Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:23])(=[O:22])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:12]([CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])(=[O:23])=[O:22])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccccc1CNS(=O)(=O)c1ccc(OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN(Cc2ccccc2OC)S(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(N-(2-methoxybenzyl)sulfamoyl)phenyl acetate (example 5-42a) (50 mg, 0.15 mmol) was dissolved in acetone (1.0 mL) followed by the addition of cesium carbonate (97 mg, 0.30 mmol) and methyl 4-(bromomethyl)benzoate (38 mg, 0.17 mmol). The mixture was stirred at room temperature overnight and then the inorganic salts were filtered off Acetone was removed in vacuo and the residue was re-dissolved in ethyl acetate and washed with water followed by brine. The organic layer was dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography with ethyl acetate/hexanes as the eluent to afford methyl 4-((4-acetoxy-N-(2-methoxybenzyl)phenylsulfonamido)methyl)benzoate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:9])[C:6]([OH:8])=[O:7].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>S(=O)(=O)(O)O>[OH:9][CH:5]([CH2:4][CH2:3][CH2:2][CH3:1])[C:6]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7]
Reactant: CCCCC(O)C(=O)O
Reactant: CCCCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCOC(=O)C(O)CCCC
Temperature: 140 °C
Yield: 41.9 %

Procedure:
A 50 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and a nitrogen inlet/outlet was charged with 5.0 g (0.038 moles) DL-2-hydroxycaproic acid, 23.95 g (0.151 moles) decyl alcohol, and 0.019 g sulfuric acid. The reactants were heated to 140° C. for 8 hours and water collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. Approximately 50 ml ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Excess decyl alcohol was removed by high vacuum distillation to yield 4.34 g (49% yield) of clear colorless liquid. According to GC the product is 95.74% pure.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:10])=[C:3](/[CH3:9])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][C:12]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(OCC)C>[Cl:11][C:12]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][C:2]([CH3:10])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:9])=[O:25])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)/C(C)=C(/C)N
Reactant: CCOC(=O)c1cc(N=C=O)ccc1Cl
Solvent: CCOCC
Product: CCOC(=O)C(C)=C(C)NC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1
Reaction time: 2 h

Procedure:
4.7 g of ethyl 3-amino-2-methylcrotonate, dissolved in 15 ml of absolute diethyl ether, are treated at 23° C., while stirring with a solution of 6.7 g of ethyl 2-chloro-5-isocyanatobenzoate and stirred for 2 hours. The reaction mixture is evaporated to dryness under reduced pressure and the residue is purified by chromatography on 400 g of silica gel using diethyl ether/n-hexane (1:1) as the eluent. There is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylpropenyl]ureido}-benzoate, m.p. 88°-91° C.
Reaction SMILES: C(=[N:8][CH:9]([P:22]([O:26][CH3:27])([O:24][CH3:25])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>CCOCC>[NH2:8][CH:9]([P:22]([O:26][CH3:27])([O:24][CH3:25])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: COc1ccc(COC(=O)C(N=Cc2ccccc2)P(=O)(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: O
Product: COc1ccc(COC(=O)C(N)P(=O)(OC)OC)cc1

Procedure:
p-Methoxybenzyl N-benzylidene-α-amino-dimethylphosphonoacetate (9.78 g) in ether (50 ml) is added over 20 minutes to a stirring solution of p-toluenesulfonic acid monohydrate (4.76 g) in ether (150 ml). Cyclohexane (100 ml) is added and the solvents are decanted off. The residue is washed with more 2:1 ether-cyclohexane, which is again decanted off. The residue is partitioned between methylene chloride and 1 M dipotassium hydrogen phosphate (50 ml). The organic portion is separated, washed with water, dried, and evaporated in vacuo to give p-methoxybenzyl α-aminodimethylphosphonoacetate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:35])[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH:10]([O:35][C:42](=[O:44])[CH3:43])[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:15]=2)=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
2-Fluoro-4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-benzonitrile (as described in Step B above) (4.05 g, 8.81 mmol), pyridine (2.14 mL, 26.4 mmol), and acetic anhydride (12.5 mL, 132 mmol) were stirred in anhydrous DMF (60 mL) for 3 h under Ar. The reaction was concentrated in vacuo, diluted with EtOAc (250 mL), washed with H2O (2×), brine, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[N+:31]([O-])=O)[CH2:20][CH2:19]3)=[O:17])=[CH:10][CH:9]=2)[CH2:4]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>[Pd].C(O)(=O)C>[CH3:1][N:2]([CH3:34])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[NH:31][C:35](=[O:37])[CH3:36])[CH2:20][CH2:19]3)=[O:17])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C1CCN(c2ccc(CNC(=O)C3CCN(c4ccc(Cl)cc4[N+](=O)[O-])CC3)cc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)ccc1N1CCC(C(=O)NCc2ccc(N3CCC(N(C)C)C3)cc2)CC1
Reaction time: 1 h

Procedure:
Palladium on carbon (10%; 10 mg) was added to a solution of 1-(4-chloro-2-nitro-phenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylamide (50 mg) in glacial acetic acid (5 ml). The solution was stirred under a hydrogen atmosphere (1 bar), and acetic anhydride (14 μl) was added. After one hour, further acetic anhydride (6 μl) were added and the mixture was stirred for 15 minutes. The suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 498.07 (C27H36ClN5O2); MS (ESI): 498 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:4][C:3]=1[NH:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: OB(O)c1cccnc1
Reactant: Nc1ccc(Br)cc1NC(=O)N1CCCC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cccnc2)cc1NC(=O)N1CCCC1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
To a solution of N-(2-amino-5-bromophenyl)pyrrolidine-1-carboxamide (0.26 g, 0.72 mmol) in THF (10 mL) and water (5 mL) were added pyridin-3-ylboronic acid (0.13 g, 1.07 mmol, 1.5 equiv.), sodium bicarbonate (0.11 g, 1.07 mmol, 1.5 equiv.) and palladium(0) (0.08 g, 0.07 mmol, 0.1 equiv.). The reaction mass was stirred at 90° C. for sixteen hours. The reaction crude was filtered on a celite bed and diluted in ethyl acetate. The organic layers were washed with water and brine then dried over Na2SO4 and concentrated. The residue was purified by column chromatography on eluting ethyl acetate and hexane to allow N-(2-amino-5-(pyridin-3-yl)phenyl)pyrrolidine-1-carboxamide (0.14 g, 63% yield).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH:9]([OH:13])[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43][NH2:44]>>[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43][NH:44][C:10](=[O:12])[CH:9]([OH:13])[CH:8]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: NCc1nc2ccccc2o1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCc1nc2ccccc2o1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 4-phenyl-2-hydroxy-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with benzo[d]oxazol-2-ylmethylamine; ESI-MS [M+H]+: 573.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](F)(F)[CH2:13][CH:12]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][Si](C)(C)C)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
To (1-{4,4-difluoro-2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (412 mg, 0.82 mmol) in MeOH (8 mL) was added K2CO3 (227 mg, 1.64 mmol). After stirring for 5 h, the reaction was filtered then concentrated. The residue was diluted with EtOAc then washed with H2O. The aqueous phase was back-extracted with EtOAc two times then the organic phases were combined, washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (20-80% EtOAc-hexanes gradient) to afford (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (371 mg, 0.82 mmol, quantitative yield). LCMS-ESI+: calc'd for C22H25F2N4O3: 431.2 (M+H+). Found: 431.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:35]=[CH:34][C:30](C(Cl)=O)=[CH:29][CH:28]=1)#[N:26].[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([CH2:45][NH2:46])=[CH:44][C:39]=2[O:38][CH2:37]1>>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([CH2:45][NH:46][C:22]([C@@H:12]3[CH2:11][C:10](=[N:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:14][N:13]3[C:15](=[O:17])[C:30]3[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:35][CH:34]=3)=[O:24])=[CH:44][C:39]=2[O:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc2c(c1)OCO2
Product: N#Cc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)NCc2ccc3c(c2)OCO3)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl-oxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=497.6.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].[C:33](O)(=[O:37])[CH:34]([CH3:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Yield: 69.8 %

Procedure:
Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (190 mg, 0.32 mmol) dissolved in DCM (40 ml) and added trifluoroacetic acid (1.5 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (190 mg). 2-Fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (190 mg, 0.42 mmol) was dissolved in DMF (7 ml) and added isobutyric acid (47 mg, 0.46 mmol), EDC.HCl (200 mg, 1.04 mmol), HOBt (70 mg, 0.5 mmol) and TEA (0.7 ml, 3.3 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (120 mg) as a brown solid. M.P.: 193-196° C. MS (m/z): 410.2 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([CH:12]=1)[NH2:11])(=[O:5])=[O:4])[CH3:2].[C:15](Cl)(Cl)=[S:16].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N:11]=[C:15]=[S:16])[CH:12]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(OC)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(OC)c(N=C=S)c1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of 5-(ethylsulfonyl)-2-methoxyaniline (15.6 g, 72.5 mmol) in dichloromethane (100 mL) was added dropwise over 1 h to a stirred solution of thiophosgene (9 g, 78.0 mmol) in dichloromethane (300 mL) at RT. After the addition was complete, the reaction was stirred for 2 h. Subsequently, saturated aqueous sodium bicarbonate (200 mL) was added, and the reaction was stirred for an additional 1 h. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (18.6 g, 72.4 mmol) as a tan solid. 1H NMR (400 MHz, d6-DMSO): δ 7.78 (dd, J1=2.2, J2=8.8, 1H), 7.71 (d, J=2.2, 1H), 7.35 (d, J=8.8, 1H), 3.95 (s, 3H), 3.22 (q, J=7.4, 2H), 1.02 (t, J=7.3, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Fc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-fluorobenzyl chloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13. found, m/z 356.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.28-7.21 (m, 1H), 6.93-6.88 (m, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.75-6.71 (m, 1H), 5.29 (s, 2H), 2.89-2.85 (m, 4H), 2.79-2.76 (m, 2H), 2.74-2.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)C(=O)Oc2ccc(Br)cc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2OC1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-Bromo-3,3-dimethyl-3H-benzofuran-2-one (1.199 g, 5.0 mmol) (described in Step 2 of Example A(68), dissolved in anhydrous CH2Cl2 (20 ml), and cooled to −78° C., was added DIBAL (3.67 mL, 5.5 mmol, 1.5M in Toluene). The reaction was stirred for 1 h at this temperature then quenched with 1N HCl until acidic. The resulting mixture was extracted with ether, which was washed with brine, dried with MgSO4, concentrated and purified by silica gel chromatography (gradient elution 5-15% Ethylacetate/Hexanes). Yield 0.95 g, 79%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=O>>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[C:10]([CH3:11])[C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[N:1]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: NC(=O)c1ccccc1
Product: COc1ccc2c(O)nc(-c3cccc(F)c3)nc2c1C
Yield: 73 %

Procedure:
The general procedure described in Example 8 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and 3-fluoro-benzoyl chloride as acid chloride [B], which gave the title compound (2.1 g, 73%), [M+H]=271.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:5][CH:4]=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH2:20]([O:27][CH2:18][CH2:17][C:16]([C:6]1[C:7]2[N:8]([N:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCC(=O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Reactant: OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(=O)CCOCc2ccccc2)c2cc(C(F)(F)F)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of the compound of Example 319 (3.42 g) and benzyl alcohol (1.37 g) in dichloromethane (50 mL) was added to dichloro bis(acetonitrile) palladium (II) (329 mg) in a stream of argon gas. The mixture was stirred at room temperature overnight, followed by addition of benzyl alcohol (500 mL) and stirring overnight. The insoluble material was removed by filtration through Celite. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2). The product was further purified by amino-silica gel column chromatography (hexane:ethyl acetate=3:2) to afford the title compound as a pale yellow powder (2.47 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C.C1(C)C=CC=CC=1.[O-]CC.[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][CH:11]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CCOc1ccc(-c2ccc(C=O)cc2)c(F)c1F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(OCC)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
4-Ethoxy-4′-formyl-2,3-difluoro-1,1′-biphenyl (s49) (30.0 g), ethyl diethylphosphonoacetate (30.8 g) and toluene (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Sodium ethoxide in ethanol solution (20%; 46.7 g) was added at the same temperature, and the stirring was continued for another 2 hours. After the reaction mixture had been returned to 25° C., the stirring was continued for another 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with a mixed solvent of toluene and heptane (toluene:heptane=2:1 by volume) as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in 2-propanol (150 ml), to which Pd/C (1.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder to give ethyl 3-(4′-ethoxy-2′,3′-difluoro-(1,1′-biphenyl)-4-yl)propionate (s50) (28.9 g). The yield based on the compound (s49) was 75.6%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([N+:7]([O-])=O)[S:5][CH:6]=1.C(O)(=O)C>[Fe].O>[Br:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([NH2:7])[S:5][CH:6]=1
Reactant: O=[N+]([O-])c1scc(Br)c1-n1nccn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1scc(Br)c1-n1nccn1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A mixture of 2-(4-bromo-2-nitrothiophen-3-yl)-2H-1,2,3-triazole (0.59 g, 2.15 mmol), iron powder (0.75 g, 13.38 mmol), glacial acetic acid (8.4 mL) and H2O (1.2 mL) was heated in an oil bath set at 70° C. under condenser with N2 (g) inlet for 1 h. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophene-2-amine (0.35 g, 66%). Retention time (min)=1.540, method [4], MS (ESI) 246.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:17](=[O:18])[NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[N:4]=2)=[CH:9][CH:10]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(-c2ccc(CCO)cc2)nc1C(=O)Nc1cccnc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a solution of the product of step (iii) (2.5 g, 7.5 mmol, 1.0 eq) and TEA (2.3 g, 22.5 mmol) in dry dichlormethane was added MsCl (1.7 g, 15 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue purified by column to afford the subtitled compounds (1.9 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[C:11]=1[CH3:12].[OH:15][CH2:16][CH2:17][NH2:18]>>[OH:15][CH2:16][CH2:17][N:18]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:4])[C:10]=2[C:11]([CH3:12])=[C:2]([CH3:1])[C:3]1=[O:14]
Reactant: NCCO
Reactant: Cc1c2c(oc(=O)c1C)CCCC2=O
Product: Cc1c2c(n(CCO)c(=O)c1C)CCCC2=O

Procedure:
Prepared from 3,4-dimethyl-5,6,7,8-tetrahydro-cumarin- 5-one and 2-hydroxy-ethylamine at 130° C. over a period of 25 minutes.