Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1F)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Cyclopropylmethyl alcohol (0.921 ml, 11.4 mmol) was added to a stirring suspension of NaH (455 mg, 11.4 mmol) in DMF (20 ml) under an argon atmosphere. The resulting solution was allowed to stir at RT for 20 min. 6-chloro-7-fluoro-8-nitro-9H-β-carboline (500 mg, 1.9 mmol) was added to the stirring solution and the resulting mixture was allowed to stir at RT. Upon addition of H2O, a brown solid precipitated out which was filtered to give the desired 6-chloro-7-cyclopropylmethyoxy-8-nitro-9H-β-carboline (510 mg, 85%). 1H-NMR (300 MHz, DMSO-d6): δ 0.35 (m, 2H), 0.59 (m, 2H), 1.32 (m, 1H), 4.04 (d, 2H), 8.21 (d, 1H), 8.46 (d, 1H), 8.90 (s, 1H), 9.02 (s, 1H), 12.32 (b, 1H). Retention Time (LC, method: ammonium acetate standard): 2.63 min. MS (M+H+): 318.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C=O>[N:12]1([C:2]2[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Nc1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube, were placed a solution of 2-chloro-5-nitropyridin-4-amine (500 mg, 2.88 mmol) in N,N-dimethylformamide (20 mL) and morpholine (503 μL, 5.77 mmol). The reaction mixture was stirred overnight at 55° C. The reaction was then quenched by the addition of 100 mL of water. The reaction mixture was extracted with 3×150 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This resulted in 733 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:28]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])#[N:27]>C1COCC1.CN(C1C=CN=CC=1)C>[C:26]([C:28]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:39])[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])#[N:27]
Reactant: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C#N)c4)c3)c2cc1OC
Yield: 54.7 %

Procedure:
Using the procedure described in Example 279a solution of 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline (103 mg, 0.3 mmol), prepared as described in Example 117B, in THF (3 ml) was added DMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (92 mg, 0.33 mmol) described in Example 278A to afford 1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (86.6 mg, 55%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.66 (s, 6H), 3.78 (s, 3H), 3.98 (s, 4H), 4.34 (s, 3H), 6.95 (d, J=7.8 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.26-7.41 (m, 5H), 7.58-7.66 (s, 3H), 8.54 (s, 1H), 8.90 (d, J=8.4 Hz, 2H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([Cl:11])[CH:3]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:6]=2[CH:5]=[C:4]([Cl:11])[CH:3]=1
Reactant: Clc1cc(Br)c2nc[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Br)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 4-bromo-6-chloro-1H-benzo[d]imidazole 109c (3.5 g, 15 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (360 mg, 15 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (2.7 g, 16.5 mmol). The reaction was stirred at room temperature for 2 h. Water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×80 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 116a as a brown solid (4.2 g, 77%). MS-ESI: [M+H]+ 361.0
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:34](=[O:37])[CH2:35][CH3:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1
Reactant: CCC(=O)Cl
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CCC(=O)OC[C@H]1O[C@@H](Oc2nn(CC3CC3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 405.5 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.40 g) in 2,4,6-trimethylpyridine (1.5 mL) was added propionyl chloride (0.0088 g) at 0° C., and the mixture was stirred for 3 hours. Citric acid monohydrate (3.3 g) and water were added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(cyclopropylmethyl)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.20 g).
Reaction SMILES: [CH3:1][C:2]([NH2:24])([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)[CH:5]=1.[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C@@H:44]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:45]Br)=[C:37]2[C:42]=1[NH:41][C:40](=[O:43])[CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[Na+].C(=O)([O-])O.[Na+]>CN1CCCC1=O.O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:44]([O:47][Si:48]([C:51]([CH3:52])([CH3:54])[CH3:53])([CH3:50])[CH3:49])[CH2:45][NH:24][C:2]([CH3:1])([CH3:23])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]34[CH2:22][CH:17]5[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]5)[CH2:20]3)[CH2:14]4)[CH:5]=2)=[C:37]2[C:42]=1[NH:41][C:40](=[O:43])[CH:39]=[CH:38]2)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(N)Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 120 °C
Yield: 34 %

Procedure:
To a solution of Intermediate 87 (0.981 g, 3.0 mmol) and (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (1.463 g, 2.99 mmol) in N-methylpyrrolidinone (5 mL) was added sodium iodide (0.471 g, 3.14 mmol) and sodium hydrogencarbonate (0.352 g, 4.19 mmol). The reaction mixture was heated at 120° C. for 4 hours and poured into excess water. The organic layer was extracted with diethyl ether and washed with water. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel, eluting with dichloromethane/methanol (from 90:1 to 90:2) to give 0.748 g (34% yield) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3])[CH3:19]
Reactant: CCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-carboxyphenylboronic acid (15 g, 0.09 mol), 99% ethanol (150 mL) and concentrated sulphuric acid (0.5 mL) was heated to reflux for two days. The volume was reduced to approximately 20 mL. The residue was triturated with petroleum ether to give 13.4 g of the desired material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.O>CCO>[Cl:1][C:2]1[C:3]([N:27]([CH3:28])[CH3:29])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1COCCN1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Solvent: O
Solvent: CCO
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CN4CCOCC4)cs3)c1)=N2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-4-[3-(4-chloromethyl-thiazol-2-yl)-phenyl]-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (89 mg) (Example 191a), morpholine (0.17 mL) and KI (3 mg) in EtOH (0.5 mL) was stirred at 60° C. for 3 h. H2O (25 mL) was added to the cooled solution and the precipitate was collected by filtration and purified by chromatography on silica gel using AcOEt/acetone (1:1) as eluent. The product was stirred with 20% aqueous MeOH (20 mL) The pH of the mixture was set to 11 by addition of 1N NaOH and the solid was subsequently isolated by filtration to give the title compound (55 mg) as yellow powder.
Reaction SMILES: [I:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:25]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[NH2:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c2ccc(I)cc2c(=O)o1
Reactant: NCCC(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Nc1ccc(I)cc1C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
a magnetically stirred solution of 5 grams of 5-iodoisatoic anhydride (0.0173 mol), 5.85 grams of β-alanine benzyl ester tosylate (0.0173 mol), 35 mL pyridine, and 0.5 of dimethylaminopyridine (0.0041 mol) was heated to 80° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in 100 mL ethyl acetate and washed 2×50 mL of 10% cupric sulfate, 1×50 mL sat. sodium bicarbonate, 1×50 mL brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was further purified by column chromatography, using silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.65, υν positive) to yield 1.85 grams (25%) of N-(2-amino-5-iodobenzoyl)-β-alanine benzyl ester. 1H NMR (CDCl3, δTMS) 7.54 (1H, d, 4JHH =2 Hz, Ar--H, o-CON), 7.42 (1H, dd, 3JHH =9 Hz, 4JHH =2 Hz, Ar--H p-CON), 7.38-7.32 (5H, s, ArH Ph), 6.65 (1H, bt, 3JHH =6 Hz, CONH), 6.46 (1H, d, 3JHH =9 Hz, Ar--H m-CON), 5.16 (2H, s, OCH2), 3.68 (2H, q, 3JHH 6 Hz, NCH2), 2.69 (2H, t, 3JHH =6 Hz, CH2CO2). 13C NMR (CDCl3, δTMS) 172.4, 167.8, 148.6, 140.6, 135.6, 135.5, 128.7, 128.4, 128.3, 119.3, 118.1, 76.3, 66.7, 35.2, 34.0.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].F[B-](F)(F)F.[O:19]=[N+:20]=[O:21]>C(#N)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:6]([N+:20]([O-:21])=[O:19])[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C#N)c(Br)c1OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])c(C#N)c(Br)c1OC
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-bromo-3,4-dimethoxybenzonitrile (prepared according to step (b), 5.77 g, 23.8 mmol) in acetonitrile (58 ml) at 0° C. was added nitronium tetrafluoroborate (5.67 g, 42.9 mmol) portionwise ensuring that the temperature did not rise above 10° C. After stirring for 4 hours in the range 0° C. to 10° C., the reaction was cautiously quenched into 10% aqueous NaHCO3 (66 ml). The resulting suspension was filtered and the solid dried in vacuo overnight to give 5.83 g of the subtitle product (85%).
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=O)C.[CH2:27]([O:34][CH2:35][CH2:36][NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:19]([O:18][C@@H:8]1[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6][C@H:5]2[C@H:10]([N:11]=[C:12]([NH:37][CH2:36][CH2:35][O:34][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:13]2)[C@H:9]1[O:14][C:15](=[O:17])[CH3:16])(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@H]1O[C@@H]2SC(NCCOCc3ccccc3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (9.8 g, 25 mmol) in dichloromethane (100 mL) was added 128 (4 g, 26 mmol) at 0° C. After stirred for 2 hours, trifluoroacetic acid (15.4 g, 159 mmol) was added. The resulting solution was stirred for 12 hours at room temperature, then quenched with ice-water (200 mL) and neutralized by the addition of NaHCO3 (26 g, 318 mmol). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by silica gel column, eluted with 10%-50% ethyl acetate in petroleum ether to afford 129 as a white syrup (9.8 g, 77%). (ES, m/z) [M+H]+ 481.0; 1H NMR (300 MHz, CDCl3) δ 7.31-7.38 (m, 5H), 6.24 (d, J=6.3 Hz, 1H), 5.41-5.43 (m, 1H), 4.94-4.98 (m, 1H), 4.55 (s, 2H), 4.34-4.37 (m, 1H), 4.14-4.16 (m, 3H), 3.83-3.87 (m, 1H), 3.64 (t, J=5.4 Hz, 2H), 3.53 (t, J=5.1 Hz, 2H), 2.12 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=[O:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6](=[O:16])[C:7](=[O:15])[C:8]=1[N+:17]([O-:19])=[O:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C1=CC(C(C)(C)C)=C([N+](=O)[O-])C(=O)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (4.20 g, 19.1 mmol) in acetic acid (115 mL) was slowly added HNO3 (15 mL). The mixture was heated at 60° C. for 40 min before it was poured into H2O (50 mL). The mixture was allowed to stand at room temperature for 2 h, then was placed in an ice bath for 1 h. The solid was collected and washed with water to provide 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (1.2 g, 24%). 1H NMR (400 MHz, DMSO-d6) δ 6.89 (s, 1H), 1.27 (s, 9H), 1.24 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[Cl:8][C:9]1[CH:20]=[CH:19][C:12]([C:13](N(OC)C)=[O:14])=[CH:11][CH:10]=1.CN1C=CN=C1.FC1N=CC(C(N(OC)C)=O)=CC=1>>[Cl:8][C:9]1[CH:20]=[CH:19][C:12]([C:13]([C:7]2[N:3]([CH2:1][CH3:2])[CH:4]=[N:5][CH:6]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: CCn1ccnc1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: CON(C)C(=O)c1ccc(F)nc1
Agent: Cn1ccnc1
Product: CCn1cncc1C(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared using 1-ethyl-1H-imidazole and 4-chloro-N-methoxy-N-methylbenzamide (Intermediate 18, step a) in place of 1-methyl-1H-imidazole and 6-fluoro-N-methoxy-N-methylpyridine-3-carboxamide, respectively, according to the procedure described for Intermediate 21, step c.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCc1ccccn1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCc3ccccn3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (2-pyridin-2-yl)ethylamine as described in Step 5, Example 24 to give the title compound. MS: m/e 404 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH2:17][CH2:16]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[O:30])[CH2:19][CH2:20]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The above white solid, {4-[1-(2,6-dichloro-benzoyl)-piperidin-4-yloxy]-phenyl}-carbamic acid tert-butyl ester, is suspended in a solution of trifluoroacetic acid in dichloromethane (25% v/v, 20 mL). The reaction mixture is stirred at 22° C. for 15 min. After removal of the solvent, the oily residue is neutralized with 0.5 N aqueous sodium hydroxide solution (50 mL) and extracted with dichloromethane (5×50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to yield a yellow solid (440.2 mg, 92.0% yield, ES+(m/z) 365.1 [M+H]).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]([F:50])([F:49])[C:41]([N:43]([CH2:45][C:46](O)=[O:47])[CH3:44])=[O:42]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[C:46](=[O:47])[CH2:45][N:43]([CH3:44])[C:41](=[O:42])[C:40]([F:49])([F:50])[F:39])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc(NCc2ccc(C3CCCCC3)cc2)cc1OCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)C(F)(F)F
Product: CN(CC(=O)N(Cc1ccc(C2CCCCC2)cc1)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)C(F)(F)F
Yield: 97 %

Procedure:
Secondary aniline 4 was coupled to carboxylic acid 44 on a 3.17 mmol scale via General Procedure B to furnish 45 (2.07 g, 97%): δH (400 MHz, CDCl3) 1.35-1.44 (m, 5H, [Cy] CH2), 1.71-1.90 (m, 6H, [Cy] CH2), 3.17 (s, 3H, CH3), 3.79 (s, 2H, CH2), 4.84 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.65 (s, 1H, CH), 6.78 (dd, J=8.4 and 1.6 Hz, 1H, CH), 7.10-7.19 (m, 4H, CH), 7.29-7.43 (m, 10H, CH), 7.86 (d, J=8.4 Hz, 1H, CH); δC (100 MHz, CDCl3) 25.8, 26.6, 34.2, 44.0, 51.2, 52.6, 66.7, 70.4, 77.2, 113.9, 115.0, 117.6, 119.8, 126.8, 126.9, 127.7, 128.0, 128.3, 128.3, 128.4, 128.6, 132.9, 133.6, 135.5, 135.6, 144.6, 147.5, 157.0, 158.4, 165.1, 165.4; LRMS (ES+) calcd for [C39H39F3N2O5+Na] 695.27. found 695.36.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]([Cl:24])(Cl)(=[O:22])=[O:21].[CH2:25]([O:32][C:33]([NH:35][CH2:36][CH2:37]S([O-])(=O)=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:24][S:20]([CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(NCCS(=O)(=O)[O-])OCc1ccccc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
This compound was prepared using the method of T. S. Widlanski and J. Huang, Tet. Lett. 1992, 33: 2657. A solution of triphenylphosphine (17.6 g, 67.4 mmol) in dry CH2Cl2 (90 mL) was cooled to zero degrees C. under nitrogen and treated with neat sulfuryl chloride (5.96 mL, 74.2 mmol) to give a yellow solution. The solution was recooled to 5 degrees C. and crushed solid sodium 2-{[(benzyloxy)carbonyl]amino}ethanesulfonate (12 g, 42.6 mmol) prepared as described by Bricas et al., Biochimica et Biophysica Acta 1955, (18), 358, was added all at once to give a white suspension. The reaction was allowed to warm to room temperature and stirred for 3 hours. The volatiles were removed in vacuo to give an oily/solid residue that was suspended in EtOAc and added to the top of a silica column (3 inches by 150 mm) packed in EtOAc. The product was eluted with EtOAc and the UV active fractions were combined and evaporated to give the product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-benzyloxybenzoic acid (116 mg, 0.51 mmol) and PS-carbodiimide (500 mg, 0.66 mmol, 1.32 mmol/g) in 5% DMF in CH2Cl2 (5 mL) is added (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (80 mg, 0.51 mmol). The mixture is stirred at room temperature for 3 days. The reaction mixture is filtered, and the resin is washed with CH2Cl2. The filtrate is concentrated and applied to silica-gel column chromatography (in CH2Cl2 followed by 5% 2M NH3 in MeOH/CH2Cl2) to give the product. 62.7 mg (34%): Observed mass: 365 (M+1).