Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:14]2[CH2:15][CH2:16][CH:11]([CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]#[N:10])[CH2:12][CH2:13]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: N#CC(c1ccccc1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of α-phenyl-4-piperidineacetonitrile hydrochloride (0.05 mole), 1-fluoro-4-nitrobenzene (0.06 mole) and potassium carbonate (0.15 mole) in DMF (200 ml) was stirred at 50° C. for four hours. Water and DIPE were added. The mixture was cooled. The precipitate was filtered off, washed with water and DIPE and dried, yielding 11.6 g of (±)-1-(4-nitrophenyl)-α-phenyl-4-piperidine-acetonitrile (intermediate 12, melting point 118° C.).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].C[Al](C)C.CO[C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1)=[O:14]>ClCCCl.C(Cl)Cl>[CH2:2]([N:4]([CH2:5][CH3:6])[C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[N:19][CH:20]=1)=[O:14])[CH3:3]
Reactant: COC(=O)c1cnc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)nc1
Reactant: CCNCC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cnc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirring suspension of diethyl amine hydrochloride (986 mg, 9.01 mmol) in 1,2-dicloroethane (25 mL) at 0° C. was added a 2.0 M solution of AlMe3 (4.5 mL, 9.01 mmol) dropwise. The resulting mixture stirred at room temperature for 1 hour. (2-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid methyl ester (750 mg, 1.80 mmol) was added in one portion and the mixture was heated to 85° C. for 16 hours. The reaction was slowly poured into a saturated solution of Rochelle salts (50 mL) and diluted with CH2Cl2 (50 mL). The layers were separated, the aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were dried and concentrated. The crude material was filtered through a plug of silica gel with 5% MeOH/CHCl3, and the resulting solution was concentrated to yield 815 mg (99% yield) of the desired amide. 1HNMR (400 MHz, CDCl3) δ 8.72 (s, 2H), 7.29-7.14 (comp, 6H), 6.97-6.95 (comp, 2H), 6.68-6.66 (comp, 1H), 3.73 (s, 3H), 3.54-3.52 (comp, 2H), 3.39 (s, 2H), 3.27-3.25 (comp, 2H), 2.98-2.95 (comp, 2H), 2.77-2.74 (comp, 2H), 2.34-2.31 (comp, 2H), 2.16-2.02 (comp, 2H), 1.26-1.17 (comp, 6H); MS (M+1) 459.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][C:18]([OH:25])=[C:19]([OH:24])[CH:20]=4)[CH2:15]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:27](Br)([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:36]([O:35][C:33]([C:27]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:24][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:25]1)[CH2:15][C@H:14]([N:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][C:11]1=[O:13])[CH2:23][CH2:22]3)=[O:34])[CH3:37]
Reactant: O=C1OC(c2cccc(Cl)c2)CN1C1CCc2cc(O)c(O)cc2C1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2cc3c(cc2O1)C[C@H](N1C[C@H](c2cccc(Cl)c2)OC1=O)CC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A mixture of 0.90 g of the above catechol derivative, 0.836 g of diethyl dibromomalonate and 1.8 g of powdered anhydrous potassium carbonate in 15 ml of acetone is stirred at room temperature for 18 hours. The reaction mixture is filtered and concentrated in vacuo to give 0.708 g of a mixture of diastereomers as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:24]=[CH:23][C:9]([CH:10]([OH:22])[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:25]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH2:26]O.C(C(C)=O)C>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH2:18]([N:17]([CH2:20][CH3:21])[C:14]1[CH:15]=[CH:16][C:11]([CH:10]([C:9]2[CH:23]=[CH:24][C:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=2)[O:22][CH2:26][C:25]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])=[CH:12][CH:13]=1)[CH3:19]
Reactant: O=C(CO)Nc1ccccc1
Reactant: CCN(CC)c1ccc(C(O)c2ccc(N(CC)CC)cc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: CS(=O)(=O)O
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: CCN(CC)c1ccc(C(OCC(=O)Nc2ccccc2)c2ccc(N(CC)CC)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-diethylamino)benzhydrol (11.0 g, 0.034 mole), glycolanilide (5.1 g, 0.034 mole), 37.5 ml of methyl ethyl ketone, 112.5 ml of n-hexane, and 7 drops of methanesulfonic acid was refluxed for about 2 hours, removing water as formed. The solution was then treated with 5 drops of tetramethyl-guanidine and filtered hot. On cooling, the filtrate yielded a tan precipitate. The precipitate was filtered, washed with n-hexane, and dried. The pale yellow solid was recrystallized from 80 ml of methylcyclohexane and 450 ml of acetone to give a solid product, mp 123°-125° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:25]([O:28][CH2:29]Br)(=[O:27])[CH3:26]>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:29][O:28][C:25](=[O:27])[CH3:26])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(=O)OCBr
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(c2cn3cncc3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
To a solution of 49 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 1 ml of DMF was added 32 mg of acetoxymethyl bromide under the atmosphere of argon at −20° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was extracted twice with 20 ml of ethyl acetate, and the organic layer was washed twice with 10 ml of semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 11 mg of the title compound.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](I)=[C:9]([F:14])[CH:8]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])=[C:9]([F:14])[CH:8]=1
Reactant: Fc1cc(Cl)ccc1I
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0 g) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][NH2:6])[CH3:2].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4][CH2:5][NH:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN(CCN)CCCCC(C)C
Product: CCN(CCCCC(C)C)CCNc1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 1 react N-ethyl N-(5-methylhexyl)-1,2-ethanediamine with 4-fluoro-1-nitrobenzene to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]2)[CH:3]=1.CC(O[K])=[O:26].O>CS(C)=O>[Cl:14][C:7]1[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([N:15]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16]1)[CH:3]=[C:2]2[OH:26]
Reactant: CC(=O)O[K]
Reactant: COc1ccc2c(Cl)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(O)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Temperature: 140 °C
Yield: 80 %

Procedure:
To a solution of compound 119b (250 mg) in DMSO (2.5 mL) was added CH3COOK (3 eq.), water (2 eq.). The reaction mixture was heated to 140° C. for 4 hrs. After cooled to RT, water (1 mL) was added to the reaction mixture slowly under stirring. Solid was filtered and washed with water to yield compound 88b in >80% yield. In a separate reaction, when 5 eq. of CH3COOK was used, the reaction was completed in 1 hr.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=[O:6])[CH3:2].[CH2:17](O)[CH3:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:17]([O:6][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[CH3:18]
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1ccc(OC)cc1F

Procedure:
A solution of (RS)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid (7.26 g, example 63.1), ethanol (16.7 ml) and DMAP (1.57 g) in dichloromethane (120 ml) was cooled to 0° and treated with EDCI (6.59 g). The reaction stirred was stirred at rt for 18 hrs, then washed with 0.5 N HCl, H2O, saturated NaHCO3 and brine. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 85:15) to give (RS)-ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid ethyl ester (4.42 g) as yellow oil. MS 256.2 ([M]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.CN(C)/[CH:28]=[N:29]/[N:30]=[CH:31]/N(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[CH:31]=[N:30][N:29]=[CH:28]5)[CH:3]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: CN(C)/C=N/N=C/N(C)C
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(-n2cnnc2)c1
Yield: 38 %

Procedure:
A mixture of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol), N,N-dimethylformamide azine (Bartlett, R. K.; Humphrey, I. R. J. Chemn. Soc. C 1967, 1664) (41.3 mg, 0.290 mmol), and p-toluenesulfonic acid (10 mg, 0.053 mmol) in toluene (4 ml) was heated at reflux under nitrogen for 7 days, adding more p-toluenesulfonic acid (10 mg, 0.053 mmol) and some DMSO after 1 day. The solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-15% MeOH/CH2Cl2), then trituration in hot MeOH-CH2Cl2, to leave 0.0436 g (38%) of the title compound as a yellow solid; mp >350° C.; 1H NMR (360 MHz, DMSO-d6) δ2.29 (3H, s), 7.41 (2H, d, J 9.1 Hz), 7.59 (1H, d, J 7.7 Hz), 7.70 (1H, t, J 7.7 Hz), 7.79 (1H, dd), 7.87 (1H, fine t), 8.11 (2H, d, J 8.9 Hz), 8.62 (1H, s), 9.18 (2H, s), 12.52 (1H, br s); MS (ES+) m/z 403/405 1MH]+. Anal. found: C, 61.14; H, 3.79; N, 20.29. C21H15ClN6O.0.5H2O requires: C, 61.24; H, 3.92; N, 20.41%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:33]=[N:34][CH:35]=2)O1.O>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[Cl-].[Na+].O>[C:15]1([CH2:14][C:13]([NH:12][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:2]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([NH:36][S:37]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)(=[O:39])=[O:38])[CH:31]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: O=C(Cc1ccccc1)Nc1cnc2ccc(Br)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Cc1ccccc1)Nc1cnc2ccc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc2n1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of N-(7-bromo-2-quinoxalinyl)-2-phenylacetamide (0.254 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.508 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.007 mmol) in 2M aqueous sodium carbonate (0.5 mL) and 1,4-dioxane (2 mL) was heated at 100° C. for 5 h. The reaction mixture was cooled, poured into water (60 mL) and brine (15 mL), and extracted with ethyl acetate (50 mL). The aqueous layer was acidified with 1N aqueous HCl until the pH was approximately 6-7 and then further extracted with (3×50 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography eluting with 50-70% ethyl acetate/hexanes followed by reverse phase HPLC (30-75% acetonitrile/water with 0.1% TFA) afforded the title product as a tan solid (42 mg, 33%). MS(ES)+ m/e 496 [M+H]+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:34][O:33][C:31](=[O:32])[NH:30][CH:26]([C:25]([N:10]1[CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][N:8]([C:6](=[O:5])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:35])[CH:27]([CH3:29])[CH3:28]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCl (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF (1 mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room temperature. After 10 minutes, all starting material was consumed. All volatiles were removed in vacuo and the crude brown solid {1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI+: calc'd for C26H28BrN5O4: 554.4 (M+). Found: 554.3/556.4 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:12](Cl)(=[O:28])[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][CH3:27]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:28])[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][CH3:27]
Reactant: CC1CCCCN1CCCN
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCCN1CCCCC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 1-(3-aminopropyl)-2-pipecoline (1.00 g, 6.40 mmole) in methylene chloride (25 mL) was added palmitoyl chloride (1.73 g, 6.40 mmole) in small portions. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed twice with saturated aqueous sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate and the salts removed by filtration. The solvent was removed under reduced pressure and the residue dried in vacuo to give the title compound (2.12 g, 83%), mp. 48°-50° C. 1H NMR (300 MHz, CDCl3): δ0.883 (3H, t, J=6.5 Hz), 1.136 (3H, d, J=5.5 Hz), 1.254 (24H, bs), 1.60 to 1.70 (4H, m), 2.157 (2H, t, J=7.6 Hz), 2.37 to 2.39 (2H, m), 2.89 to 2.94 (3H, m), 3.24 to 3.27 (1H, m), 3.40 to 3.44 (1H, m), and 7.266 (1H, bs). Analysis calculated for C25H50N2O.1/4H2O C, 75.16; H, 12.61; N, 7.01. Found: C, 75.16; H, 12.69; N, 7.16.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[CH3:9][NH2:10].ClC(Cl)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[O:20][CH2:19]2>>[Br:15][C:16]1[CH:24]=[CH:23][C:22]([C:21]([NH:10][CH3:9])=[O:25])=[C:18]([CH2:19][OH:20])[CH:17]=1
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: CN
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Br)cc1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
A 500 mL RB flask was charged with aluminum(III) chloride (4.1 g, 31 mmol) and 10 mL of 1,2-dichloroethane (99 ml, 1142 mmol), then cooled to 0° C. A separate 250 mL flask was charged with 90 mL of 1,2-dichloroethane (90 ml, 1142 mmol) and cooled to 0° C.; methylamine (gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes. The dichloroethane solution was slowly poured into the aluminum chloride solution, resulting in the formation of a thick white slush. This was warmed to room temperature. 5-bromoisobenzofuran-1(3H)-one (5.00 g, 23 mmol) was added in one portion and the reaction mixture was stirred for 2.5 hours and quenched with water. The mixture was filtered to remove the solid impurities, then the filtrate was washed with 0.5N aqueous HCl (100 mL) and brine (200 mL). The organic layer was dried with MgSO4, filtered, and concentrated to give a white solid. This was triturated with EtOAc and filtered to give 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 58% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:28][CH2:29][C@H:30]([OH:45])[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2>>[OH:45][C@H:30]([CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2)[CH2:29][NH:28][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:12])=[O:13])=[CH:20][CH:19]=2)[CH2:22][CH2:23]1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 242) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.39 (t, J=7.2 Hz, 2H), 2.50-2.75 (m, 5H), 2.82 (t, J=7.2 Hz, 2H), 3.45-3.55 (m, 2H), 3.63 (s, 3H), 3.72 (s, 3H), 3.70-3.85 (m, 3H), 4.91 (brs, 1H), 6.44 (d, J=8.8 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 6.78 (d, J=9.1 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.5, 2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H),8.72 (s, 1H), 9.17 (brs, 1H); MS (ES) m/z: 627.1 (MH+); HRMS Calcd. for C31H39N4O8S(MH+): 627.2489. Found: 627.2458.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:5]2.O>C1COCC1.[Ni]>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][C:6]([CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:5][C:4]=2[C:3]=1[NH2:16]
Reactant: CC(C)Cc1cc2c([N+](=O)[O-])c(F)ccc2cn1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1cc2c(N)c(F)ccc2cn1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 102.3 %

Procedure:
A solution of Example 139B (2.39 g, 9.63 mmol) in THF (50 mL) was added to a Ra—Ni 2800, water slurry (2.390 g, 40.7 mmol) in a 250 mL pressure bottle and stirred for 100 min at 30 psi and ambient temperature. The mixture was filtered through a nylon membrane and then concentrated under reduced pressure to provide the title compound (2.15 g, 100% yield), which was used without further purification. (ESI) m/z 219.2 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1sccc1-c1ccc2c(c1)OCO2
Product: Cc1noc(NS(=O)(=O)c2sccc2-c2ccc3c(c2)OCO3)c1Br
Yield: 60 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 60% yield, m.p. 183-186° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][CH2:14][CH2:15]Br>C(Cl)Cl.CO>[C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:15][CH2:14][O:13][CH3:12])[C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)sc1C(C)(C)C
Reactant: COCCBr
Solvent: ClCCl
Solvent: CO
Product: COCCn1c(C)c(C(C)(C)C)sc1=N
Temperature: 85 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A mixture of 5-tert-butyl-4-methylthiazole-2-ylamine (1.5 g, 8.8 mmol) and 2-bromoethyl methyl ether (0.91 mL, 9.7 mmol) was warmed to 85° C. and allowed to stir for 24 hours. The crude material was dissolved in ˜5 mL of a 1:1 mixture of CH2Cl2 and CH3OH and a small amount of silica gel was added. This mixture was concentrated to dryness and the residue was purified via flash column chromatography (SiO2, 9:1:0.1 CH2Cl2:CH3OH:NH4OH) to afford the title compound (1.0 g, 4.4 mmol, 50% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.41 (s, 9H) 2.38 (s, 3H) 3.35 (s, 3H) 3.66 (t, J=4.70 Hz, 2H) 4.16 (t, J=4.70 Hz, 2H); MS (DCI/NH3) m/z 229 (M+H)+.