Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.Br[CH2:32][C:33]#[N:34]>C1COCC1>[C:33]([CH2:32][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:34]
Reactant: N#CCBr
Reactant: CCOC(=O)C(CC)CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(CC)CC#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of ethyl 2-ethylbutyrate (21.60 g, 150 mmol) in THF (25 mL) was added dropwise to a solution of lithium diisopropylamide prepared by treating diisopropylamine (16.67 g, 165 mmol) in dry THF (150 mL) with butyllithium in hexanes (2.5M, 66 mL, 165 mmol) at -78° C. for 1 h in a nitrogen atmosphere. The resulting mixture was stirred at -78° C. for 1 h, then a solution of bromoacetonitrile (21.60 g, 180 mmol) in THF (50 mL) was introduced slowly over a period of 30 minutes (the reaction mixture starts getting darker as the addition progresses). The resulting dark mixture was stirred overnight (ca. 16 h) and allowed to warm from -78° C. to room temperature. The reaction was quenched by addition of HCl (1 N, 250 mL) at 0° C. The layers were separated, and the aqueous phase was further extracted with ether (3×100 mL). The combined organic extract was washed sequentially with 75 mL portions of saturated NaHCO3, water (several times), and brine, and dried over MgSO4. The solvent was removed in vacuo to give 27.77 g of dark colored liquid. After two vacuum distillations, the nitrile (12.35 g, 45%) was obtained as a colorless liquid: bp 84-85° C. (1.3 mmHg). Analytical sample was prepared by column chromatography over silica gel (hexanes-EtOAc, 19:1) followed by bulb-to-bulb distillation (pot temp. 80° C. (1 mmHg)).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: CN1CCNCC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1cccc(F)c1
Yield: 23 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 21) and N-methylpiperazine to give the title compound in 23% yield; NMR Spectrum: 2.09 (s, 3H), 2.28 (s, 3H), 2.50 (s, 4H), 2.77 (t, 2H), 4.42 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.31 (m, 2H), 7.43 (m, 3H), 8.16 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 492 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[N:17][S:16]2(=[O:42])=[O:41])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:25][CH2:26][OH:27])=[N:17][S:16]2(=[O:41])=[O:42])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To detach the protecting group, 40 mg of [5-(4-benzyloxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were dissolved in 5 ml of methanol and, after addition of 1 ml of 2 N hydrochloric acid, stirred at room temperature for 1 hour. The reaction solution was neutralized with 2 ml of 1 N aqueous sodium hydroxide solution and concentrated by rotary evaporation, and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (19.7 mg) with a molecular weight of 494.6 g/mol (C27H30N2O5S); MS (ESI): m/e=495 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:6]2[CH:14]=[CH:13][CH:9]=[CH:8][CH:7]=2)=[CH:8][CH:7]=1)(=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
To a stirred slurry of 50 g of aluminium chloride in 150 ml of benzene under reflux was added dropwise 40 g of terephthaloyl chloride dissolved in 250 ml of benzene. When the addition was complete the reaction was refluxed for 15 minutes, and 250 ml of water was added slowly. The benzene layer was separated and the aqueous layer was extracted with methylene chloride (2×300 ml). The combined orgainic layers were washed with 1m NaOH solution (2×400 ml) and water (400 ml), dried (MgSO4), filtered, and the solvents were removed under reduced pressure to give a nearly colorless solid. Recrystallization from 95% ethanol gave 46.8 g of colorless 1,4-dibenzoylbenzene, m.p. 160°-162°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=[O:23])=[CH:21][C:11]=2[N:10]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:26])([CH3:27])[O:18][C:19]=3[C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:11]=2[N:10]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Yield: 78.4 %

Procedure:
The title compound was prepared following the procedure described for step-2 of Intermediate-3 using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 2.00 g, 4.7 mmol), (50%) aqueous solution of sodium hydroxide (0.920 g, 23.0 mmol) methanol (2.0 mL) to afford 1.5 g of the desired product. 1HNMR (DMSO-d6): 1.46 (s, 6H), 3.37 (s, 2H), 3.56 (s, 3H), 7.10 (s, 1H), 8.45 (s, 2H), 10.77 (br s, 1H), 12.17 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>CC(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
To a mixture of methyl 3,4,5-tribenzyloxybenzoate (15) (20.60 g, 45.30 mmol) in 2-propanol (200 mL) was added a solution of potassium hydroxide (3.50 g, 85%, 53.00 mmol) in 2-propanol (25 mL). The mixture was refluxed for 1 h, cooled, and water was added (250 mL). A white precipitate appeared, and the mixture was filtered. Recrystallisation from ethyl acetate afforded the desired compound as white crystals, m.p. 194-195° C. Yield: 17.2 g (86%). 1H NMR (300 MHz, DMSO-d6): δ=5.05 (2H, s), 5.18 (4H, s), 7.24-7.50 (17H, m), 13.4 (1H, s, broad); 13C NMR (75 MHz): δ=70.3, 74.3, 108.3, 126.1, 127.7, 128.0, 128.2, 128.3, 128.5, 136.9, 137.5, 141.0, 152.1, 167.0.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)[CH2:31][NH:32]C(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C#N)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 339 (M−15,0.1), 234 (15), 233 (100), 121 (21), 102 (7), 90 (6).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][C@@H:11]3[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1)([O-])=O.CO.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][C@@H:11]3[CH2:14][CH2:15][CH2:16][N:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2OC[C@@H]2CCCN12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N1CCC[C@H]1CO2
Yield: 93.8 %

Procedure:
A solution of (S)-7-nitro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one (7.4 g), prepared as described in Example 3L, in ethanol (100 ml) and methanol (50 ml) was hydrogenated over 10% palladium on activated carbon under 2 bar hydrogen, until the uptake of hydrogen ceased. The mixture was filtered to remove the catalyst and evaporated to dryness in vacuo. The crude product was passed through a short silica column (eluting with 10% methanol in dichloromethane) to give the title product (6.1 g). EIMS: m/z=219 [M+H]+
Reaction SMILES: COCCOC.[CH2:7]([O:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[N:22]([S:30]([C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:19][CH:18]=[C:17]([C:40]([F:43])([F:42])[F:41])[CH:16]=2)=[O:11])[CH3:8].[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[N:22]([S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:19][CH:18]=[C:17]([C:40]([F:43])([F:42])[F:41])[CH:16]=2)=[O:11])[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1cccnc1)S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To 8.5 mL of degassed ethylene glycol dimethyl ether, was added 500 mg (0.85 mmol) of the ester, 110 mg (0.93 mmol) of phenylboronic acid, 80 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium and 1.1 ml (2.2 mmol) of 2M aqueous Na2CO3 and the mixture ws heated to reflux under nitrogen for 36 hr. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give 4-[(biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.O>C(OCC)C>[F:12][C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: COC(OC)c1ccc(F)c(C=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
2.8 g of 5-Dimethoxymethyl-2-fluorobenzaldehyde was dissolved in 40 ml of diethyl ether, and 0.38 g of lithium aluminum hydride was added under ice-cooling. After being stirred at room temperature for 5 minutes, the reaction solution was ice-cooled and diethylether-water was added. When the insoluble precipitate adhered to the wall of the flask, the reaction solution was dried over anhydrous magnesium sulfate, then evaporated. The residue was dissolved in 25 ml of dichloromethane, and 8 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 2.5 hours, the reaction solution was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was subjected to silica gel column chromatography (30% ethyl acetate-hexane), to give 1.6 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[CH:11]=1
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(=O)[nH]c2ccccc12
Yield: 54 %

Procedure:
To a suspension of 2.4-dihydroxy quinoline (3.00 g, 18.6 mmol) and potassium carbonate (5.14 g, 37.2 mmol) in acetone (500 mL) was added dimethyl sulfate (2.1 mL, 22 mmol) and the resulting mixture heated at reflux during 5 hrs. The solvent was removed in vacuo and the residue triturated in water. The product was collected by filtration, washed with water and triturated from methanol to give 4-methoxy 2-quinolone 187a (1.76 g, 54%) as a white solid, that had identical 1H NMR data as reported (Reisch et al., Arch. Pharm., 1980,313, 751-755).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[CH:59]=[CH:58][CH:57]=[C:56]1[S:60](Cl)(=[O:62])=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:60]([C:56]2[O:55][CH:59]=[CH:58][CH:57]=2)(=[O:62])=[O:61])[CH2:49][CH2:48]1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccco2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 8 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and furan-2-sulfonyl chloride as starting materials in 8% yield. LCMS for C28H29ClN7O4S (M+H)+: m/z=594.2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[NH:28][C:26]2[S:27][C:23]([S:22][CH3:21])=[CH:24][N:25]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CSc1cnc(N)s1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cnc(NC(=O)c2cccc(OC(C)=O)c2)s1
Yield: 64.6 %

Procedure:
Following the procedure for the synthesis of example 513, intermediate 511 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine (0.572 mL, 4.10 mmol), and 514 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL) gave 516 (0.681 g, 65%) as a tan solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([CH2:18][CH2:19][NH:20][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])([O:16][CH2:14][CH3:15])=[O:21]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 3 h

Procedure:
To a solution of 3-chlorosulfonylbenzoic acid (3-1) (Maybridge Chemicals) (1.10 g, 5 mmoles) and β-alanine ethyl ester (0.85 g, 5.5 mmoles) in CHCl3 (20 ml) at room temperature was added triethylamine (1.52 g, 15 mmoles). After stirring for 3 hrs the solvent was removed, the residue was taken up in EtOAc, washed with H2O, 10% KHSO4 solution, H2O, brine and dried (Na2SO4). Solvent removal gave a residue that was purified by flash chromatography on silica gel eluting with CHCl3 (97)/MeOH(3) to give pure 3-2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-])=O.[H][H]>[Pd].CO>[NH2:8][C:7]1[C:6]([CH3:11])=[CH:5][C:4]([C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C(=O)N2CCOCC2)cc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N2CCOCC2)cc(C)c1N

Procedure:
10% Palladium on carbon (100 mg) is added to a solution of (3,5-dimethyl-4-nitrophenyl)(morpholino)methanone (1.3 g) in methanol (10 mL) and the mixture is hydrogenated for 3 hours under 2 bar hydrogen pressure. Then the catalyst is filtered off and washed with methanol. The combined mother liquors are concentrated to give the title compound. Yield: 1.1 g; LC (method 20): tR=1.94; Mass spectrum (ESI+): m/z=235 [M+H]+.
Reaction SMILES: [NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:2]([C:20]([N:22]1[CH2:61][CH2:60][CH2:59][C@H:23]1[C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([C:49]([O:51]CC1C=CC=CC=1)=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[Cl:44])=[O:39])=[O:30])[CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:62]([O:64][C:65]([CH3:66])([CH3:68])[CH3:67])=[O:63])[C@H:2]([C:20]([N:22]1[CH2:61][CH2:60][CH2:59][C@H:23]1[C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([C:49]([OH:51])=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[Cl:44])=[O:39])=[O:30])[CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
At 0° C. to the solution of 500 mg (0.51 mmol) of Boc-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 5 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 380 mg (84%) of the title compound as a colorless powder. Mp 108–110° C., TOF-MS (m/e) 893.2[M+H]+, 915.5[M+Na]+, 937.2[M+2Na]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[BH-](O[C:25](=[O:27])[CH3:26])OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:7][C:6]2[O:27][C:25]3[C:26](=[N:9][CH:4]=[CH:3][CH:8]=3)[CH:5]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na+]
Product: COc1ccccc1N1CCN(Cc2cc3ncccc3o2)CC1

Procedure:
The product from Example 35B, 1-(2-methoxyphenyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.85 (br, 4H), 3.19 (br, 4H), 3.85 (s, 3H), 3.88 (s, 2H), 6.93 (m, 5H), 7.20 (dd, 4.75, 8.14 Hz, 1H), 7.74 (m, J=1.02, 7.12 Hz, 1H), 8.54 (br, 1H); MS (DCI/NH3) m/z 324.2 (M+H)+; Anal Calcd for C19H21N3O2: C, 70.57;H, 6.55; N, 12.99. Found: C, 69.72;H, 6.45; N, 12.81.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=3)[CH2:12][CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1nc(N2CCNCC2)ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCN(c3ccc(Br)c(OC)n3)CC2)cc1OC
Temperature: 25 °C

Procedure:
A quantity of 0.1 g (0.4 mmole, 1 eq) of 1-(5-Bromo-6-methoxy-pyridin-2-yl)-piperazine and 0.061 g (0.4 mmole, 1 eq) of 3,4-dimethoxybenzaldehyde is dissolved in 5 mL of anhydrous toluene, and 3 drops of glacial acetic acid is added. An excess of NaBH(OAc)3 is added to the solution and stirred at room temperature under a nitrogen atmosphere until no starting material is detectable by TLC. At that time the reaction is quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate. The ethyl acetate extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with 10% CH3OH (2M NH3)/CH2Cl2 to afford 1-(5-bromo-6-methoxypyridin-2-yl)-4-(3,4-dimethoxybenzyl)piperazine (compound 1). Analysis: 1H NMR (400 MHz, DMSO): 7.71 (1H, d), 7.36 (1H, s), 7.05 (2H, m), 6.39 (1H, d), 4.38 (4H, m), 3.80 (9H, m), 3.39 (4H, m), 3.02 (2H, m). MS (LC-MS): Calculated for C19H24BrN3O3 422.32. Found 436.3424.31 (M+2).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1I.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][C:23]=1[C:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1

Procedure:
A solution of Pd(Ph3P)4 (0.986 g, 0.854 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (2.000 g, 8.96 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.377 ml, 8.54 mmol), and potassium phosphate (5.44 g, 25.6 mmol) in 20 mL dioxane 10 mL water was heated to 90° C. for one hour. LC/MS showed mostly product, so the reaction mixture was poured into water and extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 97% EtOAc/heptane, 3% MeOH) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine. m/z (ESI) 320.1 (M+H)+.