Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19].O>CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CN(C)CCCCl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCCC(C#N)c1ccc(Cl)c(Cl)c1
Yield: 63 %

Procedure:
3.9 g of sodium amide are added in small portions to a solution of 18.6 g of 3,4-dichlorophenylacetonitrile in 200 ml of anhydrous ether. The mixture is refluxed for 2 hours, 12.1 g of 3-chlorodimethylaminopropane are added and refluxing is continued for 2 and a half hours. The mixture is cooled, water is added and the organic phase is decanted. It is washed with water and extracted with 10% hydrochloric acid. The aqueous phase is then neutralized with 30% sodium hydroxide and extracted with ether and the solvent is evaporated off to give 17 g of the expected product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](ON3C(=O)CCC3=O)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>O.O1CCCC1>[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]3)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
Piperidine-4-carboxylic acid (15.00 g, 116 mmol) was added to a solution of sodium hydrogen carbonate (12.7 g, 151 mmol) in water (200 mL) and the mixture was stirred for 10 min. A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 46.9 g, 139 mmol) in tetrahydrofuran (400 mL) was added. The solution was stirred at room temperature for 20 h and then acidified to pH 1 with 3 M HCl (500 mL). The mixture was extracted with ethyl acetate (200 mL then 100 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered and concentrated to approximately 100 mL. Crystallization occurred on concentration. The mixture was allowed to stand for 2 h, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 60° C. to give N-[(9H-fluoren-9-ylmethoxy)carbonyl]piperidine-4-carboxylic acid (34.51 g, 85%) as a white solid, mp 187-189° C.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:14]=2[CH:13]=1)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3].[CH:23]1([O:28][C:29](=[O:48])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[CH:23]1([O:28][C:29](=[O:48])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][NH:47][CH2:21][C:18]3[CH:19]=[CH:20][C:14]4[CH:13]=[C:12]([C:10](=[O:11])[NH:9][O:8][CH:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH3:7])[S:16][C:15]=4[CH:17]=3)=[CH:44][CH:45]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Reaction time: 3 h
Yield: 17.9 %

Procedure:
6-formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy) amide (Scheme 7) (220 mg, 0.68 mmol) and (S)-2-(4-Aminomethyl-benzylamino)-3-phenyl-propionic acid cyclopentyl ester (263 mg, 0.75 mmol) were dissolved in DCE (10 mL) under an atmosphere of N2. Sodium triacetoxyborohydride (430 mg, 2.04 mmol) and acetic acid (50 μL) were added and the reaction stirred at r.t for 3 h. Sodium hydrogen carbonate (20 mL) was added and the reaction mixture extracted with dichloromethane (3×50 mL). The organic layers were combined and concentrated. The residue was purified by column chromatography (50%-100% EtOAc/heptane) to give the protected compound (80 mg, 21%). m/z 658 [M++H]+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CC(C)=O>[Cl:24][C:23]([Cl:25])([Cl:26])[CH2:22][O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: O=C(CCCBr)OCC(Cl)(Cl)Cl
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCN1CCC(CO)CC1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A stirred solution of 4-piperidinemethanol (1.72 g, 15.0 mmol) in acetone (100 ml) was added K2CO3 (4.14 g, 30. mmol) and 2,2,2-trichloroethyl 4-bromobutyrate (4.47 g, 15.0 mmol) and heated under reflux for 3 h. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The residue was added CH2Cl2 (75 ml) and washed with brine (25 ml) and H2O (2×25 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to leave the title compound as a viscous oil (4.70 g, 94.1%).
Reaction SMILES: COC1C=CC([NH:9][C:10]2[CH:11]=[C:12]([N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:26]=3)[CH2:17][CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:14][CH:15]=2)=CC=1.CI.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54]NC2C=C(CC(NCC3C=CC=C(OC(F)(F)C(F)F)C=3)(O)C(F)(F)F)C=CC=2)=[CH:50][CH:49]=1>O1CCCC1>[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][NH:9][C:10]2[CH:11]=[C:12]([N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:34])[F:35])[CH:26]=3)[CH2:17][CH:18]([OH:23])[C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=2)=[CH:50][CH:49]=1
Reactant: COc1ccc(CNc2cccc(CC(O)(NCc3cccc(OC(F)(F)C(F)F)c3)C(F)(F)F)c2)cc1
Reactant: COc1ccc(Nc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CNc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[[3-[(4methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (44.3 mg, 0.083 mmol) in tetrahydrofuran (1.0 mL), methyl iodide (6.21 μL, 0.099 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were added. The dark solution was stirred at 23° C. for 2 h, then heated to 55° C. for 12 h. The reaction mixture was filtered through celite, and the residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 25.2 mg (55%) of the desired 3-[[3-[(4methoxyphenyl)methylamino]-phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methylamino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C26H25F7N2O3: 546.1753, found: 546.1750 [M]+. 1H NMR (CDCl3), δ 3.54 (m, 1H), 3.38 (s, 3H), 3.65-3.80 (m, 4H), 4.59 (s, 2H), 5.90 (tt, 1H), 6.20 (d, 1H), 6.37 (d, 1H), 6.68 (s, 1H), 6.76 (d, 2H), 6.90-7.15 (m, 6H), 7.31 (t, 1H). 19F NMR (CDCl3), δ −137.21 (d, 2F), −88.52 (s, 2F), −78.79 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[NH2:18].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:12]([N:8]1[C:9]2[C:4](=[C:3]([O:16][C:23]3[CH:24]=[CH:25][C:20]([C:17]([NH2:18])=[O:19])=[CH:21][CH:22]=3)[C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.6 %

Procedure:
A 100-mL, round-bottom flask equipped with a balloon filled with air was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.300 g, 1.06 mmol), 4-carbamoylphenylboronic acid (0.437 g, 2.65 mmol), pyridine (1 mL), dichloromethane (40 mL), copper (II) acetate (0.580 g, 3.20 mmol) and 4 Å molecular sieves (4.0 g). The resulting mixture stirred for 3 days at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 3:1, ethyl acetate/petroleum ether) to afford (S)-4-(1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide (0.148 g, 35%) as yellow oil. MS (ESI, pos. ion) m/z 403, 405 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1>CC#N>[F:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:2][CH3:1])=[CH:6][CH:5]=1
Reactant: CN
Reactant: Fc1ccc(CBr)cn1
Solvent: CC#N
Product: CNCc1ccc(F)nc1
Reaction time: 8 h
Yield: 61 %

Procedure:
To a mixture of 2.5 g of 40% aqueous methylamine solution and 30 ml of CH3CN was added dropwise 3.0 g of crude (6-fluoro-3-pyridyl)methyl bromide with constant stirring. The mixture was allowed to stand at room temperature overnight and concentrated under reduced pressure. The residue was extracted with AcOEt and the extract was dried over MgSO4 and concentrated. The procedure gave 1.35 g of the title compound as a crude orange-colored oil.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-n4ccnc4)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
4-(1H-Imidazol-1-yl)aniline (0.159 g, 1.003 mmol), triethylamine (0.101 g, 1.003 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.170 g, 1.003 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (2:1) to obtain the titled compound (0.140 g, 0.272 mmol, 41%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=3)=[CH:18][C:17]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(S(N)(=O)=O)s3)cc21

Procedure:
Prepared according to procedure B from 5-bromothiophene-2-sulphonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 258-260° C.; 1H-NMR (DMSO-d6) δ 10.41 (s, 1H), 7.71 (s, 2H), 7.58 (m, 2H), 7.52 (d, 1H, J=3.9 Hz), 7.48 (d, 1H, J=8.16 Hz), 6.95 (d, 1H, J=8.16 Hz), 1.66 (s, 6H); MS m/z 337 (M−H). Anal. Calc. for C14H14N2O4S2: C, 49.69; H, 4.17; N, 8.28. Found: C, 49.90; H, 4.28; N, 8.12.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 6,6-dimethyl-5,7-dioxaspiro[2,5]-octane-4,8-dione (1.02 g, 6.0 mmol, Aldrich) in 3 mL of DMF was added 4-fluorobenzenamine (666 mg, 6.0 mmol, Aldrich). The reaction mixture was stirred at rt overnight. The reaction mixture was poured into cold water (10 mL). The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford the desired product (980 mg, 73%) as a tan solid. MS(ESI+) m/z 224.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:37])[N:24]=[C:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[N:20]([CH3:35])[C:19]1=[O:36])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:37])[N:24]=[C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[N:20]([CH3:35])[C:19]2=[O:36])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(C2CCCCC2)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(C2CCCCC2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one (Example 8-G), the title compound was prepared as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cc1cc(O)ccc1NS(C)(=O)=O
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a mixture of 24.00 g (0.089 mol) of N-(2-methyl-4-hydroxyphenyl)methanesulfonamide, 9.00 g (0.089 mol) of triethylamine, and 150 ml of methylene chloride cooled to approximately 0° C. was added a solution of 9.32 g (0.089 mol) of methacryloyl chloride in 150 ml of methylene chloride and 50 ml of methylene chloride wash over approximately 20 minutes. The reaction mixture was then stirred for another 4 hours at reduced temperature, after which it was washed with 2 percent hydrochloric acid and twice with water. The organic phase was dried over magnesium sulfate, treated with decolorizing carbon, filtered and concentrated to an oil, which crystallized on cooling. The solid was recrystallized from 1:1 dichloroethane:hexane to give 14.7 g (61.3 percent of theory) of N-(2-methyl-4-methacryloyloxyphenyl)methanesulfonamide, m.p.=95° to 97° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7](O)(=[O:35])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Sn]>>[C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])(=[O:35])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: OCCCCO
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCCCO
Temperature: 100 °C

Procedure:
57.2 g 1,4-butanediol (0.636 mole), 254.2 g montanic acid and 0.4 g tin powder were heated to 210° C. as in Example 1 with application of a gentle vacuum. The vacuum was increased to 152 mbar over a period of 3 hours. The mixture had an acid value of 1.5. A brownish-yellow wax having a dropping point of 77° C. was obtained after cooling to 100° C., bleaching and filtering.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@@H:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:5][C@@H:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC[C@H](N)c3ccccc32)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −78° C., acetyl chloride (1 ml, 12 mmol) was added to a solution of the amine (B3) (3.2 g, 10 mmol) in dry acetonitrile (100 ml) followed by the dropwise addition of triethylamine. The reaction mixture was warmed to room temperature, stirred for 1 hour then concentrated. The residue was dissolved in ethyl acetate. The solution washed with saturated NaHCO3 and brine, dried and concentrated. The crude product was further purified by silica gel chromatography (CH2Cl2/CH3CN 9:1 to 7:3) to give (S)-tert-butyl 4-acetamido -3, 4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B4). LC-MS: m/e=359.3 (M+H), 303.3 (M+H−Me3CO). Rt=2.94 min. 1H-NMR (500 MHz, DMSO-d6): 8.17 (d, 1H), 7.36 (d, 1H), 7.22 (ddd, 1H), 7.14 (m, 2H), 4.95 (m, 1H), 3.86 (m, 2H), 2.97 (m, 2H), 2.01 (m, 1H), 1.85 (s, 3H), 1.80 (m, 4H), 1.61 (m 2H), 1.48 (d, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([N+:12]([O-])=O)[C:5]=1[NH2:15].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([NH2:12])[C:5]=1[NH2:15]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)cc(N)c1N

Procedure:
A slurry of 2-amino-5-methoxy-3-nitro-benzoic acid methyl ester (1 g, 4.4 mmol) and 10% Pd/C (0.2 g, 20%) in methanol was hydrogenated with a hydrogen balloon for 6 h. After the reaction was completed, the mixture was filtered through a celite bed and the filtrates were evaporated to dryness. The obtained residue was purified over silica gel column using (30% ethyl acetate/hexane) as eluent to obtain the title compound as off white solid.
Reaction SMILES: C(S([CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31](=[O:33])[CH3:32])[S:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:34])[CH2:6]1)=O)C.C(Cl)(=O)C([Cl:38])=O>C(Cl)Cl>[Cl:38][CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31](=[O:33])[CH3:32])[S:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:34])[CH2:6]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1S(=O)CC
Solvent: ClCCl
Product: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl

Procedure:
A solution of 1.2 g p-nitrobenzyl 2-(4-ethylsulfinyl-2-oxo-1-azetidinyl)-3-acetylthio-3-(2-ethoxyethylthio)-acrylate in 50 ml methylene chloride was cooled to -50° C. under a nitrogen atmosphere. Oxalyl chloride (0.196 ml) was added dropwise at -50° C., then the reaction mixture was allowed to warm to -15°. After 1 hour at -15° C. the methylene chloride solution was washed with 20 ml saturated aqueous sodium bicarbonate solution and 20 ml water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (1.2 g). The crude title compound was used without further purification. The NMR spectrum of a deuterochloroform solution showed peaks at 1.23(m,3H); 2.3-3.72(c,11H); 5.23(m,2H); 5.7-6.32(c,1H); 7.52(m,2H); and 8.2(m,2H) ppm. The infrared spectrum of a chloroform solution had absorption bands at 5.6 and 5.78 microns.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([NH:16]C(OC(C)(C)C)=O)[CH2:10]2)=[O:6])[CH2:2][CH3:3].[ClH:24].O1CCOCC1>C(O)(=O)C>[ClH:24].[CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([NH2:16])[CH2:10]2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCNC(=O)c1ccc2c(c1)CC(N)C2

Procedure:
Using N-propyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (22 mg, 0.070 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6.0 ml), a similar procedure to Example 24 was carried out to obtain N-propyl-2-amino-5-indan carboxamide hydrochloride. Then using ethanol (1 ml), triethylamine (0.50 ml, 3.6 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (18 mg, 1.0 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1 to 1:2) to obtain the title compound (12 mg, 0.033 mmol) having the following physical properties:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([OH:11])=[CH:9][C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1.Cl[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN(C)C=O.C(OCC)C>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH2:16][O:11][C:10]1[C:5]([O:4][CH3:3])=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[CH:9]=1
Reactant: ClCc1nc2ccccc2o1
Reactant: CCc1cc(O)c(OC)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1cc(OCc2nc3ccccc3o2)c(OC)nc1C
Temperature: 60 °C
Yield: 33.5 %

Procedure:
A quantity of 60% sodium hydride in mineral oil (24 mg, 0.6 mmol) was added to a solution of 2-methoxy-3-hydroxy-5-ethyl-6-methylpyridine (77 mg, 0.46 mmol) in dry dimethylformamide (2 mL). After gas evolution ceased, 2-(chloromethyl) benzoxazole (100 mg, 0.6 mmol) was added and the reaction mixture warmed at 60° C. for one hour. The reaction was then cooled, diluted with diethyl ether, the ether extract washed with water, dried (Na2SO4), filtered and evaporated to give 151 mg of crude mixture. This mixture was flash chromatographed on silica gel, eluting with 0.5% methanol/chloroform. Combined appropriate fractions gave 46 mg (32%) of oily product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(N[S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:11]=[C:10]([O:12][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])=[O:21]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OS(=O)(=O)C(F)(F)F
Yield: 88.8 %

Procedure:
A solution of methyl 2,4-dihydroxybenzoate 46 (0.5 g, 2.97 mmol), N-phenyltrifluoro-methanesulfonamide (2.125 g, 5.95 mmol) and DIPEA (1.039 mL, 5.95 mmol) in DCM (15 mL) was stirred at room temperature for 2 days then washed with saturated NaHCO3, brine, dried over MgSO4, filtered and solvent evaporated to provide methyl 2,4-bis(trifluoromethylsulfonyloxy)benzoate 47 (1.14 g, 89% yield) after purification by Biotage (0 to 10% EtOAc in Hexane). LRMS (ESI): (calc.) 431.94 (found) 455.0 (MNa)+