Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[C:19]2=[C:20]([N:26]3[CH:30]=[N:29][C:28]([CH3:31])=[N:27]3)[N:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]2[C:17]([C:32](=[O:50])[C:33]([N:35]2[CH2:40][CH2:39][C:38](=[C:41]([C:48]#[N:49])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[CH2:37][CH2:36]2)=[O:34])=[CH:16]1)([O:8]C(C)(C)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)(C(F)(F)F)=O.ClCCl>[P:1]([OH:8])([O:13][CH2:14][N:15]1[C:19]2=[C:20]([N:26]3[CH:30]=[N:29][C:28]([CH3:31])=[N:27]3)[N:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]2[C:17]([C:32](=[O:50])[C:33]([N:35]2[CH2:36][CH2:37][C:38](=[C:41]([C:48]#[N:49])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[CH2:39][CH2:40]2)=[O:34])=[CH:16]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[C:19]2=[C:20]([N:26]3[CH:30]=[N:29][C:28]([CH3:31])=[N:27]3)[N:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]2[C:17]([C:32](=[O:50])[C:33]([N:35]2[CH2:36][CH2:37][C:38](=[C:41]([C:48]#[N:49])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[CH2:39][CH2:40]2)=[O:34])=[CH:16]1)=[O:2]
Reactant: COc1cnc(-n2cnc(C)n2)c2c1c(C(=O)C(=O)N1CCC(=C(C#N)c3ccccn3)CC1)cn2COP(=O)(OC(C)(C)C)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(-n2cnc(C)n2)c2c1c(C(=O)C(=O)N1CCC(=C(C#N)c3ccccn3)CC1)cn2COP(=O)(O)O
Product: COc1cnc(-n2cnc(C)n2)c2c1c(C(=O)C(=O)N1CCC(=C(C#N)c3ccccn3)CC1)cn2COP(=O)(O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Di-tert-butyl (3-(2-(4-(cyano(pyridin-2-yl)methylene)piperidin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl phosphate (IIe) was dissolved in 8 ml of a mixed solution of TFA and dichloromethane (10% TFA/CH2Cl2) and the mixture was stirred for three hours. All the solvents were removed under vacuum and the residue was purified using a Shimadzu automated preparative HPLC System to give 25 mg of tert-butyl (3-(2-(4-(cyano(pyridin-2-yl)methylene)piperidin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl hydrogen phosphate (II′e) and 33 mg of (3-(2-(4-(cyano(pyridin-2-yl)methylene)piperidin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl dihydrogen phosphate (Ie).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:17][CH3:18])=[N:14][C:15]#[N:16])[N:3]=1.[F:19][C:20]([F:26])([F:25])[CH2:21][N:22]=[C:23]=S.[N:27]1C=CC=CC=1>>[F:19][C:20]([F:26])([F:25])[CH2:21][N:22]=[C:23]([NH2:27])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:14][C:15]#[N:16])=[N:17][CH3:18])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: CNC(=NC#N)NCCSCc1nccc(N)n1
Reactant: c1ccncc1
Product: CN=C(NC#N)NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-amino-2-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyrimidine (0.5 g.), 2,2,2-trifluoroethylisothiocyanate (0.55 g.) and pyridine (10 ml.) was heated at 70° for 18 hours and then evaporated to dryness. The residue was dissolved in ethyl acetate and the solution washed with 2N aqueous acetic acid, dried and evaporated to dryness. The residue was dissolved in ethanolic ammonia (15 ml.), treated with yellow mercuric oxide (0.4 g.) and the mixture stirred at room temperature for 4 hours. The mixture was filtered and the filtrate evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[2-(3-cyano-2-methylguanidino)ethylthiomethyl]pyrimidine (0.2 g.) characterised as the hydrogen maleate, m.p. 111°-114° (decomp.) after recrystallisation from acetonitrile.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[N+:17]([C:20]1[CH:38]=[CH:37][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].O>O1CCCC1>[CH2:13]([O:12][C:10]([CH:9]=[C:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:26]([C:24](=[O:25])[C:23]2[CH:37]=[CH:38][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)=[O:11])[CH3:14].[CH2:13]([O:12][C:10]([CH2:9][C:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:26]([C:24](=[O:25])[C:23]2[CH:37]=[CH:38][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH:29]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Product: CCOC(=O)CC1=CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl diethylphosphonoacetate (6.10 g) in tetrahydrofuran (50 ml) was added sodium hydride (60% in oil, 599 mg) and the solution was stirred at ambient temperature for 30 minutes. To the solution was added a solution of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro -1H-1-benzazepine (3.10 g) in tetrahydrofuran (10 ml) dropwise and the mixture was stirred at ambient temperature for 5 hours. The solution was poured into water and the aqueous solution was extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the crude product was purified by silica gel column (100 g, 1% methanol in chloroform) to give 5-ethoxycarbonylmethylene-1-(4-nitrobenzoyl) -2,3,4,5-tetrahydro-1H-1-benzazepine (689 mg) and 5-ethoxycarbonylmethyl-1-(4-nitrobenzoyl)-2,3-dihydro -1H-1-benzazepine (905 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:29](O)=[O:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:29]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:3]=1)=[O:30]
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)CCc1ccccc1Cl
Product: Cn1cc(C(=O)c2cncc(NC(=O)CCc3ccccc3Cl)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described above for Example 167 starting from (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 110) and 3-(2-chlorophenyl)propanoic acid.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH:9]([O:12][C:13]1[N:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1)([CH3:11])[CH3:10]>CC(C)=O.C(OCC)C>[CH:9]([O:12][C:13]1[N:18]=[CH:17][C:16]([OH:2])=[CH:15][N:14]=1)([CH3:11])[CH3:10]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)Oc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
An aqueous solution (5 mL) of potassium peroxymonosulfate (1.40 g, 2.27 mmol) was added dropwise to a solution of 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Preparation 100, 500 mg, 1.89 mmol) in acetone (5 ml) under a nitrogen atmosphere at 0° C. The mixture was stirred at room temperature for 2 hours, then filtered, the filtrate diluted with water (30 mL) and extracted with EtOAc (1×20 mL). The organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The resulting oil was dissolved in dichloromethane and purified by silica gel chromatography eluting with 0 to 5% MeOH (with 10% aqueous ammonia) in dichloromethane to yield a solid. The solid was suspended in diethyl ether and evaporated to yield the title compound as a white solid (100 mg, 34%):
Reaction SMILES: ClC1C=C(OC)C=CC=1N1C(C)=C(C(N[C:19]2[C:20](=[O:32])N(C3CCCCC3)N(C)[C:23]=2[CH3:24])=O)N=N1.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[N+:34]=[N-:35].CC([O:47]C)(C)C>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([N:33]2[C:23]([CH3:24])=[C:19]([C:20]([OH:32])=[O:47])[N:35]=[N:34]2)=[CH:37][CH:38]=1
Reactant: COC(C)(C)C
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1
Reactant: COc1ccc(-n2nnc(C(=O)Nc3c(C)n(C)n(C4CCCCC4)c3=O)c2C)c(Cl)c1
Product: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared analogously to 1-(2-chloro-4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Example 1 step 2) by replacing 1-azido-2-chloro-4-methoxybenzene with 1-azido-4-chlorobenzene in (0.5 M in TBME).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:7]=1[C:8]([NH:10][C:11]1[C:19]2[O:18][C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:9].O>C(O)(=O)C>[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:7]=1[C:8]([NH:10][C:11]1[C:19]2[O:18][C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:14]=[CH:13][C:12]=1[N+:1]([O-:4])=[O:2])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1cccc2c3c(oc12)CCCC3)c1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1c([N+](=O)[O-])ccc2c3c(oc12)CCCC3)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Nitric acid (d; 1.5, 0.033 ml) was added to a solution of 6-(2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (200 mg) in acetic acid at 4° C. The mixture was stirred at ambient temperature for 5 hours and poured into cold water. The separated solid was collected and washed with isopropyl alcohol to give 6-(2,6-dichlorobenzoylamino)-7-nitro-1,2,3,4-tetrahydrodibenzofuran (17 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[O:19]=[C:7]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CSCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)N1CCSCC1

Procedure:
Example 1 was repeated using thiomorpholine in place of morpholine with dodecanoyl chloride to obtain N-(1-oxododecyl)thiomorpholine.
Reaction SMILES: [S:1](Cl)([N:4]=C=O)(=[O:3])=[O:2].CC(O)(C)C.[NH2:13][C@@H:14]([CH2:25][C:26]1[O:27][C:28]([CH2:31][C:32]2[S:33][C:34]3[CH:40]=[C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:38]=[CH:37][C:35]=3[N:36]=2)=[N:29][N:30]=1)[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl>[C:41]1([C:39]2[CH:38]=[CH:37][C:35]3[N:36]=[C:32]([CH2:31][C:28]4[O:27][C:26]([CH2:25][C@H:14]([NH:13][S:1](=[O:3])(=[O:2])[NH2:4])[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:16])=[N:30][N:29]=4)[S:33][C:34]=3[CH:40]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: NS(=O)(=O)N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a solution of Compound 45a (460 mg, 0.81 mmol) in DCM (5 mL) was added TFA (5 mL) and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with toluene (3×) and DCM, then dried under high vacuum to give (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 100% yield) as a yellow solid. LCMS=1.90 min using analytical method (B), 471.0 (M+H). In a separate flask, to a solution of sulfurisocyanatidic chloride (170 mg, 1.2 mmol) in DCM (2 mL) was added 2-methylpropan-2-ol (90 mg, 1.2 mmol) in DCM (2 mL) and the reaction mixture stirred for 20 min. The resulting solution was then added to a mixture of (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 0.81 mmol) and TEA (0.56 mL, 4.0 mmol) in DCM (5 mL) and the reaction mixture stirred for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with 1 N HCl solution and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (6 mL) and treated with TFA (3 mL) then stirred for 1 h. The mixture was concentrated under reduced pressure, co-evaporated under reduced pressure with toluene and DCM, and the residue purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give Compound 45b (380 mg, 86% yield) as a yellow solid. LCMS=2.00 min using analytical method (B), 550.2 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.15-8.08 (m, 1H), 8.06-8.00 (m, 1H), 7.76-7.70 (m, 1H), 7.66-7.58 (m, 2H), 7.50-7.44 (m, 2H), 7.42-7.27 (m, 7H), 5.65-5.58 (m, 1H), 5.23-5.19 (m, 1H), 5.16-5.09 (m, 2H), 4.73-4.61 (m, 3H), 3.53-3.30 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:13]([C:14](=[O:18])[NH:15][C:16]=2[CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:13]([C:14](=[O:18])[NH:15][C:16]=2[CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c2ccccc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)[nH]c(=O)c1ccccc12
Reaction time: 2 h
Yield: 126.8 %

Procedure:
A mixture of 3-nitro-6(5H)-phenanthridinone (structure 55 of Scheme XVI, where R1 =H, R2 =R3 =benzo, Z=NH) (480 mg, 1.5 mmol) and 50 mg of 10% Pd/C in 60 mL of DMF was stirred under an atmosphere of H2 for 2 h. The mixture was filtered through a Celite™ pad and the filtrate was concentrated to give 0.4 g of the crude aniline as a yellow solid. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15])=[O:4].[C:16](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH3:16])[C:6]=1[CH3:15])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(C)[nH]c2cc(Cl)ccc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C)n(C)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of 6-chloro-2-methyl-1H-indole-3-carboxylic acid methyl ester (2.76 g, 12.3 mmol), potassium carbonate (6.80 g, 49.2 mmol), iodomethane (1.07 mL, 17.2 mmol) and DMF (36 mL) is stirred overnight at room temperature. The mixture is diluted with ethyl acetate, washed twice with water, washed with brine and dried (MgSO4) and concentrated. The residue is triturated in 25 mL of 1:3 ethyl acetate-heptane and filtered to provide 1.63 g (55%) of pure title product. Additional material can be obtained through further trituration of the mother liquor. ES/MS m/e 238.0 (M+1).
Reaction SMILES: N#N.Br[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])O1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: N#CCc1ccc(Br)s1
Agent: [Pd]
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: N#CCc1ccc(-c2ccccc2N)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
(The following reaction is done in an oxygenfree N2 atmosphere.) Dissolve tetrakis-(triphenylphosphine)-palladium(0) (29 mg, 2.5 mol %) and nitrile (83) (101 mg, 0.50 mmol) in DME (3.7 mL). The reaction mixture is degassed 5 times and flooded with N2 again. Add 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (84) (120 mg, 0.55 mmol), rinse with DME (0.5 mL), add aqu. 1M NaHCO3, degas again (5 times) and stir the reaction solution 2 h at 90° C. (reflux). After cooling to rt partition the reaction mixture between EtOAc and brine (1+1) and extract the separated aqueous layer 3 times with EtOAc. Wash combined organic layer with brine and dry with Na2SO4. Remove solvent under reduced pressure and purify the crude product by preparative radial chromatography (silica gel 60 PF, CyH/EtOAc 2+1) to obtain [5-(2-amino-phenyl)-thiophen-2-yl]-acetonitrile (85) as a brownish oil (84 mg, 78%). 1H NMR (400 MHz, CDCl3): 3.89 (br.s, 2H); 5.20-6.50 (br.s, 2H); 6.92 (t, 1H; J=7.6 Hz); 6.95-7.00 (m, 1H); 6.99 (d, 1H; J=3.8 Hz); 7.11 (d, 1H; J=3.8 Hz); 7.21 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz); 7.27 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz).
Reaction SMILES: [CH:1]1([CH:6]([OH:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:12][C@H:13]([C:15]([C:17]1([NH2:38])[C:23](=[O:24])[N:22]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:18]1=[O:37])=[O:16])[CH3:14]>>[CH:1]1([CH:6]([OH:10])[C:7]([NH:12][C@H:13]([C:15]([C:17]2([NH2:38])[C:23](=[O:24])[N:22]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:18]2=[O:37])=[O:16])[CH3:14])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(O)C1CCCC1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentyl-α-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by L.C. 2000 eluting with CH2Cl2/EtOAc (1:1 gradient to 1:2) then flash chromatography eluting with 2:1 EtOAc/CH2Cl2. Rf=0.47 and 0.37 (CH2Cl2/EtOAc, 1:2).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(Cl)Cl.OS(O)(=O)=O.[Br:22]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[Br:22][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.6 %

Procedure:
To a solution of 4-trifluoromethoxybenzaldehyde (215 g, 1.13 mol) in a mixture of TFA (300 mL), CH2Cl2 (300 mL) and H2SO4 (150 mL) was added at room temperature N-bromosuccinimide (402 g, 2.26 mol) in equal portion over 7 hours. The reaction mixture was stirred for 4 days at room temperature, poured into ice-water and extracted with CH2Cl2. The organic layer was washed with water then treated with saturated NaHCO3 (1.5 L) for 2 hrs. The layers were separated and the organic layer further washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and filtered. After evaporation of the solvent, the residue was distilled to give 3-bromo-4-trifluoromethoxybenzaldehyde (190.2 g, 81° C., 1.0 mm/Hg, 62%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N:19]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[C:33]5[C:38]=4[N:37]=[CH:36][CH:35]=[CH:34]5)(=[O:28])=[O:27])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][N:14]3[CH:39]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N:19]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[C:33]5[C:38]=4[N:37]=[CH:36][CH:35]=[CH:34]5)(=[O:27])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][N:14]3[CH:39]=2)=[CH:5][CH:4]=1)(=[NH:45])[NH2:2]
Reactant: CCOC(=O)CN(c1ccc2nc(CNc3ccc(C#N)cc3)cn2c1)S(=O)(=O)c1cccc2cccnc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2nc(CNc3ccc(C(=N)N)cc3)cn2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 2-[N-(4-cyanophenyl)-aminomethyl]-6-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-imidazo[1,2-a]pyridine and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[CH:9]=1)=[O:4].[H-].[Na+].I[CH3:28]>O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:28])[CH:7]=[C:8]([C:10]([C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[CH:9]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1cc(C(=O)c2c(-c3ccc(Br)cc3)noc2C)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(-c3ccc(Br)cc3)noc2C)cn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A mixture of 212 mg (0.5 mmol) 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-1H-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 28 mg (0.66 mmol) NaH and 116 mg (0.65 mmol) iodomethane was stirred at room temperature for 24 h. The mixture was then diluted with water and the product extracted with ethyl acetate. The combined organic extracts were then dried with Na2SO4 and evaporated to yield 133 mg (61%) of the title compound as a light yellow solid after purification by chromatography on silica gel eluting with ethyl acetate/heptane. (m/e): 403.3/405.2 (M+H, 100%).
Reaction SMILES: [F:1][C:2]([F:18])([S:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].ClC1C=CC=C(C(OO)=O)C=1.[OH2:30].[OH2:31].O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>C(Cl)Cl>[F:18][C:2]([F:1])([S:13]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:31])=[O:30])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O
Reactant: OCCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCCO)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 93.1 %

Procedure:
3-(Perfluorobutylthio)propanol (8.60 g, 27.6 mmol) prepared in Synthetic Example 1 was dissolved in methylene chloride (80 ml), and m-chloroperbenzoic acid (m-CPBA) (52 g, 232 mmol) was added at room temperature in two portions with stirring, the reaction vessel being equipped with a calcium chloride tube. The mixture was stirred at room temperature for 7 days. The reaction mixture was injected into a mixture of sodium thiosulfate pentahydrate (130 g) and water (200 ml), and stirred for 1 hour. Methylene chloride (100 mL) was added and an organic layer was removed and an aqueous layer was extracted with methylene chloride (50 ml). Organic layers were joined, washed with a 5% aqueous sodium hydrogen carbonate and with a saturated saline solution, and then dried over sodium sulfate. A filtrate after filtration was concentrated under reduced pressure. A residue was subjected to a silica gel column chromatography (eluting solvent:hexane-ethyl acetate (2/1)), and fractions having Rf value of 0.32 [Rf value (Thin Layer Chromatography (TLC))=(Migration distance of sample)/(Migration distance of eluting solvent)] were gathered, concentrated under reduced pressure and dried under vacuum to give crystalline 3-(perfluorobutylsulfonyl)propanol (8.79 g). Yield: 91.8%.
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH3:3]>C1COCC1.C(OCC)(=O)C>[CH2:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:1])(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])=[C:6]([O:22][CH3:23])[CH:5]=1)[CH3:3]
Reactant: N
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2F)c(OC)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(N)(=O)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
Conc. NH3 (5.0 mmol; 0.28 mL) was slowly added to a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride (1.0 mmol; 344 mg) in THF (5 mL), under argon at 0° C. The reaction was stirred overnight with slow warming to room temperature. Diluted with ethyl acetate (5 mL), the mixture was washed with HCl (1N), and sat. NH4Cl. The organic phase was dried over MgSO4, concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate gradient) to yield the title compound as an off-white solid (108 mg; 0.33 mmol; 33%).