Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][CH:20]=1.[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1(C)C(C)=CC=CC=1>[Br:21][C:17]1[CH:16]=[C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cccc(I)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
The 200 ml round-bottom flask equipped with reflux condenser and magnetic stirrer was charged with carbazole (14.75 g, 88 mmol), 3-iodobromobenzene (25.0 g, 88 mmol), Pd2(dba)3 (0.8 g, 0.85 mmol) and dppf (1,1′-bis(diphenylphosphino)ferrocene, 0.98 g, 1.8 mmol), sodium t-buthoxide (25 g, 265 mmol) and 100 ml of dry xylene. Reaction mixture was refluxed under N2 atmosphere for 48 hours, cooled down to room temperature and evaporated. The solid residue was subjected to column chromatography on silica (eluent —hexane/ethyl acetate 9/1) providing 11.7 g of 9-(3-bromophenyl) -9H-carbazole as white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[CH3:44][NH:45][CH2:46][CH2:47][OH:48].O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:45]([CH2:46][CH2:47][OH:48])[CH3:44])=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: CNCCO
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCN(C)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 58 mg (yield 100%) of the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:13][C:11]([C:9]1[CH:8]=[N:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([F:14])[CH3:12]
Reactant: CC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Product: CC(F)(F)c1cnn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1
Yield: 44 %

Procedure:
This compound was prepared in 44% yield as described in the final paragraph of Example 2, step d, but using 7-bromo-3-(1,1-difluoroethyl)imidazo[1,2-b][1,2,4]triazine instead of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine, and using 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (prepared as described in Example 3, step f) instead of 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile: 1H NMR (360 MHz, CDCl3) δ 2.19 (3H, t, J 18.8 Hz), 7.36-7.47 (2H, m), 7.98 (1H, m), 8.08 (1H, m), 8.22 (1H, dd, J 2.3, 7.2 Hz), 8.45 (1H, s), 8.78 (1H, d, J 11.2 Hz), 8.85 (1H, s), 8.88 (1H, s); MS (ES+) m/z 356 [M+H]+. Anal. Found: C, 60.85; H, 3.45; N, 19.69%. Required for C18H12F3N5: C, 60.85; H, 3.40; N, 19.71%.
Reaction SMILES: C(=O)([O-])OCC[CH2:5]/[C:6](/[CH3:16])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]([CH2:5]/[C:6](/[CH3:16])=[CH:7]/[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)[S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])=[CH:37][CH:38]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: C/C(=C\c1cccc(C#N)c1)CCCOC(=O)[O-]
Reactant: CCS(=O)(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C/C(C)=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a suspension of [3-(3-cyanophenyl)-2-methyl-2-(E)-propenyl]ethyl carbonate (1.10 g) and N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]ethanesulfonamide (1.15 g) in tetrahydrofuran (9 ml) were added tris(dibenzylideneacetone)palladium chloroform complex (78 mg) and triphenylphosphine (39 mg) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=12/1 as an eluant to give the desired compound (0.58 g, yield 36%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[N:36]1[C:41]2[NH:42][C:43]3[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=3[NH:45][CH2:46][C:40]=2[CH:39]=[CH:38][CH:37]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:45]1[C:44]2[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=2[NH:42][C:41]2[N:36]=[CH:37][CH:38]=[CH:39][C:40]=2[CH2:46]1)=[O:6]
Reactant: Cn1ccc(-c2ccc(C(=O)O)c(Cl)c2)n1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions a solution of 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid of Step E (2.1 g, 8.88 mmol) and triethylamine (1.3 mL, 9.2 mmol) in 75 mL of dichloromethane was treated in one portion with 2,4,6-trichlorobenzoyl chloride (1.48 mL, 9.2 mmol) and stirred at ambient temperature for 2 hours. To the solution was added the 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (1.74 g, 8.9 mmol) followed by 4-dimethylaminopyridine (1.1 g, 8.9 mmol) and stirring was continued for 18 hours. The reaction mixture was washed sequentially with saturated sodium bicarbonate and brine. After drying over sodium sulfate, the solution was concentrated to small volume and absorbed onto silica Merck-60. Elution with ethyl acetate-hexane (gradient from 4:3 to 2:1) gave the pure title compound as a syrup which crystallized from diethylether. The white solid (0.78 g) melted at 196-197° C.
Reaction SMILES: [C@@H:1]12[N:7](C(OC(C)(C)C)=O)[C@@H:4]([CH2:5][CH2:6]1)[CH:3]([C:15]([O:17][CH3:18])=[O:16])[CH:2]2[C:19]([O:21][CH3:22])=[O:20].Cl.CCOC(C)=O>CCOC(C)=O>[C@@H:4]12[NH:7][C@@H:1]([CH2:6][CH2:5]1)[CH:2]([C:19]([O:21][CH3:22])=[O:20])[CH:3]2[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1C(C(=O)OC)[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1C(C(=O)OC)[C@H]2CC[C@@H]1N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
(1R,4S)-7-tert-butyl 2,3-dimethyl 7-azabicyclo[2.2.1]heptane-2,3,7-tricarboxylate (XLVIII) (3.28 g, 10.49 mmol) was dissolved in EtOAc (20 mL) and treated with 1M HCl/EtOAc (20 mL) and stirred for 15 minutes at room temperature. The solvent was removed under vacuum and the oily residue triturated with Et2O to give (1R,4S)-dimethyl 7-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (LXIX) as a light pink solid (2.46 g, 9.86 mmol, 94% yield). 1H NMR (DMSO-d6) (two isomers in a 4/1 ratio) δ ppm [1.41-1.53 (m, 2nd isomer), 1.77-1.83 (m, 1st isomer), 2H], [1.63-1.72 (m, 2nd isomer), 1.93-2.02 (m, 1st isomer), 2H], [3.16 (d. J=6 Hz, 2nd isomer), 3.38 (brs, 1st isomer), 2H], [3.57 (s, 1st isomer), 3.62 (s, 2nd isomer), 6H], [4.34 (brs, 1st isomer), 4.40 (d, J=4 Hz, 2nd isomer), 2H], [9.68 (brs, 1st isomer), 9.92 (brs, 2nd isomer, 2H]. ESIMS found for C10H15NO4 m/z 214 (M+H).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH2:12][C@@:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]1[OH:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCCC1.CO>[Br:26][C:22]1[CH:21]=[C:20]([C@:13]2([NH:12][C:10]([NH2:9])=[S:11])[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[OH:19])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(=S)N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Benzoyl isothiocyanate (7.20 g) was added to a suspension of (±)-(3R*,4R*)-4-amino-4-(3-bromophenyl)tetrahydropyran-3-ol (10.9 g) in toluene (200 mL). The mixture was stirred at room temperature overnight and then diluted with tetrahydrofuran, followed by addition of silica gel. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain an intermediate crude product. The resulting intermediate was suspended in methanol (300 mL), and potassium carbonate (20.0 g) was added. The mixture was stirred at room temperature overnight. Then, the insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the resulting solid was removed by filtration through celite. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (8.63 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:9]2[C:8]1=[O:17].C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.CC(C)=O>[C:25]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:9]2[C:8]1=[O:17])(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)Cl
Reactant: O=C1C2CCCCC2C(=O)N1CCOCCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOCCN1C(=O)C2CCCCC2C1=O
Reaction time: 12 h
Yield: 59.5 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 100 g of N-(2-hydroxyethoxyethyl)hexahydrophthalimide (0.41 mol.), 42 g of triethylamine (0.41 mol.), 1 g of phenothiazine and 400 ml of acetone. Next, 38 g of acryloyl chloride (0.41 mol.) was added slowly to the flask via the addition funnel over 45 minutes. The reaction was stirred for an additional 12 hours. The triethylamine hydrochloride salt was removed by filtration and the remaining mother liquor was evaporated with a rotoevaporator. The resulting red-orange liquid was dissolved in chloroform and extracted with HCl(10%), NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was removed with a rotoevaporator to yield 72 g (59%) of an orange-red liquid. The product was confirmed by IR and 13C NMR.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:25][C:26]([O:28][CH2:29]C)=[O:27]>>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[CH:10]([C:9](=[O:21])[NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=1)[O:11][CH3:12]
Reactant: CCOC(=O)CBr
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(O)cccc1F
Product: COC(=O)COc1cccc(F)c1C(OC)C(=O)NCc1ccc(C#N)cc1

Procedure:
In analogy to example 16.4 (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-6-hydroxy-phenyl)-2-methoxy-acetamide (example 80.4) was reacted with ethyl bromoacetate to give (RS)-{2-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-3-fluoro-phenoxy}-acetic acid methyl ester. Yellow oil. MS 387.2 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:28][CH3:29])[C:5]2[N:6]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:30]([O:34][C:35]([N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:30]([O:34][C:35]([N:37]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]([O:28][CH3:29])[C:5]3[N:6]([C:8]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5([NH2:21])[CH2:18][CH2:19][CH2:20]5)=[CH:13][CH:12]=4)[N:10]=3)[CH:7]=2)[CH:39]=[N:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: COc1cc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cc(-c2cnn(C(=O)OC(C)(C)C)c2)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Temperature: 120 °C

Procedure:
A mixture of 1-[4-(6-bromo-8-methoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (120 mg), [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid (170 mg) and potassium phosphate (170 mg) in toluene (0.9 mL), EtOH (1.86 mL) and water (0.93 mL) was placed under argon and bis(tri-tert-butyl phosphine)palladium(0) (13.7 mg) was added. The mixture was heated at 120° C. under microwave irradiation for 30 minutes. On cooling the mixture was partitioned between DCM and water and the phases separated. The organic portion was concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH2:23])[CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH:23][S:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[CH:22]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cn1nc(NS(=O)(=O)c2ccccc2)cc1C(=O)NC1CCCCC1OCc1ccccc1)NC1CCCCC1OCc1ccccc1
Reaction time: 1 h

Procedure:
5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid (2-benzyloxy-cyclohexyl)-amide (40 mg, 0.067 mmol) was dissolved in 1 ml of dry pyridine. Benzenesulfonyl chloride (0.0085 ml) was added and the reaction mixture stirred for 1 hour. The mixture was added to brine and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate, filtered. 29 mg of title compound was obtained after preparative thin layer chromatography using 50% ethyl acetate/hexanes as the eluent. ESI M+1=700.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][NH2:36])[N:30]=[CH:29]1>CO>[NH:28]1[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][NH:36][C:15]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:4]=3)=[O:10])=[CH:21][CH:20]=2)=[NH:19])[N:30]=[CH:29]1
Reactant: NCCCc1c[nH]cn1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: N=C(NCCCc1c[nH]cn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 3-(1H-imidazol-4-yl)propan-1-amine (27 μl, 0.23 mmol) via procedure W to afford 83 mg of 4-(N-(3-(1H-imidazol-4-yl)propyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 459 (M)+.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2.[O:13]1[C@@H:15]([CH3:16])[CH:14]1[N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[N:20]2[CH2:19][CH2:18][N:17]([CH2:14][C@H:15]([OH:13])[CH2:16][S:3][C:4]3[N:12]=[CH:11][N:10]=[C:9]4[C:5]=3[NH:6][CH:7]=[N:8]4)[CH2:22][CH2:21]2)=[CH:25][CH:26]=1
Reactant: Sc1ncnc2nc[nH]c12
Reactant: C[C@@H]1OC1N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@H](CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To NaH (0.56 g, 11.6 mmol, 50% suspension in mineral oil prewashed with pentane) in DMF (12 mL) at 0° C. 6-mercaptopurine (1.97 g, 11.6 mmol) was added in portions over 10 min. (2S)-(-)-(1,2-Epoxypropyl)-4-[bis(4-fluorophenyl)methyl]piperazine (4.0 g, 11.6 mmol) in DMF (10 mL) was added dropwise at 0° C. over a 5 min period. The reaction mixture was allowed to warm to room temperature after an additional 5 min and was stirred for 72 h. DMF was removed in vacuo (1 mm Hg, 55° C.) and the residue was dissolved in CH2Cl2 (100 mL). The solution was filtered through celite, concentrated and the residue was purified by flash chromatography on silica gel using 10% MeOH:CH2Cl2 to give the title compound as a white solid, 1.37 g (23%), mp 118°-120° C. (dec.); DCI/MS (M+1) 497. 400 MHz 1H NMR (CDCl3)δ: 8.65 (s, 1H), 8.2 (s, 1H), 7.35 (m, 4H), 6.98 (m, 4H), 4.2 (s, 1H), 4.18 (m, 1H), 3.65-3.45 (m, 2H), 2.7-2.4 (m, 10H); [δ]D22 +7.3° (0.5% in EtOH).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:30]>O>[CH3:30][C:7]1[CH:8]=[C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:31])=[O:2]
Reactant: COC(=O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Solvent: O
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 3C. mp 140-141° C.; 400 MHz 1H NMR (DMSO-d6) δ 12.95 (br(s), 1H), 7.82 (d, 2H, J=8.4 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.10 (m, 2H), 6.70 (d, 1H, J=8.4 Hz), 4.62 (s, 2H), 4.13 (s, 2H), 2.08 (s, 3H); MS m/z 431 (M−1). Anal. Calc'd for C23H19F3O3S.0.7 H2O C, 62.07; H, 4.62. found: C, 61.98; H, 4.22.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC.C(N(CC)CC)C.[C:23](Cl)(Cl)=[O:24]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[O:15][C:23](=[O:24])[NH:11][C:10]1=[O:14]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccccc2Cl)O1
Reaction time: 1 h
Yield: 68 %

Procedure:
Ethyl 1-(2-chlorophenyl)-1-hydroxymethanecarboximidate hydrochloride (13 g., 52 mmoles) was combined with 350 ml. of tetrahydrofuran and cooled in an ice-water bath. Triethylamine (16.77 g., 0.166 mole) was added and the stirred mixture perfused with phosgene for 45 minutes at 0° C. After an additional 1 hour at the same temperature, the reaction mixture was poured slowly over 1 l. of crushed ice, with isolation and recrystallization from toluene according to Example 3 to yield 5-(2-chlorophenyl)oxazolidine-2,4-dione (7.43 g., 68%; m.p. 106°-108° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([OH:32])[N:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:46]([O:48][C:49]([C:51]1(Br)[CH2:54][CH2:53][CH2:52]1)=[O:50])[CH3:47]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][C:51]3([C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:54][CH2:53][CH2:52]3)[N:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-{(S)-5-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-pentanoyl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 119 mg of cesium carbonate and 76 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with DCM. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM, 0.2 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=O)=[C:4]([NH:11][C:12]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:13])[CH:3]=1.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:9])[N:14]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:12](=[O:13])[NH:11][C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-({[5-bromo-2-(methoxycarbonyl)thiophen-3-yl]carbamoyl}amino)piperidine-1-carboxylate (37.6 g; compound B54a) in dry MeOH (205 ml) under argon atmosphere is added sodium methoxide (6.16 g) at RT. The reaction mixture is refluxed for 3 h, allowed to cool to RT and then poured into a solution of citric acid (21.9 g) in ice cold water (961 ml). The precipitated solid is filtered off, washed with ice cold water and dried in vacuo. The residue is taken up in MeOH (205 ml) and the resulting suspension is refluxed for 1 h. After cooling to RT all solids are filtered off, washed with MeOH and dried in vacuo to afford the title compound as a solid.