Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][S:12]3)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][S:12]3=[O:31])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc3n(c2-c2ccncc2)CCS3)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc3n(c2-c2ccncc2)CCS3=O)cc1
Yield: 63.4 %

Procedure:
To 2.4 g of 6-(4-methoxyphenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole in 200 ml methylene chloride was added 1.34 g of m-chloroperbenzoic acid in 150 ml of methylene chloride at ice-bath temperature. After 10 minutes the reaction mixture was diluted with methylene chloride and washed twice with 100 ml of 5 N sodium carbonate. Evaporation of the dried extracts left a solid which when recrystallized from chloroform-ether gave 1.6 g of the title product, m.p. 165°-170°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[F:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>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.CN(C=O)C>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH:16]=[N:15][CH:14]=1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: Nc1c(-c2cncc(F)c2)cncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 73.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (790 mg, 3.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LXX) (1.01 g, 4.35 mmol), K3PO4 (1.15 g, 5.44 mmol), water (10 mL) and DMF (10 mL) was degassed with argon thrice. Pd(PPh3)4 (209 mg, 0.18 mmol) was added to the reaction and the solution was heated at 90° C. for 4 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→1.5:98.5 MeOH[7N NH3]:CHCl3) to give 5′-fluoro-5-nitro-3,3′-bipyridin-4-amine (LXXI) as a yellow solid (626 mg, 2.67 mmol, 74% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.62 (brs, 2H), 7.86-7.89 (m, 1H), 8.15 (s, 1H), 8.47-8.48 (m, 1H), 8.67 (d, J=2.7 Hz, 1H), 9.07 (s, 1H); ESIMS found C10H7FN4O2 m/z 235 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](F)[C:3]=1[Cl:10].[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:12][CH3:11])[C:3]=1[Cl:10]
Reactant: Fc1cc(Cl)cc(Br)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc(Br)c1Cl
Temperature: 25 °C
Yield: 97.7 %

Procedure:
1-Bromo-2,5-dichloro-3-fluorobenzene (40 g, 160 mmol) and sodium methoxide (44.3 g, 820 mmol) were stirred in methanol (500 ml) at reflux for 16 hours. The reaction was cooled to ambient temperature then quenched with water (500 ml). The mixture was extracted with diethyl ether (3×300 ml), dried over Na2SO4 and evaporated to afford the title compound as a white solid (40 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[O:23][C:22]([C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)=[O:25])=[N:21][N:20]=1.C(N(CC)CC)C>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[O:23][C:22]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:35][CH2:34]3)=[N:29][CH:28]=2)=[O:25])=[N:21][N:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(C(=O)Oc3ccccc3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 2 h
Yield: 30.6 %

Procedure:
Phenyl chloroformate (0.036 mL, 0.29 mmol) was added to a mixture of 5-[(2-fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41, 100 mg, 0.26 mmol) and triethylamine (0.07 mL, 0.52 mmol) in DMF (1.5 mL). The mixture was stirred for 2 h then directly purified by reverse phase HPLC eluting with a gradient of acetonitrile/water containing 0.2% TFA to give the title compound (40 mg, 31%) as a solid; 1H NMR δ 10.95 (1H, s), 10.73 (1H, s), 8.50 (1H, s), 8.05-7.95 (2H, m), 7.45-7.10 (8H, m), 6.90 (1H, d), 3.80-3.60 (8H, m); MS m/e MH+ 504.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].O.[NH3:13]>C(#N)C>[NH2:13][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1c(F)ccc(F)c1F
Solvent: O
Solvent: CC#N
Product: N#Cc1c(F)ccc(F)c1N

Procedure:
2,3,6-Trifluorobenzonitrile (1.76 ml, 15.2 mmol) in aqueous ammonia (20 ml) and acetonitrile (10 ml) was stirred for 7 days. Water was added. The whole was extracted with ether, the ether was dried (sodium sulphate) and evaporated. Flash column chromatography on silica gel, eluting with dichloromethane, gave the product (1.2 g), MS (+EI) 154 (M+), 1H NMR (CDCl3) 7.07-7.16 (1H, m), 6.36-6.43 (1H, m), 4.62 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[Br:18]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Cl:17][C:6]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][C:14]=2[Br:18])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1cccc(Oc2c(Cl)ncnc2Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Br)c(Oc2c(Cl)ncnc2Cl)c1

Procedure:
By brominating 4,6-dichloro-5-(3-methoxyphenoxy)-pyrimidine with N-bromosuccinimide in acetic acid/acetic anhydride at 100° C. there was obtained 4,6-dichloro-5-(2-bromo-5-methoxyphenoxy)pyrimidine; therefrom with p-tert-benzenesulfonamide K there was obtained N-[5-(2-bromo-5-methoxyphenoxy)-6-chloropyrimidin-4-yl]-4-tert-butyl -benzenesulfonamide and therefrom with Na ethylene glycolate there was obtained p-tert-butyl-N-[5-(2-bromo-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-benzenesulfonamide.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)[N:17]=2)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CS(C)=O>[C:25]1([CH3:29])[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:18]2[N:17]=[C:16]([C:14]3[S:15][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:12][CH:13]=3)[CH:21]=[CH:20][N:19]=2)[CH:24]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2nccc(-c3ccc(NC(=O)c4ccccc4)s3)n2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
Benzoic acid (5.2 mg, 0.042 mmol), [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (10 mg, 0.035 mmol), DMAP (4.2 mg, 0.035 mmol) and HATU (15.9 mg, 0.042 mmol) were combined in 400 uL DMF and the solution was heated on a hot plate in a capped vial at 70° C. After 16 hours, the mixture was diluted with DMSO and prep purified to afford N-[5-(2-m-tolylamino-pyrimidin-4-yl)-thiophene-2-yl]-benzamide (3.0 mg, 22%). 1H NMR (500 MHz, DMSO-d6) δ 1.29 (s, 3H), 6.70 (d, J=7.5 Hz, 1H), 6.93 (d, J=4 Hz, 1H), 7.10 (t, J=8 Hz, 1H), 7.16 (d, J=5.5 Hz. 1H), 7.47 (d, J=7.5 Hz, 1H), 7.51 (m, 2H), 7.58 (m, 1H), 7.74 (d, J=4 Hz, 1H), 7.78 (s, 1H), 7.95 (m, 2H), 8.31 (d, J=5.5 Hz, 1H), 9.42 (s, 1H). MS: m/z 387 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:32]6[N:33]=[CH:34][CH:35]=[CH:36][N:31]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: NC1(c2ncccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.041 g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0.086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylehtylamine (0.16 g, 1.3 mmol). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.33-1.36 (m, 2H), 1.59-1.61 (m, 2H), 2.31 (s, 3H), 2.82-2.83 (d, 3H, J=4.8 Hz), 7.26-7.29 (t, 1H, J=4.8 Hz), 7.39-7.45 (m, 4H), 7.59 (s, 1H), 7.76-7.78 (d, 1H, J=8.4 Hz), 7.86-7.87 (d, 2H, J=4.4 Hz), 7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 8.67-8.68 (d, 2H, J=4.8 Hz), 9.20 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:29]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
Methyl 4-aminobenzoate (Aldrich, 5.0 g, 33 mmol) was dissolved in 120 mL of anhydrous methylene chloride containing pyridine (3.2 mL, 39.6 mmol) and dimethylaminopyridine (DMAP, 500 mg) was added. To the ice-cooled mixture was added methyl chloroformate (2.80 mL, 36.3 mmol) while stirring. The stirring was continued for 16 h at room temperature. The reaction was quenched with water (50 mL) and the organic layer separated. The aqueous layer was extracted with chloroform (50 mL). The combined organic extract was dried over sodium sulfate. The volatiles were evaporated on a rotoevaporator to give a residue, which was crystallized from chloroform-methanol. The white solid was separated, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 4.95 g (71.7%) of methyl 4-(methoxycarbonyl)aminobenzoate, mp 177°-178° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16](C1C=CC(OC)=C2C=1C=CN2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Reactant: Brc1cccc2[nH]ncc12
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]ncc12

Procedure:
3-(1H-Indazol-4-yl)-3-phenyl-acrylic acid ethyl ester CXCI was prepared from using 4-bromo-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.O>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: OCc1nccs1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2nccs2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
2-(2-Chloro-4-nitro-phenoxymethyl) thiazole is prepared by adding thiazol-2-yl-methanol (2.74 g, 23.76 mmol) to a slurry of sodium hydride (1.21 g of a 60% dispersion in oil, 30.2 mmol) in DMF (10 ml) at 0° C. After several minutes, 2-chloro-1-fluoro-4-nitro-benzene (3.79 g, 21.60 mmol) is added and the reaction mixture warmed to room temperature. The reaction mixture is stirred at room temperature for 3 h, and 60° C. for 16 h. After cooling to room temperature, the reaction mixture is poured into 200 ml water. The resulting precipitate is collected by filtration, washed with water, and dried in vacuo to give 2-(2-chloro-4-nitro-phenoxymethyl)-thiazole (5.80 g, 99%) which is used without further purification.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]2)[CH2:2]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH2:2]1[C:3]2([CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)NC1CCC2(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC2(CC1)CC2
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Compound 7-3 (1.5 g, 6.7 mmol) was dissolved in 15 mL of DCM and TFA (2.5 mL) was added and stirred for 1 hour to give Compound 7-4 (1.6 g, 99.8% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:23]C(OCC1C=CC=CC=1)=O)[CH:9]([OH:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:34])[CH2:7][C@H:8]([NH2:23])[CH:9]([OH:22])[CH2:10][O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(O)COc1c(F)c(F)cc(F)c1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
10% Pd on carbon (2.92 g) was added portionwise to a solution of 3-benzyloxycarbonylamino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (14.6 g) in anhydrous MeOH (350 mL) which had been degassed under nitrogen (5×). The reaction was further degassed under nitrogen (3×) and hydrogen (5×) and stirred at room temperature for 20 minutes. The palladium catalyst was removed by filtration and the filtrate concentrated to give the sub-titled compound as a white solid (9.5 g, 90%). 1H NMR (400 MHz, CDCl3) δ 1.49 (9H, s), 2.35-2.43 (1H, m), 5.67-5.64 (1H, m), 3.37-3.43 (1H, m), 3.77-3.87 (1H, m), 4.28-4.63 (2H, m), 6.77-6.86 (1H, m) ppm; 19F NMR (346 MHz, CDCl3) (proton decoupled) δ −139.95, −139.97, −140.00, −140.03, −140.05, −140.08, −140.11, −140.13, −157.15, −157.18, −157.21, −157.23, −157.27, −157.29.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])[N:34]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Oc3ccccc3)c2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc(Oc4ccccc4)c3)cc2=O)n1
Yield: 48 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(3-phenoxy-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 49) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(3-phenoxy-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (0.63 g, 48%); ES+-HRMS m/e calcd for C31H35N5O5 [M+H+] 558.2711 found 558.2706. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.24-0-1.77 (m, 8H), 1.91 (m, 1H), 2.27 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.46 (dd, J=4.4, J=11.0 Hz, 1H), 5.89 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.4 Hz, 1 Hr), 6.94 (m, 1H), 6.96 (d, Jm=1.5 Hz, 1H), 7.05 (m, 1H), 7.11 (dd, Jo=7.8 Hz, 2H), 7.19 (t, Jo=7.4 Hz, 1H), 7.38-7.55 (m, 4H), 8.10 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>[OH-].[Na+]>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCNS(=O)(=O)c1cccc(Cl)c1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 3-chlorobenzenesulphonylchloride in the manner of Example 2 to give the title compound which, after recrystallisation from aqueous ethanol, had a melting point of 85°-86° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][N:5]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]2[CH:16]=[N:17][C:18]([C:19]([O:21]CC)=O)=[C:7]2[CH2:6]1>C(O)C>[CH3:4][N:5]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]2[CH:16]=[N:17][C:18]([C:19]([NH:2][NH2:3])=[O:21])=[C:7]2[CH2:6]1
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccsc2C1=O
Yield: 97 %

Procedure:
13 ml of hydrazine hydrate were added to a suspension of 7.0 g (24 mmol) of ethyl 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate in 70 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 6.5 g (97%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid hydrazide as colourless needles of m.p. >260°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[F:1][C:2]1[C:3]([CH2:3][CH2:2][CH2:12][CH2:11][N:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:20])[CH2:22][CH2:23]2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOC(=O)c1cccc(F)c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Step (c) of Example 75 was repeated, except that the compound prepared in step (a) of Example 81 was used and 4-(t-butoxycarbonyl)piperazine was used instead of 4-(3,3-diphenyl-1-propyl)piperazine. Thus, ethyl 3-fluoro-[4-[4-(t-butoxycarbonyl)piperazin-1-yl]butyl]-benzoate was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=[C:19]([CH3:20])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:21]([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:15]=3[CH:16]=2)=[O:22])=[CH:37][CH:36]=1)[CH3:35]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(C)cc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydrobenzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. Orange solid, MS (ISP)=530.9 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([NH2:26])[C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:16]([C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[NH:26][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: O=C(O)c1ccccc1
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1ccccc1
Yield: 9 %

Procedure:
Using the procedure described for Example 43 with benzoic acid at room temperature, the reaction was stopped once 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated. The solid was collected by filtration and dried to provide N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]benzamide (9 mg, 9%) as an off-white solid: mp 206-208° C.; 1H NMR (300 MHz, CD3OD) δ6.31 (1H, s), 6.67 (1H, s), 7.43-7.51 (9H, m), 7.89-7.92 (2H, m), 8.02 (1H, d, J=5.6 Hz), 8.60 (1H, s); ESI MS m/z 328 [C21H17N3O+H]+; HPLC (Method A) >99% (AUC) tR=16.2 min.