Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+].Cl>C(#N)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccccc1CCCc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccccc1CCCc1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 26.7 %

Procedure:
1 g of methyl 2-[3-(2-aminophenyl)propyl]benzoate obtained in Example 5 (3.7 mM), 0.71 g of 4-methylphenylsulfonyl chloride (3.7 mM) and 34 mg of NaHCO3 (4.1 mM) are added to 15 ml of acetonitrile in a 50 ml reactor. The reaction medium is stirred at 20° C. for 20 hours. 5 ml of 1M HCl are then added and the mixture is extracted with ethyl acetate. The organic phase is separated out after settling of the phases, washed and then dried over Na2SO4. After evaporation under vacuum, an oil is obtained, which is precipitated from ethyl ether. The solid is filtered off and washed with ether. 0.42 g of a grey-white solid is obtained (yield: 27%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[CH2:6][CH2:7][CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:1][C:2]([NH2:4])=[O:3]
Reactant: NC(N)=O
Reactant: NCCCCO
Product: NC(=O)NCCCCO

Procedure:
A mixture of 6.0 g (0.1 mole) of urea and 9.8 g (0.11 mole) of 4-amino-1-butanol was heated at 130°-135° C. for 4 hours to form monohydroxybutylurea. Without isolation the reaction mixture was cooled to 70° C. and then 31.0 g (0.21 mole) of chloral was slowly added while the temperature was maintained below 80° C. using external cooling. The reaction mixture was vigorously stirred and heated at 80°-85° C. for 1 hour. On cooling 43 g of a viscous syrupy product was isolated.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[O:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1>C1(C)C(C)=CC=CC=1>[C:20]1([C:18]2[N:19]=[C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[O:16][CH:17]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1nc(-c2ccccc2)co1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)co2)CC1
Yield: 36.4 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (1.21 g, 6.51 mmol) and 2-chloro-4-phenyl-1,3-oxazole (390 mg, 2.17 mmol) in xylene (50 ml) was stirred at 155° C. for 12 hours. The solvent was distilled off under reduced pressure. The residue was poured to water, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give 260 mg (12.1%) of the desired product as a solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[F:30][C:31]1[C:36]([F:37])=[C:35]([C:38]#[N:39])[CH:34]=[CH:33][C:32]=1O.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[C:36]([F:37])[C:31]=2[F:30])=[O:26])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: N#Cc1ccc(O)c(F)c1F
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(C(=O)Oc2ccc(C#N)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.11 mol of dicyclohexylcarbodiimide and 20 ml of toluene is added to a mixture of 0.1 mol of p-pentylbenzoic acid, 0.1 mol of 2,3-difluoro-4-cyanophenol (prepared according to Example 4), 1.5 g of 4-N,N-dimethylaminopyridine and 200 ml of toluene. After the mixture has been stirred at room temperature for 4 hours, 0.4 g of oxalic acid is added and stirring is continued for a further 30 minutes. Customary working up gives 4-(4-pentylbenzoyloxy)-2,3-difluorobenzonitrile, mp. 33° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N.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].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].[Zn].C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[F:11][C:9]1[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=[C:2]([C:12]#[N:13])[CH:10]=1
Reactant: Fc1cc(Br)cc2nc[nH]c12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: N#Cc1cc(F)c2[nH]cnc2c1
Temperature: 120 °C

Procedure:
A suspension of 5-bromo-7-fluoro-1H-benzimidazole obtained from step 1 (2.50 g; 11.63 mmol), zinc cyanide (Adrich, 819 mg; 6.98 mmol), tris(dibenzylideneacetone)dipalladium (Adrich, 319 mg; 0.35 mmol), 1,1-bis(diphenylphosphino)ferrocene (483 mg; 0.87 mmol), zinc (Adrich, 30 mg; 0.47 mmol) and zinc acetate (Adrich, 85 mg; 0.47 mmol) in dry DMF (25 mL) under inert atmosphere was heated at 120° C. for 16 hours. Reaction mixture was filtered over a pad of celite washed with EtOAc. The organics were washed with water, dried over MgSO4 and evaporated under vacuum to afford a brown solid that was triturated with EtOH and filtered to give the title compound as a brown solid 1H NMR (DMSO-d6) δ 13.40 (bs, 1H), 8.55 (s, 1H), 8.04 (s, 1H), 7.51-7.48 (d, J=10.7 Hz, 1H). LC/MS (Method B): 162.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=3)[C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)n1
Temperature: 120 °C

Procedure:
6-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester (0.0563 g, 0.16 mmol), 4-bromo-1-ethyl-1H-pyrazole (0.042 g, 0.24 mmol), tripotassium phosphate (0.067 g, 0.32 mmol), copper(I) iodide (0.006 g, 0.032 mmol) and N,N-dimethylethylenediamine (0.014 mL, 0.13 mmol) were combined in toluene (1 mL) in a sealed vial. The mixture was heated to 120° C. overnight. The crude reaction mixture was used directly in the next step.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8]([C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([CH3:10])[CH3:9]>>[CH:8]([C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])=[CH:20][CH:21]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccccc1Oc1ccc(C=O)cc1
Reactant: O=C1CSC(=S)N1
Product: CC(C)c1ccccc1Oc1ccc(C=C2SC(=S)NC2=O)cc1

Procedure:
The title compound was prepared using rhodanine and 4-(2-Isopropyl-phenoxy)-benzaldehyde according to General Procedure B.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([O:35]C)=[O:34])(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([OH:35])=[O:34])(=[O:30])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Prepared using General Procedure 7: To a stirring solution of (R)-methyl 2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)acetate INT-14 (0.082 g, 0.16 mmol) in MeOH (1.5 mL) was added 6N NaOH (0.08 mL). The reaction was stirred at room temperature for 6 h. The crude reaction was diluted with water, acidified with 1N HCl and extracted with DCM and EA. The organic layer was dried over Na2SO4, concentrated, and isolated after preparative HPLC purification to give 0.057 g (72%) of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)acetic acid 34. An analytically pure sample was prepared by preparative HPLC purification. LCMS-ESI (m/z) calculated for C24H26N4O6S: 496.5; found 520.1 [M+Na]+, tR=3.47 min.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH:13](O)[CH:12]([C:15]2[C:16](=[O:28])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:29]#[N:30])[CH:10]=2)[O:5]1>O1CCOCC1.N#N>[CH3:3][C:4]1([CH3:31])[CH:13]=[C:12]([C:15]2[C:16](=[O:28])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:29]#[N:30])[CH:10]=2)[O:5]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(c2cccn(Cc3ccccc3)c2=O)C1O
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C=C(c2cccn(Cc3ccccc3)c2=O)c2cc(C#N)ccc2O1
Reaction time: 10 h

Procedure:
0.4 g of NaH is added to a solution of 1 g of 2,2-dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6-cyano-3-chromanol in 40 ml of dioxane while stirring and passing in N2, the mixture is subsequently boiled for 10 hours and evaporated, and the residue is worked up in the customary manner. 2,2-Dimethyl-4-(1-benzyl-1,2-dihydro-2-oxo-3-pyridyl)-6-cyano-3-chromene is obtained, m.p. 130°-132°.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 57 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 57% of theory, C35H43N7O5 (641.8); Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=642; (M+H+Na)++=332.8; (M+Na)+=664.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1.C(Cl)Cl>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:18](=[O:17])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OC(=O)c4ccccc4)cc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Reaction time: 23 h
Yield: 163.4 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (200 mg, 0.52 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added benzoyl chloride (0.18 mL, 1.56 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (30 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with NaHCO3 (40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a colourless solid (252 mg, 82%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.21 (d, J=8.0 Hz, 2H), 8.07 (d, J=6.4 Hz, 2H), 8.00 (dm, J=8.4 Hz, 2H), 7.68 (t, J=6.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.54 (t, J=7.8 Hz, 2H), 7.49 (t, J=8.0 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.35 (dm, J=8.4 Hz, 2H), 6.85 (d, J=8.6 Hz, 1H), 5.82 (pentet, J=6.3 Hz, 1H), 5.37 (d, J=7.6 Hz, 1H), 5.21 (dd, J=5.9, 7.6 Hz, 1H), 2.34 (s, 3H), 1.51 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][NH2:8])[O:4][N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.I[C:47]1[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=1[C:49]([O:51][CH3:52])=[O:50]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][NH:8][C:47]2[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=2[C:49]([O:51][CH3:52])=[O:50])[O:4][N:3]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Cc1cc(CN)on1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1NCc1cc(C)no1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
1-(3-Methylisoxazol-5-yl)methanamine (155 mg, 1.37 mmol, 1.2 eq), potassium phosphate (341 mg, 1.60 mmol, 1.4 eq), S-Phos (95 mg, 0.230 mmol, 0.2 eq) and Pd2dba3 (13 mg, 0.06 mmol, 0.05 eq) were stirred in toluene (5 ml) under nitrogen. Methyl 2-iodobenzoate (300 mg, 1.14 mmol, 1 eq) was added and the mixture was stirred at room temperature for 3 days, then at 90° C. for 6 h. The reaction mixture was allowed to cool, poured into water (100 ml) and extracted with ethyl acetate (3×60 ml). The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated. The residual gummy oil was triturated with ether resulting in precipitation of a small amount of a yellow solid which was filtered off. The filtrate was evaporated and triturated again with methanol and a second precipitate was removed by filtration. The filtrate was evaporated, then purified by silica column chromatography, eluting with DCM. The product fractions were evaporated to afford methyl 2-{[(3-methylisoxazol-5-yl)methyl]amino}-benzoate as a yellow oily gum (128 mg, 45% yield); 1H NMR (399.902 MHz, CDCl3) δ 2.25 (s, 3H), 3.88 (s, 3H), 4.53 (d, 2H), 5.99 (s, 1H), 6.62-6.70 (m, 2H), 7.32-7.38 (m, 1H), 7.92-7.96 (m, 1H), 8.19 (t, 1H). MS: m/z 247 (MH+)
Reaction SMILES: [C:1]([S:9][CH:10]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([O:25]C(C)(C)C)=[O:24])[CH2:18][C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[CH2:15]1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([S:9][CH:10]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([OH:25])=[O:24])[CH2:18][C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[CH2:15]1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(NC(=O)C(Cc2ccccc2)SC(=O)c2ccccc2)C1=O
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(C(=O)O)N1Cc2ccccc2CC(NC(=O)C(Cc2ccccc2)SC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 122.7 %

Procedure:
Dissolve 2-[4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-4-methyl-valeric acid, tert-butyl ester (141 mg, 0.229 mmol) in methylene chloride (5 mL) and treat with anisole (0.12 mL, 1.15 mmol) then with trifluoroacetic acid (1.5M). Stir at room temperature for 15 hours, partition between ethyl acetate (25 mL) and brine (15 mL). Wash the organic layer with brine (15 mL), dry (Na2SO4) and purify by silica gel chromatography (1:1 hexane/ethyl acetate followed by 1:1:0.01 hexane/ethyl acetate/acetic acid) to give the title compound as a white solid (157 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH3:21][C:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][C:22]1([C:28]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=N)c1c(F)cccc1Cl
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=NC(=O)C1(C)CCCCC1)c1c(F)cccc1Cl

Procedure:
Ethyl 2-chloro-6-fluoro-benzimidate (1.61 g) and triethylamine (1.0 g) are dissolved in toluene (100 ml), to which is added dropwise 1-methylcyclohexylcarbonyl chloride (1.5 g) at 5°-10° C. with stirring and thereafter stirred at room temperature for 1 hour. Further, it is reacted at 80°-100° C. for 16 hours. After the completion of the reaction, the reaction solution is washed with a saline solution and further with water and then the resulting toluene layer is dried on sodium sulfate and concentrated to obtain crude product of ethyl N-(1-methylcyclohexylcarbonyl)-2-chloro-6-fluorobenzimidate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])=[C:8]([C:16]([NH2:18])=[O:17])[CH:7]=[N:6][N:5]2[CH:19]=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCOC(C)=O.CO.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>[CH:13]1([C@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:19]=[C:2]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([CH:20]=[CH2:21])[CH:27]=4)[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:16]([NH2:18])=[O:17])[CH3:12])[CH2:15][CH2:14]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reactant: C=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CO
Product: C=Cc1cccc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)c1
Temperature: 90 °C
Yield: 27.2 %

Procedure:
A degassed solution of (R)-6-bromo-4-(1-cyclopropylethylamino) pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 4, 25 mg, 0.077 mmol), 3-vinylphenyl boronic acid (34.3 mg, 0.232 mmol) and 2M aq. potassium carbonate (0.116 mL, 0.232 mmol) in DME (1 mL) was added Pd(Ph3P)4 (5.36 mg, 4.64 mmol) and the resulting reaction mixture was heated to 90° C. for 2 hrs. The reaction mixture was diluted with 10 mL of EtOAc which was washed with 5 mL of water and 5 mL of brine. The organic phase was concentrated to yield a crude product which was purified on a preparative silica gel TLC plate with hexanes/EtOAc (2/1) as the eluent to yield a product. After trituration in MeOH, the resulting solid obtained was dried to afford the title compound (7.25 mg, 26%). HPLC (condition G): retention time=3.833 min. LC/MS (M+H)+=m/z 347.2. 1H NMR (400 MHz, MeOD) δ ppm 8.12 (1 H, s), 7.93-7.95 (1 H, m), 7.72 (1 H, s), 7.55-7.60 (1 H, m), 7.34-7.37 (2 H, m), 7.22 (1 H, d, J=1.8 Hz), 6.81 (1 H, dd, J=17.8, 11.0 Hz), 5.86 (1 H, dd, J=17.7, 1.0 Hz), 5.27 (1 H, dd, J=11.0, 0.9 Hz), 4.09-4.17 (1 H, m), 1.46 (3 H, d, J=6.4 Hz), 1.11-1.21 (1 H, m), 0.53-0.64 (2 H, m), 0.37-0.47 (2 H, m).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].Cl>O1CCOCC1.C(O)(C)C>[CH:10]([NH:13][C:14]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[O:15])([CH3:12])[CH3:11]
Reactant: CC(C)N=C=O
Reactant: c1nc2c([nH]1)CCNC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(C)NC(=O)N1CCc2[nH]cnc2C1

Procedure:
A solution of 2.46 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 6.8 g of isopropyl isocyanate in 50 ml of dry dioxane is refluxed for 2 h. After evaporation to dryness, the residue is dissolved in 25 ml of methanol and treated with 12.5 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization, the solution is extracted with chloroform. Evaporation of the solvent leaves a residue (2.21 g, oil) that is treated with one equivalent of hydrogen chloride in isopropanol. After cooling, 1.7 g of 5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 190°, are collected.
Reaction SMILES: [CH2:1]([C:3]1([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-])=O)=[CH:8][CH:9]=2)[C:4]1=[O:15])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:12][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:3]([CH2:1][CH3:2])([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[C:4]2=[O:15])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: CCC1(c2c[nH]cn2)Cc2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCC1(c2c[nH]cn2)Cc2ccc(N)cc2C1=O
Yield: 93.2 %

Procedure:
To 7.20 g (0.0265 mol) of 2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-6-nitro-1H-inden-1-one dissolved in 70 ml of ethanol was added 0.7 g of 10% palladium on carbon and the mixture was shaken in an atmosphere of hydrogen at the room temperature. When the reduction came to a standstill the catalyst was removed. The filtrate was concentrated to give 6-amino-2-ethyl-2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-1-one (5.96 g, 93%). The product was purified by flash chromatography eluting with methylene chloride--methanol mixture (9.5:0.5).