Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)[CH:17]=[CH:16][C:15]=1[OH:29]>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)[CH:17]=[CH:16][C:15]=1[O:29][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: BrCc1cc2ccccc2o1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCc1cc2ccccc2o1
Yield: 29 %

Procedure:
Alkylation of 2-bromomethyl-benzofuran with 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to Example 136, Step 3, to give 2-[2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran in 29% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.3 (s, 12 H) 3.9 (s, 3 H) 5.3 (s, 2 H) 6.8 (d, J=0.8 Hz, 1 H) 7.0 (d, J=8.1 Hz, 1 H) 7.2 (m, 1 H) 7.3 (m, 2 H) 7.4 (dd, J=8.0, 1.4 Hz, 1 H) 7.5 (dd, J=8.1, 0.8 Hz, 1 H) 7.5 (dd, J=8.0, 1.1 Hz, 1 H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1([CH2:16]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:13]1([CH2:16][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1CC1
Temperature: 6 °C
Reaction time: 15 h
Yield: 172.6 %

Procedure:
To a stirring solution/suspension comprised of N-hydroxyphthalimide (Aldrich, 57.15 g, 339.8 mmol), cyclopropanemethanol (Aldrich, 25.10 g, 341.1 mmol), and triphenylphosphine (“DEAD,” Aldrich, 91.0 g, 344 mmol) in 1.00 L of tetrahydrofuran under a nitrogen atmosphere and cooled to 6° C. (internal mixture temperature) with an ice-water bath was added diethyl azodicarboxylate (Aldrich, 56 ml, 356 mmol) dropwise over 20 minutes via addition funnel. The reaction mixture temperature was kept below 20° C. during the addition. Following addition of the DEAD, the cold bath was removed and the reaction mixture was stirred for 15 hours. The mixture was concentrated to a paste under reduced pressure. Chloroform (ca. 300 ml) was added and the mixture swirled to loosen all solids. Vacuum filtration removed the insolubles. The filtrate was likewise filtered to remove white precipitate that formed and to give a clear filtrate. Concentration under reduced pressure afforded a clear oil. Flash filtration through silica gel (100% chloroform) gave filtrates containing unseparated product. These filtrates were combined and concentrated under reduced pressure to afford 127.4 g of a clear oil. The oil was dissolved in absolute ethanol (400 ml) and the solution was refrigerated for two hours. A white crystalline solid had precipitated and was subsequently collected by vacuum filtration. The product was dried in the vacuum oven (60° C.) to afford 42.66 g (58%) of the desired material; m.p. 71-77° C.; 1H-NMR (400 MHz; CDCl3 signal offset to δ6.96) δ7.54-7.43 (m, 4H), 3.74 (d, 2H, J=7.6 Hz), 1.02-0.95 (m, 1H), 0.34-0.30 (m, 1H) 0.04-0.00 (m, 1H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:16]([O-])([OH:18])=[O:17].O>C(OC(=O)C)(=O)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(CC(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(CC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a suspension of N-(4-neopentylphenyl)acetamide (Preparation 98, 2.54 g, 12.4 mmol) in acetic anhydride (20 mL) cooled in an ice bath was added a solution of nitric acid (0.78 mL, 18 mmol) in acetic anhydride (5 mL) dropwise. The solution was allowed to warm to room temperature for 18 hours. The yellow solution was added to water and extracted with dichloromethane (3×). The organic layers were dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-50% ethyl acetate/hexanes gradient to provide the title compound (3.0 g, 97%) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([NH:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCCSc1cccc[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCSc2cccc[n+]2[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
To a solution of 4.12 g of 2-β-aminoethylthio pyridine N-oxide hydrochloride in 60 cc of water, there are added 4 cc of 5N soda, then 3.8 g of p-toluenesulfonyl chloride. The mixture is agitated for 5 hours at ambient temperature. The pH is maintained at 9.5 by the addition of normal soda. The precipitate is filtered and crystallized in aqueous ethanol. Yield = 88%. Fusion point: 201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:25][CH:26]=O)[CH2:10][N:11]([CH3:24])[C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:31])=[O:30]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:25][CH2:26][N:41]2[CH2:40][CH2:39][CH:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[S:29]([CH3:28])(=[O:31])=[O:30])[CH2:43][CH2:42]2)[CH2:10][N:11]([CH3:24])[C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccccc1C1CCNCC1
Reactant: CN(CC(CC=O)c1ccc(F)c(F)c1)C(=O)c1cccc2c1CCCC2
Solvent: O
Product: CN(CC(CCN1CCC(c2ccccc2S(C)(=O)=O)CC1)c1ccc(F)c(F)c1)C(=O)c1cccc2c1CCCC2

Procedure:
Using standard reductive amination conditions N-[2-(3,4-difluorophenyl)-4-oxobutyl]-N-methyl-5,6,7,8-tetrahydro-1-naphthamide was reacted with 4-[2-methylsulfonylphenyl]piperidine and converted to the citrate salt. MS: m/z 595 (M+H). Analysis for C34H40F2N2O3S.C6H8O7.1.4 H2O: calculated: C, 59.16; H, 6.31; N, 3.45; found: C, 59.04; H, 6.10; N, 4.08.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:19]2[CH2:23][CH2:22][C@H:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[O:20]2)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH2:15]Br)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:36][N:37]([CH3:45])[C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:19]2[CH2:23][CH2:22][C@H:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[O:20]2)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH2:15][S:44][C:41]1[CH:42]=[CH:43][C:38]([N:37]([CH3:45])[CH3:36])=[CH:39][CH:40]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CN(C)c1ccc(S)cc1
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCSc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trans-2-[3-n-propylsulfonyl-4-(2-bromoethoxy)-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (100 mg) (Step 30G) was added to a stirred solution of 4-dimethylaminothiophenol (76 mg, 0.5 mmol) and sodium hydride (56%; 20 mg, 0.5 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 20 min and partitioned between ethyl ether and water. The organic layer was separated, dried, and evaporated to a crystalline mass. Recrystallized from ethyl ether-hexane gave pure product: mp 113°-115° C.; NMR (CDCl3) δ 1.0 (t, CH2CH2CH3), 1.70 (m, CH2CH2CH3), 2.0 & 2.49 (2 m, H-3 & H-4), 3.0 [m, (CH3)2N], 3.4 (m, CH2CH2CH3), 3.84 3.88 & 3.9 (3 s, 3 OCH3), 4.30 (t, SCH2CH2O), 5.22 (m, H-2 & H-5), 6.62 (s, C5ArH), 7.23 & 7.47 (2 d, J=1.5 Hz, C2ArH), 7.42 (m, ArH).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:42]1([O:51]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN1CCCC1=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:42][OH:51])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(propylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 9) (66 mg, 0.18 mmol) and N,N-diisopropylethylamine (31 μl, 0.18 mmol) in N-methyl-2-pyrrolidinone (3 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (102 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. N,N-diisopropylethylamine (93 μl, 0.54 mmol) was then added, followed by hydroxylamine hydrochloride (37.5 mg, 0.54 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and pH 7 aqueous buffer. The combined organic layers were washed sequentially with aqueous citric acid solution (5% w/v) and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (90:10) gradually changing to dichloromethane:ethyl acetate (0:100) then to dichloromethane:methanol (95:5) to afford the title compound as an oil (31 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]4[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=4)[C:28]([O:30]CC=C)=[O:29])=[CH:18][CH:19]=3)[O:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].N1CCOCC1>O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]4[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=4)[C:28]([OH:30])=[O:29])=[CH:18][CH:19]=3)[O:14][CH:13]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)c1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(OCc4cccc(C(=O)O)c4)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of prop-2-enyl 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate (88.8 mg, 0.176 mmol), tetrakis(triphenyl-phosphine)palladium(0) (10 mg, 0.009 mmol) in dry tetrahydrofuran 2 ml) was added morpholine (77 mg, 0.88 mmol), and the mixture was stirred at room temperature under argon for 2 hours. Solvent was then removed reduced pressure, and the residue dissolved in acetone, mixed with silica gel, the solvent removed under reduced pressure, and the silica gel eluted with methylene chloride/methanol (95/5) containing 1% acetic acid, to provide 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ: 13.1 (br s, 1H), 9.84 (s, 1H), 8.47 (s, 1H), 8.08-8.06 (m, 2H), 7.94 (d, 1H, J=7.8 Hz), 7.76 (d, 1H, J=7.7 Hz), 7.58-7.45 (m, 3H), 7.30 (d, 1H, J=1.8 Hz), 7.27 (d, 2H, J=8.5 Hz), 7.20 (dd, 1H, J=1.8 Hz, J=8.9 Hz), 5.38 (s, 2H), 3.03 (s, 3H). (ESI) m/z 466 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]([CH3:15])[CH3:14].[C:16]1([CH:22](Br)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(O)c(CC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(c2ccccc2)c2ccccc2)c(CC(C)C)c1
Temperature: 0 °C
Yield: 31.3 %

Procedure:
A solution of methyl 4-hydroxy-3-isobutylbenzoate (0.80 g, 3.84 mmol), diphenylmethyl bromide (1.05 g, 4.25 mmol) and potassium carbonate (0.69 g, 4.99 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 3 days. The reaction solution was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous citric acid solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=3/97-15/85) to give the title compound (450 mg, yield 31%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:43][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([CH3:38])[CH:40]=2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: Cc1cccc(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2cccc(C)c2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 3-methylbenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.28-1.35 (m, 3H) 2.23-2.31 (m, 3H) 4.40-4.54 (m, 4H) 7.03-7.12 (m, 3H) 7.17-7.24 (m, 1H) 9.02-9.12 (m, 1H). MS (ESI) positive ion 311 (M+H)+; negative ion 309 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35](F)[CH:36]=3)[C:31](=[O:40])[N:30]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]2=[O:49])[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:36]=3)[C:31](=[O:40])[N:30]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:29]2=[O:49])[CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2cccc(F)c2)C1
Yield: 85.2 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.266 g, 1.43 mmol), triethylamine (0.2 mL, 1.43 mmol), and 1-(3-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example G-1, 0.19 g, 0.48 mmol) provided 0.231 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[CH2:6][OH:7].S(=O)(=O)(O)O>C(Cl)Cl>[C:2]([O:7][CH2:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])([CH3:3])([CH3:1])[CH3:4]
Reactant: CCCCOC(=O)CO
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCOC(=O)COC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 500-ml, thick-walled Erlenynmeyer flask equipped with a magnetic stirring bar was cooled to -78° C. (dry iece-acetone bath) and charged with isobutylene (150 ml). Then, n-butyl glycolate (20.0 g, 0.151 mol) and 50 ml of methylene chloride was added along with 1 ml of concentrated sulfuric acid. The cold bath was removed and the mixture stirred for 3 days at room temperature. The reaction was quenched with 50 ml of saturated sodium bicarbonate and the product extracted with ether. The ether layer was dried over sodium sulfate and concentrated. After distillation, the title compound was obtained as a colorless oil: bp 64°-65° C. (0.7 mm).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16]C)=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.[NH2:18][NH2:19].CO>O>[NH2:1][C:2]1[C:3]([C:14]([NH:18][NH2:19])=[O:16])=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: NN
Reactant: COC(=O)c1nc(-c2cccnc2)cnc1N
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(-c2cccnc2)cnc1N
Yield: 58.5 %

Procedure:
Methyl 3-amino-6-(3-pyridyl)pyrazine-2-carboxylate (2 g, 8.687 mmol) was heated in hydrazine (1.392 g, 1.363 mL, 43.43 mmol) with a minimal amount of MeOH (5 mL) added at 80° C. for 2 hours. The reaction was treated with water and the product collected by filtration, washed with methanol and dried to give the desired product as a brown solid (1.17 g, 58% Yield). 1H NMR (400.0 MHz, DMSO) d 7.43 (1H, m), 7.47 (2H, br s), 8.54 (2H, m), 8.90 (1H, s), 9.38 (1H, m), 10.16 (1H, br s); MS (ES+) 231.96
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:20][C:19]2[CH:21]=[C:22]([Cl:27])[C:23]([CH2:25]Cl)=[CH:24][C:18]=2[O:17]1.CCN(CC)CC>O1CCCC1>[Cl:27][C:22]1[C:23]([CH2:25][N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][CH2:14]2)=[CH:24][C:18]2[O:17][CH2:16][O:20][C:19]=2[CH:21]=1
Reactant: c1ccc(OCCN2CCNCC2)cc1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1cc2c(cc1CN1CCN(CCOc3ccccc3)CC1)OCO2
Temperature: 60 °C

Procedure:
1-[2-(phenoxy)-ethyl]piperazine (200 mg, 0.974 mmol), 6-chloropiperonyl chloride (200 mg, 0.974 mmol), and Et3N (415 μL, 3 mmol) were combined in tetrahydrofuran (THF 20 mL). The reaction mixture was heated at 60° C. for 12 h. The reaction mixture was cooled and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated. The crude residue was chromatographed on silica (20% EtOAc/Hexanes) and the product fractions were collected and evaporated to an amber solid (186 mg, 51%). 1H NMR (CDCl3) δ: 2.5-2.7 (m, 8H), 2.8 (t, 2H), 3.5 (s, 2H), 4.1 (t, 2H), 5.9 (s, 2H), 6.81 (s, 1H), 6.9-6.94 (m, 3H), 6.96-6.98 (m, 1H), 7.26-7.3 (m, 1H). MS ELS+ 376. CHN: calc., 64.08, 6.18, 7.47; found, 63.87, 6.12, 7.44. mp: 72-76° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[NH2:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CCO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:12])[F:13])=[C:5]([NH:11][C:14](=[O:16])[CH3:15])[CH:6]=1
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cc(Br)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of 2-trifluoromethoxy-5-bromo-phenylamine (5.12 g, 20 mmol) in EtOH (50 mL) at 0° C. was added a solution of acetic anhydride (4.7 mL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide.
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:10]1[CH:9]=[CH:8][C:7]2[S:1](=[O:12])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=S1(=O)CCCCc2ccccc21
Reactant: CNC
Product: CN(C)c1ccc2c(c1)CCCCS2(=O)=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 13.00 g (28.98 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor was added about 20 mL of neat dimethylamine. The mixture was sealed and stirred at 110° C. overnight, and cooled to ambient temperature. The excess dimethylamine was evaporated. The crude oil was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water, dried over MgSO4 and concentrated in vacuo. Purification on a silica gel column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g (90.5%) of the enantiomerically-enriched 7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a colorless solid: 1H NMR (CDCl3) δ 0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (d, J=15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d, J=7.5 Hz, 1H), 5.49 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). The product was determined to have 78% e.e. by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. Recrystallization of this solid from ethyl acetate/hexane gave 1.70 g of the racemic product. The remaining solution was concentrated and recrystallized to give 9.8 g of colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. It showed to have 96% e.e with the first eluting peak as the major product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[OH:1][CH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: OCCc1c(O)ccc(Cl)c1Cl
Reactant: O=C(O)CCCCCBr
Product: O=C(O)CCCCCOc1ccc(Cl)c(Cl)c1CCO

Procedure:
Following the procedure of Example 1C, two millimoles each of 2-(2-hydroxyethyl)-3,4-dichlorophenol and 6-bromohexanoic acid were reacted to provide 55 mg. of the desired title product which crystallized from methylene chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=3)[C:17]#[N:18])[CH:10]=[C:11]([O:12]C)[C:6]=2[NH:5][C:4](=[O:23])[O:3]1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[CH3:1][C:2]1([CH3:24])[C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=3)[C:17]#[N:18])[CH:10]=[C:11]([OH:12])[C:6]=2[NH:5][C:4](=[O:23])[O:3]1
Reactant: COc1cc(-c2cc(F)cc(C#N)c2)cc2c1NC(=O)OC2(C)C
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CC1(C)OC(=O)Nc2c(O)cc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
A mixture of 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.1 g, 0.31 mmol), Lithium iodide (0.3 g, 2.24 mmol) in 2,4,6-collidine was heated at reflux under nitrogen for 5 hours. The solvent was removed in vacuo and the residue was taken in a mixture of brine (10 mL) and ethyl acetate (30 mL). The organic layer was separated, dried (MgSO4), and evaporated. The resultant residue was purified on a silica gel column chromatography (hexane:ethyl acetate/1:1) to give the title compound as white plates (0.03 mg, 31%): mp 197-198° C.; 1H-NMR (DMSO-d6) δ10.16 (s, 1H), 9.55 (s, 1H), 8.01 (s, 1H), 7.79-7.87 (m, 2H), 7.20 (s, 1H), 7.08 (d, 1H, J=1.0 Hz), 1.65 (s, 6H). MS (ESI) m/z 311 [M−H]−.