Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]1[O:17][C@@H:16]1[CH2:18][OH:19]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:15][C@H:16]([OH:17])[CH2:18][OH:19])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: OC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Temperature: 100 °C
Yield: 45.9 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared as in Example 5, 3.00 g, 26.55 mmol) in N,N-dimethylformamide (15 mL) was treated with solid potassium carbonate (11.0 g, 79.65 mmol) and (R)-(+)-glycidol (3.93 g, 53.10 mmol) and placed in a sealed tube and heated at 100° C. for 1 h in an oil bath. After this time the N,N-dimethylformamide was removed in vacuo. Purification by AnaLogix Intelliflash system (80 g column, 0% to 10% methanol/dichloromethane) afforded (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (2.28 g, 46%) as a yellow oil: LR-ES-MS m/z calculated for C6H9N3O4 [M]+ 187, observed [M+H]+ 188.
Reaction SMILES: [NH2:1][C:2]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]([OH:22])=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])[N:10]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C(Cl)(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:9]2[N:10]=[C:5]([C:2]([NH:1][C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])([CH3:4])[CH3:3])[N:6]([CH3:24])[C:7](=[O:23])[C:8]=2[OH:22])=[O:12])=[CH:20][CH:19]=1
Reactant: Cn1c(C(C)(C)N)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: COC(=O)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)NC(C)(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 25 °C

Procedure:
To a stirred mixture of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (4) and triethyl amine (3 eq) in chloroform, methyl chlorooxoacetate (1.5 eq) was added with an external cooling. Finished the addition, the ice bath was removed and the mixture was stirred at room temperature for 3 H. Reaction mixture was then partitioned between chloroform and 1N HCl. Organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated to obtain title product.
Reaction SMILES: [H-].[Na+].CN1C(=O)N(C)CCC1.[CH2:12]([OH:17])[C:13]#[C:14][CH2:15][OH:16].[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]2[C:36]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[C:35](Cl)[N:34]=[C:33]([C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[N:32]=2)(=[O:29])=[O:28])=[N:25][CH:26]=1)([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]2[C:36]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[C:35]([O:16][CH2:15][C:14]#[C:13][CH2:12][OH:17])[N:34]=[C:33]([C:45]3[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=3)[N:32]=2)(=[O:28])=[O:29])=[N:25][CH:26]=1)([CH3:20])[CH3:19]
Reactant: OCC#CCO
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)C)cn3)nc(-c3ccncc3)nc2OCC#CCO)cc1

Procedure:
To a slurry of 0.34 g of sodium hydride in 15 ml of DMF and 4 ml of DMPU 2.4 g of 2-butyne-1,4-diol was added at room temperature. The mixture was stirred until no more gas evolved. Then 0.67 g of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the mixture was stirred at 90° C. for 48 h. The solvent was removed in vacuo and the residue was taken up in 100 ml of 10% aqueous acetic acid. The mixture was extracted three times with 100 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The resulting brown oil was purified by column chromatography on silica gel eluting with DCM containing 4-10% of methanol. This furnished a fraction which after recrystallisation from DCM: ethyl acetate gave 43 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as pale yellow crystals. A second fraction gave 456 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide with about 90% purity as a brown oil. LC-MS: tR=4.53 min, [M+1]+=530.23, [M−1]−=528.21.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C=O)C>[Cl:1][CH2:2][C:3]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
Chloroacetyl chloride (11 ml) was added dropwise to a stirred mixture of potassium carbonate (18.8 g) and 4-nitroaniline (15 g) in DMF (100 ml) maintained at 0°. The mixture was then allowed to stand overnight at room temperature and poured into crushed ice. A yellow solid was recovered and crystallised from toluene containing isopropyl alcohol (10%) to give the title compound (10 g), MP: 180°.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:30]3[N:26]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][O:20]4)[N:27]=[CH:28][CH:29]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1cccc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (1.3 g, 3.3 mmol, from Step 2), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 3.9 mmol, Aldrich), and Na2CO3 (1.7 g, 16 mmol) in 1,2-dimethoxyethane (40 mL) and water (6 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol, Strem) was added, and the reaction was heated to reflux for 35 minutes. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc three times. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a light yellow oil (0.87 g, 56%).
Reaction SMILES: [NH2:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH:14](OCC)=[O:15]>ClCCl>[CH:14]([NH:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:15]
Reactant: NC1(CO)CCc2ccccc2C1
Reactant: CCOC=O
Solvent: ClCCl
Product: O=CNC1(CO)CCc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution containing 5.6 mmol of the compound obtained in Stage D of Example 35 in 5 ml of ethyl formate is left overnight at room temperature. The solution is then diluted with 25 ml of dichloromethane, the solid is filtered off and the tiltrate is evaporated. The residue is then purified by chromatography on a silica column using a dichloromethane/ethanol (95:5) mixture as eluent.
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:34])[CH:26]=[CH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:16][CH2:15]1>C1COCC1>[C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:34])[CH:26]=[CH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:16][CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(=O)Nc2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.35 g (13.9 mmol) 1-naphthyl isocyanate are dissolved in 10 ml abs. THF and a solution of 4.0 g (13.9 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide (substance 14) in 30 ml abs. THF is added dropwise at RT under moisture exclusion. After ca one hour, a white precipitate forms and the suspension is stirred at RT overnight. The solid is drawn off, chromatographically purified over silica gel with CHCl3/CH3OH (95/5 to 93/7) and crystallized from isopropanol after removal of the solvent. Colorless crystals remain with a MP of 198–200° C.; yield: 2.2 g (34%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][NH:10][C:11](=[S:14])[NH:12][NH2:13]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:13][NH:12][C:11]([NH:10][CH3:9])=[S:14])=[O:7]
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccco1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Furoyl chloride (31 g. or 0.238 mole) was added dropwise to a slurry of 4-methylthiosemicarbazide (25 g. or 0.238 moles) in dry pyridine (200 ml. cooled to -10°. The slurry was allowed to come to ambient temperature and stirred overnight. The reaction mixture was poured into 1500 ml. of crushed ice, the precipitate was collected, dried and recrystallized from EtOH to give (1-(2-furoyl)-4-methyl thiosemicarbazide (28.0 g.). This melted at 204°-206° C. (doc.) and was found to contain by analysis 42.4% C, 4.6% H, 21.2%, N, 16.1%, O, 15.9% S; C7H9X3O2S requires 42.2% C, 4.5% H, 21.1% N, 16.1% O, 16.1% S. The structure was confirmed by its infrared spectrum and nuclear magnetic resonance spectrum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:24][P:25]([O:37]COC(=O)C(C)(C)C)([CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH2:7][N:8]1[CH2:23][CH2:22][CH2:21][C@H:9]1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11].CC1C=CC(S(O)(=O)=[O:54])=CC=1>CO.C(O)(=O)C.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:24][P:25]([OH:37])([CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[C:7]([N:8]1[CH2:23][CH2:22][CH2:21][C@H:9]1[C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])=[O:54]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H]1CCCN1CC(CCCCN)CP(=O)(CCCCc1ccccc1)OCOC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H]1CCCN1C(=O)C(CCCCN)CP(=O)(O)CCCCc1ccccc1
Yield: 75 %

Procedure:
A solution of 0.800 g (1.16 mmol) of (±)-1-[6-amino-2-[[[(2,2-dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]methyl]hexyl]-L-proline, (2,2-dimethyl-1-oxopropoxy)methyl ester, 4-methylbenzenesulfonic acid (1:1) salt (prepared as described in Example 12) in a mixture of 15 ml of methanol and 1 ml of acetic acid was cooled in an ice-water bath under argon and treated with 250 mg of 10% Pd-C. The reaction mixture was subjected to a slow flow of H2 at 1 atm for 31/2 hours, then filtered and concentrated in vacuo to 0.710 g of residue which was purified by reverse phase gradient elution chromatography on a 25×250 mm HP-20 column (500 ml H2O to 500 ml CH3CN, linear gradient at ca. 4 ml/min flow). The product containing fractions were pooled and lyophilized to yield 0.476 g (75%) of the title product isolated as a 0.9 H2O solvate.
Reaction SMILES: [NH2:1][C:2]1[C:27]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[CH:26][C:25]([F:37])=[CH:24][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:12])=[O:11].[CH:38]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:38]1([S:41]([NH:1][C:2]2[C:27]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])=[CH:26][C:25]([F:37])=[CH:24][C:3]=2[O:4][C:5]2[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=2)[CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:12])=[O:11])(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Reaction time: 16 h
Yield: 79.2 %

Procedure:
864 mg of crude tert-butyl [(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}benzyl)sulfamoyl]carbamate (1.37 mmol, 1 eq.) were dissolved in 13 mL pyridine and 250 mg cyclopropyl sulfonyl chloride (1.78 mmol, 1.3 eq.) and stirring was continued at that temperature for 16 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The residue was further purified by flash column chromatography (hexan to hexan/ethyl acetate 1:1 gradient) to yield 814 mg of the target compound (70% UV-purity), which was used for the subsequent transformation.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.C([O-])([O-])=O.[Na+].[Na+].[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(O)CCC>[N+:10]([C:6]1[C:5]2[NH:23][CH2:22][CH2:21][NH:24][C:3](=[O:14])[C:4]=2[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Temperature: 80 °C
Yield: 46.7 %

Procedure:
2-Chloro-3-nitro-benzoic acid methyl ester (2.00 g, 9.3 mmol) was dissolved in n-butanol (10 ml). Na2CO3 (986 mg, 9.3 mmol) was added followed by ethylenediamine (622 μL, 9.3 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled, filtered, and washed with water (200 ml) to afford 9-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a bright orange solid (900 mg, 46%). mp 196-197° C.; LCMS: m/z=208.22 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 8.70 (m, 1H), 8.39 (m, 1H), 8.22 (dd, J=8.3 Hz, 1.8 Hz, 1H), 8.14 (dd, J=7.8 Hz, 1.8 Hz, 1H), 6.75 (t, J=7.8 Hz, 1H), 3.65 (m, 2H), 3.35 (m, 2H).
Reaction SMILES: COCCOC.[CH2:7]([O:14][CH2:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]1[CH:35]=[O:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:37][C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:7]([O:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[F:37])[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]1[CH:35]=[O:36])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)cn(COCc2ccccc2)c1C=O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(Cc2ccccc2F)cn(COCc2ccccc2)c1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To 100 ml of 1,2-dimethoxyethane solution containing 4.38 g (10.6 mmol) of ethyl 1-benzyloxymethyl-2-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrol-3-carboxylate obtained in Reference example 36-(c) were added 2.60 ml (21.4 mmol) of 2-fluorobenzyl bromide and 100 ml of 2M sodium carbonate aqueous solution, the mixture was degassed under reduced pressure and replaced with argon. Further, 2.47 g (2.14 mmol) of tetrakistriphenylphosphine palladium was added to the mixture, and the resulting mixture was stirred at 50° C. for 3 hours. After completion of the reaction, to the reaction mixture were added water and a saturated aqueous solution of sodium chloride, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 3.80 g of the title compound as a yellowish oil. (Yield: 91%)
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[F:20][C:21]([F:28])([F:27])[C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:9][C:8]1[C:3]([CH2:2][N:24]2[CH:25]=[CH:26][C:22]([C:21]([F:28])([F:27])[F:20])=[N:23]2)=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cn1ccc(C(F)(F)F)n1
Yield: 67.3 %

Procedure:
The title compound of Step C (0.7 g, 2 mmol), 3-trifluoromethylpyrazole (0.27 g, 2 mmol) and potassium carbonate (0.83 g, 6 mmol) were suspended in 10 mL of acetonitrile and heated to reflux for 1 h. The salts were filtered and the acetonitrile was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (85:15) to afford 0.52 g of the title compound of Step D, a compound of this invention, as a white solid melting at 112-114° C. 1H NMR (CDCl3): δ2.39 (s, 3H), 5.53 (s, 2H), 6.62 (d, 1H), 7.6-7.8 (m, 3H), 8.44 (d, 2H), 8.6 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Br:8][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(-c2cccc(Br)n2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
Part A. A solution of 2,6-dibromopyridine (6.16 g, 26 mmol) and 3-carboethoxybenzeneboronic acid (0.5 g, 2.6 mmol) in acetonitrile (20 mL) is treated with a solution of sodium carbonate (0.88 g) in water (5 mL). The mixture is degassed twice, and a catalytic amount of tetrakis(triphenylphosphine)palladium is added. The reaction mixture is heated to 80° C. and stirred for 12 h., then cooled, filtered and evaporated. The residue is partitioned between water and ethyl acetate, and the organic phase is washed with satd. aq. brine, dried over sodium sulfate, filtered and evaporated. The residual material is separated by column chromatography to give ethyl 3-(6-bromo-pyridin-2-yl)-benzoate (154 mg, 20%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11]>C(Cl)(Cl)Cl.C1COCC1.[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: OC(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanol (0.500 g, 1.245 mmol) in Chloroform (50 mL) and THF (50.0 mL) was treated with manganese dioxide (1.083 g, 12.45 mmol) at RT under nitrogen. The mixture was heated to 50° C. while stirring. After 40 mins, the reaction was filtered while warm through a small pad of celite. The filtrate was reduced and purified by column chromatography on silica gel using a gradient of 0 to 10% MeOH is DCM. The pure fractions were reduced and the residue was triturated in ethyl ether to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone as an off-white solid. MS (ESI, pos. ion) m/z: 399.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH2:39]>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])=[O:22])(=[O:15])=[O:16])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CN(C)CCCNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.033 cm3 of N,N-dimethyl-1,3-propanediamine. 52 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamide are thus obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.65 (mt, 2H), 2.18 (s, 6H), from 2.20 to 2.35 (mt, 2H), 2.98 (s, 3H), from 3.25 to 3.45 (mt, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.57 (t, J=5.5 Hz, 1H)].
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH2:12])=[C:7]([CH3:13])[CH:6]=1.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17]>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH:12][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])=[C:7]([CH3:13])[CH:6]=1
Reactant: CNC(=O)Oc1cc(C)c(N)c(C)c1
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1c(C)cc(OC(=O)NC)cc1C

Procedure:
Following the procedure of Example 22, 3,5-dimethyl-4-aminophenyl N-methylcarbamate (0.8g., 0.004 mole) was reacted with n-propanesulfonyl chloride (0.60g., 0.0042 mole) in pyridine. The product (0.8g.) melted at 173°-76° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:24])[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>O1CCOCC1.CCOC(C)=O>[ClH:32].[F:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:15]([O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[N:16][N:17]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccccc3F)c3cccc(F)c23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccccc1-n1nc(OC2CCNCC2)c2c(F)cccc21

Procedure:
The title product was prepared as described above for Example 41 using (Intermediate 46) (265 mg, 0.617 mmol) and 4 M HCl in dioxane (2.00 ml) in EtOAc (2 ml) to afford 202 mg (89%) as a white solid.