35][C:27]([O:26][CH2:25][C:24]([OH:57])=[O:23])=[C:28]3[C:32]=2[CH2:31][CH2:30][CH2:29]3)=[CH:47][C:48]=1[C:53]([F:56])([F:54])[F:55]
Reactant: COC(=O)COc1ccc(SCc2cccc(OCc3ccc(Cl)c(C(F)(F)F)c3)c2)c2c1CCC2
Agent: OCc1cccc(OCc2ccc(Cl)c(C(F)(F)F)c2)c1
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(Cl)c(C(F)(F)F)c3)c2)c2c1CCC2

Procedure:
Preparation of [3-(4Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-methanol (compound 80A) The title compound was prepared in the manner analogous to Example 14A using 4-bromomethyl-1chloro-2-trifluoromethyl-benzene and 3-hydroxymethyl-phenol. MS m/z 299 (M-OH). Step 2. Preparation of 1-Chloro-4-(3-chloromethyl-phenoxymethyl)-2-trifluoromethyl-benzene (compound 80B) The title compound was prepared in the manner analogous to Example 3B using 80A. MS m/z 299 (M-Cl). Step 3. Preparation of {7-[3-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 80C) The title compound was prepared in the manner analogous to Example 1F using 80B and 12C. MS m/z 537 (M+1). Step 4. Preparation of {7-[3-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 80) The title compound was prepared in the manner analogous to Example 1 using 80C. mp 121-122° C.; IR (KBr) cm−1: 3027, 2584, 1742, 1255, 1129, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.87 (s, 1H), 7.64-7.75 (m, 2H), 7.09-7.19 (m, 1H), 7.01-7.09 (m, 1H), 6.73-6.88 (m, 3H), 6.56 (d, 1H, J=8.5 Hz), 5.06 (s, 2H), 4.60 (s, 2H), 3.95 (s, 2H), 2.74 (t, 2H, J=7.4 Hz), 2.63 (t, 2H, J=7.4 Hz), 1.87 (pentet, 2H); MS m/z 523 (M+1). Anal. Calc'd for C26H22ClF3O4S: C, 59.71; H, 4.24; found: C, 59.45; H, 4.08.
Reaction SMILES: COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)S2)=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=O)[C@@H:32]([NH:34][C:35]2[N:43]=[CH:42][N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][N:39]3C2CCCCO2)[CH3:33])=[C:26]([NH:51][C:52]2[N:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[CH:25]=1>O1CCCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]2[N:30]=[C:31]([C@@H:32]([NH:34][C:35]3[N:43]=[CH:42][N:41]=[C:40]4[C:36]=3[NH:37][CH:38]=[N:39]4)[CH3:33])[N:51]([C:52]3[N:57]=[CH:56][CH:55]=[CH:54][N:53]=3)[C:26]=2[CH:25]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: C[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ncccn1
Temperature: 80 °C
Yield: 40.5 %

Procedure:
2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (369 mg, 0.91 mmol) was added to (S)—N-[4-fluoro-2-(pyrimidin-2-ylamino)phenyl]-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionamide (109 mg, 0.23 mmol) in tetrahydrofuran (5.0 ml) and heated to 80° C. overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was taken up in EtOAc/1M hydrochloric acid (aqueous), and the aqueous layer extracted with EtOAc three times. The aqueous layer was neutralised with sodium hydroxide (1M aqueous) and extracted with EtOAc (×3). The neutral organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-20% methanol in DCM) to yield 261 (35 mg, 41%). LCMS: RT 3.08 min [M+H]+ 376.0. 1H NMR (CDCl3, 400 MHz): δ 8.90 (2H, d, J=4.9 Hz), 8.02 (2H, s), 7.97 (1H, dd, J=9.8, 2.7 Hz), 7.60 (1H, dd, J=8.7, 5.0 Hz), 7.42 (1H, t, J=4.8 Hz), 7.08 (1H, td, J 9.0, 2.6 Hz), 6.52 (1H, br s), 1.83 (3H, d, J=6.8 Hz)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:30][CH2:31][OH:32])[C:23]([O:25][C:26](C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.F[B-](F)(F)F.C[O+](C)C>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:30][CH2:31][OH:32])[C:23]([O:25][CH3:26])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: C[O+](C)C
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 29.8 %

Procedure:
To a mixture of No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (25 mg, 0.0357 mmol), 2,6-di-tert-butyl-4-methyl pyridine (15.4 mg, 0.075 mmol), and dichloromethane (2 mL) was added trimethyloxonium tetrafluoroborate (11 mg, 0.075 mmol) and the mixture was stirred at room temperature for 21 hours. After confirming the consumption of the starting materials by LCMS, methanol and water were added. The organic solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain the title compound (7 mg, 30% yield, white solid).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4][NH:3]1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>C(OCC)C>[C:19]([N:3]1[C:2]([CH3:11])([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4]1)(=[O:21])[CH3:20]
Reactant: CC1(C)N[Se]c2ccccc21
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1[Se]c2ccccc2C1(C)C
Reaction time: 1 h
Yield: 26 %

Procedure:
The derivative 3,3-dimethyl-benzisoselenazoline (148 mg; 0.7 mmole) was dissolved at room temperature in ethyl ether (4 ml). Triethylamine (107 μl; 0.77 mmole) and acetyl chloride (54 μl; 0.77 mmole) were added. A white precipitate appeared immediately. After 1 h, 1 ml of water was added to the reaction mixture. The crude product was extracted with 3×20 ml of dichloroethane. The organic phases were combined, washed with 2×20 ml of a saturated NaCl solution, dried over MgSO4 then filtered. The solvent was evaporated off under reduced pressure. The desired product was obtained after purification by liquid chromatography on a silica column (eluent: cyclohexane-ethyl acetate, 1/1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:13]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl-].[K+]>O>[NH:2]([C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[NH2:13]
Reactant: O=N[O-]
Reactant: CC1Cc2cccc(N)c2O1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: CC1Cc2cccc(NN)c2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 157 ml of concentrated hydrochloric acid and 66.1 g of 1C was stirred at room temperature for one hour, then 485 ml of water was added. The mixture was warmed to 70° C., then allowed to cool and stand at room temperature for 18 hours, then cooled to 5° C., while a solution of 33.7 g of sodium nitrite in 48 ml of water was added drop-by-drop (over 20 minutes). The resulting solution was stirred at 5° C. for 1 hour, then added drop-by-drop (over 10 minutes) to a stirred mixture of 393.5 g of sodium sulfite in 755 ml of water, at 5° C. The resulting mixture was stirred at room temperature for 2 hours, then a slurry of 77.2 g of sodium dithionite in 100 ml of water was added, in portions, to the stirred mixture. The mixture was stirred for 2 hours at room temperature, then at 70° C. for 15 minutes, when 1 pound of potassium chloride was added. The mixture was stirred at room temperature for 18 hours, cooled to 4° C. and filtered. 125 g of the resulting solid product was mixed with 500 ml of methanol. The resulting suspension was stirred at 0° C. while an excess of anhydrous hydrogen chloride was added. The mixture was stirred for 1 hour at 0° C., then most of the methanol was evaporated under reduced pressure at room temperature. The mixture was mixed with 500 ml of cold water, made basic by the addition of 50% aqueous sodium hydroxide solution, and extracted with ether. The extract was dried (MgSO4), and the solvent was evaporated to give 7-hydrazino-2,3-dihydro-2-methylbenzofuran (1D), as an amber syrup.