Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([NH:14]C(=O)C(F)(F)F)[CH:11]=[CH:10][C:9]=1[S:21](Cl)(=[O:23])=[O:22])(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>C(#N)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([S:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)(=[O:22])=[O:23])=[C:8]([CH2:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])[CH:13]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CCCS(=O)(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCS(=O)(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
To a stirred solution of 2-(propylsulfonylmethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (700 mg, 1.7 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (384 mg, 2.58 mmol) in 10 mL of ACN was added pyridine (278 uL, 3.4 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. A solution of this crude compound in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 4 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as an off-white solid (428 mg, yield 59%). MS calcd for (C17H21BN2O6S2): 424.3. MS found (ESI negative): (M−H)−=423.1. 1H NMR (DMSO-d6) δ (ppm): 9.88 (s, 1H), 9.20 (bs, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.73 (s, 1H), 6.47 (d, J=8.4 Hz, 1H), 4.86 (s, 2H), 4.69 (s, 2H), 2.97 (t, 2H), 1.61 (m, 2H), 0.89 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCCC2)CC1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (93%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][N:16]([CH3:29])[S:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([S:17]([N:16]([CH3:15])[CH3:29])(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(C)S(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 4-[(dimethylamino)sulfonyl]benzoic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(dimethylamino)sulfonyl]-benzamide. MS (Q1) 416.0 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[CH:11]=1
Reactant: BrBr
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cc(Br)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00323 mol) in chloroform is cooled, treated with a solution of bromine (0.52 g, 0.00323 mol) in chloroform, stirred at room temperature overnight, diluted with chloroform, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark syrup. Flash chromatography of the syrup using silical gel and a 1:5 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.31 g, mp 73°-760° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11]O)=[CH:7][CH:6]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.O>C(OCC)C>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][Cl:29])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(CCl)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Yield: 78.7 %

Procedure:
3.0 g of β-[4-(2,4-Dichlorophenoxy)phenoxy]propanol and 1.1 g of pyridine were dissolved in 50 ml of anhydrous diethyl ether, and 1.5 g of thionyl chloride was added dropwise to the solution while cooling. The mixture was then heated for 1 hour while refluxing. The reaction mixture was poured into an appropriate amount of water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was removed by distillation and the residue was distilled under reduced pressure to obtain 2.5 g of the desired product having a boiling point of 192° to 194° C./2 mmHg.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH:38]1(N2C3C(O[C@@H]([C@H]4CNC(=O)C4)C)=NC(C4C=CC(N5CCNCC5)=CC=4)=CC=3N=C2)CC1.C(S(Cl)(=O)=O)C>>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH2:28][CH3:38])(=[O:26])=[O:27])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCN(c2ccc(-c3cc4ncn(C5CC5)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1

Procedure:
Following the procedure described for intermediate 3.45, starting from (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (100 mg, 0.22 mmol) and ethanesulfonyl chloride (0.02 ml, 0.25 mmol), to provide 49.3 mg of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:42]=[CH:41][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[Li+].[OH-].O.Cl>C1COCC1.CO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:42]=[CH:41][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)CCNC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 7a (0.20 g, 0.36 mmol) was suspended in THF/MeOH (4:1 v/v, 5 mL), and treated with 1 N LiOH solution (2.0 mL). The resulting mixture was stirred at rt for 3 h, and treated with water. The pH of the mixture was adjusted to ca. pH 5 using 1 N HCl solution. The resulting mixture was extracted with DCM (2×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue obtained was washed with MeOH, and dried under high vacuum to give the title compound 44 as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.14 (d, J=8.6 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.97-8.03 (m, 3H), 7.94 (d, J=15.6 Hz, 1H), 7.76-7.86 (m, 3H), 7.64-7.76 (m, 3H), 7.46-7.55 (m, 1H), 6.15 (d, J=5.6 Hz, 1H), 4.08 (d, J=3.4 Hz, 4H), 4.01 (d, J=3.4 Hz, 4H), 3.74 (t, J=5.9 Hz, 2H), 2.70 (t, J=5.9 Hz, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H28N6O4: 549.2 (M+H). Found 549.2.
Reaction SMILES: C1(C2C=CC=CC=2CO)C2C(=CC=CC=2)C=CC=1.[CH3:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.[BH4-].[Na+]>>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[OH:25])=[CH:33][CH:34]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: OCc1ccccc1-c1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc(C(O)c2ccc(C)cc2)cc1

Procedure:
With the same method as for Compound 13, 4,4′-dimethylbenzophenone (Wako Pure Chemical Industries, Ltd.) and sodium borohydride (Wako Pure Chemical Industries, Ltd.) were used, to thereby obtain the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][CH2:36][NH2:37]>>[CH2:5]([C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:2]([OH:1])[CH2:3][NH:37][CH2:36][CH2:35][CH2:34][C:28]1[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(CCCN)c(C)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(CCCNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c(C)c1

Procedure:
A stirred mixture of tert-butyl (1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V, 247 mg, 0.939 mmol), sodium carbonate (299 mg, 2.82 mmol), and 3-(2,4-dimethylphenyl)propylamine (VI, 628 mg, 2.82 mmol) is heated at reflux overnight. The reaction mixture is cooled to 20–25 degrees C. and concentrated under reduced pressure. Purification by flash column chromatography (silica; methylene chloride/methanol/ammonium hydroxide, 98/2/1) gives tert-butyl (1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropylcarbamate (VII), NMR (300 MHz, CD3OD): δ 7.22–7.16, 3.81, 3.18, 2.77, 2.54, 2.15, 2.13, 1.89 and 1.23.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](=[S:41])[NH2:40]>CC(N(C)C)=O.CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:41][C:39]([C:38]([CH3:43])([CH3:42])[CH3:37])=[N:40][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a solution of N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (1.0 g, 2.4 mmol) in 25 mL DMA, NBS (0.420 g, 2.4 mmol) was added and the solution was allowed to stir 15 minutes at rt. 2,2-Dimethylpropanethioamide (0.277 g, 2.359 mmol) was then added and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with water×3. The organic layer was dried over MgSO4 and filtered. The organic solution was evaporated onto silica gel and chromatographed. 0-50% EtOAc in DCM to give the title compound (1.01 g, 81% yield). ES-LCMS m/z 521.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:44])[C:10]1[CH:11]=[C:12]([CH:41]=[CH:42][CH:43]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:40])=[C:20]([NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH:25]=2)[CH:21]=1)=[O:14]>C(Cl)Cl>[CH3:44][N:9]([CH3:8])[C:10]1[CH:11]=[C:12]([CH:41]=[CH:42][CH:43]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:40])=[C:20]([NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([OH:34])=[O:33])[CH:25]=2)[CH:21]=1)=[O:14].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (10 ml) was added to a stirred solution of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-tert-butoxycarbonylmethoxybenzamide (0.5 g) in methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was azeotroped with toluene. The resultant gum was triturated under diethyl ether. The solid so obtained was isolated and dried under vacuum at 60° C. There was thus obtained the title compound as its trifluoroacetic acid salt (0.39 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.93 (s, 6H), 4.76 (s, 2H), 6.93 (m, 1H), 7.13 (m, 1H), 7.23 (m, 3H), 7.3 (t, 1H), 7.43 (t, 1H), 7.51 (d, 1H), 7.59 (d, 2H), 7.78 (d, 1H), 9.88 (br s, 1H), 10.1 (br s, 1H); Mass Spectrum: M−H− 446.
Reaction SMILES: [N:1]1([C:51](OC(C)(C)C)=O)[CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-Phe-PheNHNH2 (Example 1, 1.09 g.) and HGly-Leu-NleNH2 (0.70 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-Leu-NleNH2 in 69% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Leu-NleNH2 (1.0 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Leu-NleNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 65% yield.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.[Cl:10][C:11]1[S:12][CH:13]=[C:14]([Cl:19])[C:15]=1[N:16]=[C:17]=[S:18].C(N(C(C)C)C(C)C)C>C1COCC1>[NH2:9][C:8]1[C:4]([NH:3][C:17]([NH:16][C:15]2[C:14]([Cl:19])=[CH:13][S:12][C:11]=2[Cl:10])=[S:18])=[CH:5][S:6][CH:7]=1
Reactant: S=C=Nc1c(Cl)csc1Cl
Reactant: Nc1cscc1N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cscc1NC(=S)Nc1c(Cl)csc1Cl

Procedure:
was obtained in a similar manner to the method described in Example 5e by reacting 0.84 g of 3,4-diaminothiophene dihydrobromide with 0.8 g of 2,4-dichloro-3-thienyl isothiocyanate and 0.49 g of N-ethyl-N,N-diisopropylamine in THF. Crystalline product. M.p. 110–115° C.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][OH:14])(=[O:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:4][CH:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])(=[O:3])[CH3:2]
Reactant: CCCCCCCCC(/C=C/C=C/c1cccc(CO)c1)OC(C)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCCCCC(/C=C/C=C/c1cccc(C=O)c1)OC(C)=O
Temperature: 24 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
11 g of manganese dioxide is added to a solution of 1.5 g of the above-produced benzyl alcohol in 30 ml of methylene chloride and stirred for 3 hours at 24° C. Then, it is filtered, washed with methylene chloride and concentrated by evaporation in a vacuum. 1.3 g of 3-[(1E,3E)-5-acetoxy-1,3-tridecadienyl]-benzaldehyde is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:11])([CH3:10])[CH3:9].Cl[C:13]1[N:18]=[C:17]([S:19][C:20]#[N:21])[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:11][C:13]1[N:18]=[C:17]([S:19][C:20]#[N:21])[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][N:14]=1)([CH3:9])[CH3:10]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(C)(N)c1ccccc1Cl
Product: CC(C)(Nc1ncc([N+](=O)[O-])c(SC#N)n1)c1ccccc1Cl

Procedure:
[1-(2-Chlorophenyl)-1-methyl-ethyl]-(5-nitro-4-thiocyanato-pyrimidin-2-yl)-amine was prepared by addition of the above amine to 2-chloro-5-nitro-4-thiocyanato-pyrimidine using the procedure described in Example 17. m/z calcd. C14H11N5O2S [M−H]−: 348.79. Found: 348.05.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:6]=1.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([Br:29])=[C:5]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCN(c1cccc(-c2csc(N)n2)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: ClCCl
Product: COCN(c1cccc(-c2nc(N)sc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
1.26 g (2.94 mmol) of N-[3-(2-amino-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)-benzenesulfonamide were dissolved in 30 ml of dry DCM and 523 mg (2.94 mmol) of N-bromosuccinimide were added. The resulting solution was stirred at r.t. for 30 min. The mixture was diluted with the same solvent and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with diisopropyl ether and filtered to afford 1.4 g (93%) of the title compound.
Reaction SMILES: F[B-](F)(F)F.ClC1C=CC=C[N+]=1CC.O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C(N(CC)CC)C>C(#N)C>[CH2:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[O:32][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: CC[n+]1ccccc1Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 75 %

Procedure:
To a refluxing solution of 460 mg (2.0 mmol) of 2-chloro-1-ethylpyridinium tetrafluoroborate in 50 ml of acetonitrile, there was added a solution of 134 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15-pentadecanolide was obtained in 75% yield.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:23]=[CH:22][C:7]([NH:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)[C:10]#N)=[CH:6][CH:5]=1)[CH3:2].O=[CH:25][C:26](=C)[CH3:27]>>[CH2:1]([S:3][C:4]1[CH:23]=[CH:22][C:7]([N:8]2[CH:25]=[C:26]([CH3:27])[CH:10]=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=C(C)C=O
Product: CCSc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-ethylthioanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 69%), melting at 139-141° C.
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1>[CH3:56][N:55]([CH3:57])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in Ch2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).