Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:25]=[CH:24][C:13]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>>[OH:31][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([C:21]4[N:32]=[N:33][NH:34][N:22]=4)[CH:23]=3)=[O:15])=[CH:24][CH:25]=2)[CH:26]=[CH:27][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2ccc(C(=O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2ccc(C(=O)c3cncc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Yield: 68.4 %

Procedure:
The title compound is prepared essentially as described in Example 1 using 5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile (448 mg, 1.08 mmol), sodium azide (703 mg, 10.8 mmol), and triethylamine hydrochloride (1.49 g, 10.8 mmol) to yield the title product as a white solid (338 mg, 66%): 1H NMR (DMSO-d6) δ 0.90 (t, 3H), 1.53 (sextet, 2H), 2.59 (s, 3H), 2.64 (t, 2H), 5.43 (s, 2H), 6.76 (d, 1H), 7.67 (d, 2H), 7.84 (d, 1H), 7.92 (d, 2H), 8.68 (t, 1H), 9.05 (d, 1H), 9.46 (d, 1H), 12.86 (s, 1H); MS (esi negative) m/z (rel intensity) 456 (100).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH2:24][C@H:25]([NH:30][C:31](=[O:43])[C@@H:32]([NH:35]C(OC(C)(C)C)=O)[CH2:33][OH:34])[C:26]([O:28][CH3:29])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:35][C@@H:32]([CH2:33][OH:34])[C:31]([NH:30][C@@H:25]([CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:17]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:43].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)[C@@H](N)CO

Procedure:
TFA (20 mL) was added to a solution of (S)-methyl 3-(3-(benzyloxy)-4-methoxyphenyl)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)propanoate (4.4 g, 8.7 mmol) in CH2Cl2 (50 mL) at 0° C. with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped three times with EtOAc (20 mL for each portion) to remove residual TFA to afford crude (S)-methyl 2-((S)-2-amino-3-hydroxypropanamido)-3-(3-(benzyloxy)-4-methoxyphenyl)propanoate as its TFA salt.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH2:17]2)=[O:15])[CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:38]1[CH:43]=[CH:42][C:41]([C:44](=[O:49])NCCC)=[CH:40][CH:39]=1)=O)C2>>[C:44]([N:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH2:17]2)=[O:15])[CH2:6]1)(=[O:49])[C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(NCCCCC1CNC1)N1Cc2ccncc2C1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CN(C(=O)c2ccccc2)C1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-(azetidin-3-yl)butyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.46 (d, J=5.0 Hz, 1H), 7.67-7.55 (m, 2H), 7.55-7.34 (m, 4H), 6.37 (t, J=5.5 Hz, 1H), 4.60 (d, J=2.3 Hz, 4H), 4.35 (t, J=8.3 Hz, 1H), 4.11 (t, J=9.1 Hz, 1H), 3.96-3.83 (m, 1H), 3.65 (dd, J=9.7, 5.7 Hz, 1H), 3.07 (dd, J=12.8, 6.7 Hz, 2H), 2.65-2.53 (m, 1H), 1.59 (dd, J=15.2, 7.6 Hz, 2H), 1.43 (dd, J=14.4, 7.2 Hz, 2H), 1.34-1.09 (m, 2H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17](OC)[O:18]C)[NH:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:17][OH:18])[NH:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C[C@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Yield: 63.6 %

Procedure:
To a solution of (3R,4R)-3-(benzyloxycarbonylamino)-4-(2,2-dimethoxyethyl)azetidin-2-one (1.014 g) in tetrahydrofuran (15 ml) were added portionwise a solution of sodium cyanoborohydride (460 mg) in tetrahydrofuran (2.30 ml) and 2N hydrochloric acid (7.5 ml) at ambient temperature during a period of 90 minutes. The solution was adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate and concentrated in vacuo. The concentrate was acidified to pH 4 with 2N hydrochloric acid, saturated with sodium chloride and extracted four times with chloroform. The combined extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g, eluting with 3-10% methanol in dichloromethane) to give a crystalline solid, which was washed with ether and collected by filtration to give 553 mg of (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:13][O:14][C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][S:9](/[CH:8]=[CH:7]/[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:11])=[O:10])[CH:19]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: COC(=O)C=Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Yield: 70.2 %

Procedure:
A solution of (E)-2-phenylethenesulfonyl chloride (24a) (0.59 g, 2.82 mmol) in dioxane (3 ml) was added to a mixture of 3-(3-aminophenyl)-acrylic acid methyl ester (23) (0.50 g, 2.82 mmol) in dioxane (12 ml) and NaHCO3 (0.36 g, 4.28 mmol) in water (8 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (100:2, v/v) as eluent to give the title compound (0.68 g, 70%) as a white solid. 1H NMR (CDCl3, HMDSO), δ: 3.78 (3H, s); 6.39 (1H, d, J=16.0 Hz); 6.77 (1H, d, J=15.8 Hz); 6.78 (1H, s); 7.17-7.48 (9H, m); 7.49 (1H, d, J=15.8 Hz); 7.58 (1H, d, J=16.0 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:7]=12.C([O-])([O-])=O.[K+].[K+].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CCO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:8]2[C:7]3=[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)n2ccc3ccnc(Br)c32)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)n2ccc3ccnc(-c4ccccc4)c32)cc1
Yield: 26.7 %

Procedure:
A solution of 3 (0.1 g, 0.273 mmol) in toluene (8 mL) was treated with tetrakis(triphenylphosphine) palladium (0.016 g, 0.014 mmol). An aqueous solution of K2CO3 (2 M, 1 mL) was then added, followed by a solution of phenylboronic acid (0.037 g, 0.3 mmol) in EtOH (5 mL). The resulting mixture was then refluxed for 24 h. The solvent was removed and the residue was purified by flash chromatography (EtOAc:n-hexane=2:3) to give Compound 6 (26.6 mg, 27%).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([OH:5])=[O:4].[CH3:9][C:10](O)([CH3:12])[CH3:11].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([O:5][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:4]
Reactant: O=C(O)C(Br)CCBr
Reactant: CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Br)CCBr
Temperature: 27.5 °C
Yield: 39 %

Procedure:
2,4-Dibromobutanoic acid (the crude product from above) dissolved in DCM (10 L) in a 50 L-reactor. 2-Methylpropan-2-ol (12000 g, 162.16 mol) and boron anhydride (8000 g, 114.29 mol) were added to the above solution. 1680 g of H2SO4 was added dropwise to the above solution under N2 (gas) while maintaining the temperature at room temperature (25-30° C.). The mixture was allowed to react for 24 h at room temperature. Then 15 L aqueous Na2CO3 (sat.) was added to quench the reaction. The organic phase was separated and dried over Na2SO4. The solvent was removed under vacuum to give the crude product, which was purified by silica gel column chromatography to give tert-butyl 2,4-dibromobutanoate as a brown oil (3800 g, 12.58 mol, 39%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16]>>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:1][C@@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:17])=[O:16]
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C(O)[C@H](CO)NS(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 2, L-serine was reacted with 2-chlorobenzenesulfonyl chloride to give (S)-2-(2-chloro-benzenesulfonylamino)-3-hydroxy-propionic acid as a colorless solid. MS: 278.1 ([M−H]−)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-:20].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:13][CH2:14][CH2:15][C:16]([OH:19])=[O:20])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCOc1ccc(N2CCN(c3ccncc3)CC2)cc1

Procedure:
A solution of the product of Example 50 (0.1 g) in aqueous sodium hydroxide (1N, 0.8 ml) and ethanol (2 ml) was kept for 2 hours. The solution was evaporated and the residue dissolved in water (5 ml). Hydrochloric acid (1N, 0.8 ml) was added and the precipitate was filtered and washed with water and ether to give the title compound as a solid: m.p 305°-306° C.; m/e 342(M+H)+ ; NMR(d6DMSO) δ8.0(2H,d); 6.72(6H,m); 3.74(2H,t); 3.3(4H,m); 2.94(4H,m); 2.19(2H,t); 1.72(2H,m); calculated for C19H23N3O3 : C, 66.8; H, 6.8; N, 12.3. Found: C, 67.0; H, 6.8; N, 12.2%.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH2:23]([SH:26])[CH2:24][SH:25]>C(Cl)Cl>[C:2]1([C:1]2([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[S:26][CH2:23][CH2:24][S:25]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(c3ccccc3)SCCS2)cc1
Reaction time: 8 h

Procedure:
Methyl 4-benzoylbenzoate 18a (0.50 g, 2.08 mmol) and BF3.(OAc)2 (0.73 mL, 5.2 mmol) were dissolved in dry CH2Cl2 under a N2 atmosphere. Ethane-1,2-dithiol (0.333 mL, 3.95 mmol) was added and the solution was stirred overnight. The reaction mixture was partitioned between CH2Cl2 and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to afford compound 18b.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:19]([OH:21])=[O:20])[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:19]([O:21][CH3:26])=[O:20])[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: CO
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)O)cc2[nH]1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)c2nc(C)[nH]c2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carboxylic acid (10.0 g, 35.4 mmol, STEP 4 in Example 1), and thionyl chloride (5.2 mL, 7.1 mmol) in methanol (300 mL) was stirred at 80° C. for 3 hours. The mixture was diluted with ethyl acetate, and washed with saturated ammonium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated in vacuum. The residue was diluted with methanol, filtered to remove the precipitate, and the filtrate was concentrated in vacuum. The resulted solid was washed with dichloromethane to give the title compound as a brown solid (29.8 g, crude), which was used in the next step without further purification. MS (ESI) m/z: 297 (M+H)+, 295 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCc2cc(OCCc3ccccc3)ccc21
Yield: 61.1 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (2.0 g, 12.3 mmol) and (2-bromoethyl)benzene (4.8 g, 25.8 mmol) in ACN (20 mL) was added potassium carbonate (3.4 g, 24.6 mmol) at rt. The solution was heated at reflux overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc/DCM=10:1:2) to give 2.0 g (61%) of the title compound as a brown oil. 1H NMR (300 MHz, CDCl3): δ 2.08-2.16 (2H, m), 2.62 (2H, t, J=6.3 Hz), 2.92 (2H, t, J=6.3 Hz), 3.13 (2H, t, J=7.2 Hz), 2.92 (2H, t, J=7.2 Hz), 6.71 (1H, d, J=2.1 Hz), 6.83 (1H, dd, J=2.4, 8.7 Hz), 7.27-7.38 (5H, m), 8.01 (1H, dd, J=8.7 Hz).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](OCC)=[O:18])[C@@H:12]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:9][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][OH:18])[C@@H:12]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C[C@H]2[C@@H](CO)CCCN2C)cc1

Procedure:
Reduction of 8.2 g. of cis ethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-piperidinecarboxylate with 1.52 g. of lithium aluminum hydride in 97 ml. of tetrahydrofuran yielded cis-1-methyl-2-(p-methoxybenzyl)-3-piperidinemethanol, isolated as its hydrochloride (in a yield of 2.8 g.), a white crystalline solid which melted at 185°-186°C. trans-1-Methyl-2-(p-methoxybenzyl)-3-piperidinemethanol, a white crystalline solid which melted at 66°-68°C., can be obtained in similar fashion.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:15])[CH3:16])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(3-dimethylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (91 mg, 43%). LCMS (m/e) 526 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 8.07 (s, 1H), 7.35-7.25 (m, 3H), 7.15 (s, 1H), 7.10 (d, 1H, J=8.3 Hz), 6.89 (d, 1H, J=8.3 Hz), 6.83 (s, 1H), 6.17-6.10 (m, 1H), 3.28 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.92 (d, 3H, J=4.8 Hz), 2.89-2.83 (m, 2H), 2.79-2.73 (m, 2H), 2.69-2.61 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:11][NH:12][CH2:13][CH:14]([CH:18]3[CH2:22][O:21]C(C)(C)[O:19]3)[CH2:15][S:16][CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.C(Cl)(=O)C>CO>[OH:19][CH:18]([CH2:22][OH:21])[CH:14]([CH2:15][S:16][CH3:17])[CH2:13][NH:12][CH2:11][C:8]1[C:4]2[N:5]=[CH:6][NH:7][C:2](=[O:1])[C:3]=2[NH:10][CH:9]=1
Reactant: CSCC(CNCc1c[nH]c2c(O)ncnc12)C1COC(C)(C)O1
Solvent: CC(=O)Cl
Solvent: CO
Product: CSCC(CNCc1c[nH]c2c(=O)[nH]cnc12)C(O)CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of N-{4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl}methyl-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methylthio)propan-1-amine (0.1 g, 0.28 mmol) in methanol (7 ml) was added a solution of acetyl chloride (0.22 g, 2.8 mmol) in methanol (3 ml) and the solution stirred at ambient temperature for 2.5 hr. Amberlyst A-21 resin was added and the solution made neutral before being filtered free of resin and concentrated to a light yellow gum (0.072 g). This was dissolved in aqueous methanol (1:1) and preabsorbed onto silica for chromatography over silica. Gradient elution with DCM/MeOH/0.88 NH3 cocktails ranging from 9:1:0.1 through to 6:4:0.1 in composition furnished the title compound as a precipitate (free base) in the latter fractions. This was recovered by filtration and dried to give a colourless solid (0.026 g). 1H NMR (CD3OD+DCl) δ 7.93 (s, 1H), 7.42 (s, 1H), 3.94 (s, 2H), 3.82 (q, J=4.8 Hz 1H), 3.58 (m, 2H), 2.89 (m, 2H), 2.66 (dd J=13.2, 6.6 Hz, 1H), 2.55 (dd J=13.2, 7.5 Hz, 1H), 2.13 (s, 3H), 1.94 (m, 1H). 13C NMR (CD3OD+DCl) δ 156.6, 145.2, 143.4, 129.1, 119.7, 115.8, 75.0, 65.9, 50.0, 45.9, 41.5, 36.6, 16.3. HR-ESMS MH+ 313.1332 C13H21N4O3S requires MH+ 313.1334 Δ 0.6 ppm.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[C:28](=[NH:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28](=[N:41][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
1q (2.2 g, 5.3 mmol), benzophenone imine (1.1 g, 5.8 mmol), and sodium tert-butoxide (620 mg, 6.5 mmol) were dissolved in toluene (50 mL). Pd2dba3 (98 mg, 0.11 mmol) and BINAP (270 mg, 0.43 mmol) were added, and the reaction was heated to 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated to give the desired product, 1r.
Reaction SMILES: [CH:1]([F:10])([F:9])[C:2]([F:8])([F:7])[C:3](Cl)(Cl)F.FC(F)(C(F)F)CO.[Cl-].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[F:7][C:2]([F:8])([CH:1]([F:10])[F:9])[CH2:3][O:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:27])=[O:28]
Reactant: FC(F)C(F)(F)C(F)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: OCC(F)(F)C(F)F
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1

Procedure:
Until HCFC-225cc becomes available in commercial quantities, HCFC-225cc may be prepared by a standard and well-known organic synthesis technique. For example, 1,1-dichloro-1,2,2,3,3-pentafluoropropane may be prepared by reacting 2,2,3,3-tetrafluoro-1-propanol and p-toluenesulfonate chloride to form 2,2,3,3-tetrafluoropropyl-p-toluenesulfonate. Next, the 2,2,3,3-tetrafluoropropyl-p-toluenesulfonate is reacted with potassium fluoride in N-methylpyrrolidone to form 1,1,2,2,3-pentafluoropropane. Then, the 1,1,2,2,3-pentafluoropropane is reacted with chlorine to form 1,1-dichloro-1,2,2,3,3-pentafluoropropane.
Reaction SMILES: OO.Cl.[Cl-].[Mg+2].[Cl-].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1.[Cl:18][C:19]1[C:24]([OH:25])=[C:23]([Cl:26])[C:22]([Cl:27])=[C:21]([OH:28])[C:20]=1[Cl:29]>>[C:19]1([Cl:18])[C:24](=[O:25])[C:23]([Cl:26])=[C:22]([Cl:27])[C:21](=[O:28])[C:20]=1[Cl:29]
Reactant: Oc1c(Cl)c(Cl)c(O)c(Cl)c1Cl
Agent: Cl
Agent: O=C1C=C(Cl)C(=O)C(Cl)=C1Cl
Agent: OO
Product: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Yield: 95 %

Procedure:
Re 1: A very large excess of hydrochloric acid (96 times the molar quantity) is required, and a very high salt load results due to the addition of 7.4 times the molar quantity of magnesium chloride. Furthermore, the prescribed temperature/time control during the addition of hydrogen peroxide cannot be maintained because of the high heat of reaction. A repeat of this process using only 30 times the molar quantity of hydrochloric acid, 3 times the molar quantity of magnesium chloride and more suitable temperature control gave a qualitatively poor chloranil (melting point 215°-220° C., yield 95% of theory) with trichloro-1,4-benzoquinone and tetrachlorohydroquinone as impurities.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc(Br)c([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
1.0 g (4.3 mmol) 4-bromo-3-nitroanisole is nitrated by dropwise addition of 1.0 ml of a mixture of 0.4 ml nitric acid (100%) and 0.6 ml concentrated sulfuric acid. Stirring is continued for 1 h. After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine (2×), dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 630 mg of the title compound as yellow crystals.