Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)cc(NCc2ccccc2F)n1

Procedure:
53 g (323 mmol) of 2-amino-4,6-dichloropyrimidine, 40.4 g (323 mmol) of 2-fluorobenzylamine and 33.4 g (330 mmol) of triethylamine are dissolved in 800 ml of ethanol and the reaction mixture is heated under reflux for 20 hours. After 400 ml of ethanol have been distilled off, the residue is diluted with 500 ml of water, and the precipitated product is filtered off with suction and recrystallised from 1 l of toluene. In this manner 2-amino-4-chloro-6-(2-fluorobenzylamino)-pyrimidine having a melting point of 130°-133° is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:29][CH:30]([CH2:32][OH:33])[CH3:31]>ClCCl>[OH:33][CH2:32][CH:30]([NH:29][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)[CH3:31]
Reactant: CC(N)CO
Reactant: O=C(O)c1cccc(I)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CO)NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
To a solution of 3-iodobenzoic acid (10.02 g, 40.30 mmol), in dry dichloromethane, at room temperature (180 mL) under a nitrogen atmosphere, EDCI (7.72 g, 40.30 mmol) was added followed by triethylamine (8.0 mL, 60.45 mmol) and the mixture was stirred at room temperature for further 5 minutes. DL Alaninol (3.02 g, 40.3 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organics were separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 1% to 8% methanol gradient) to afford compound 1 (4.14 g, 13.6 mmol, 34% yield) as an off white solid.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][CH:14]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and the contents were stirred for 10 min. after which the solution of 1-(4-chlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h; the reaction was monitored by LCMS. After completion, the reaction mixture was poured in ice water, extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the crude product. 1H NMR (CDCl3, freebase) δ (ppm): 7.38 (m, 4H), 2.97 (d, 1H), 2.78 (d, 1H), 1.69 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH:8]1([CH2:11][O:12][C:13]2[C:14]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[N:25]([CH3:34])[CH:24]=3)=[N:15][C:16](S(C)(=O)=O)=[N:17][CH:18]=2)[CH2:10][CH2:9]1.C(O)(=O)C>CN(C=O)C>[CH:8]1([CH2:11][O:12][C:13]2[C:14]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[N:25]([CH3:34])[CH:24]=3)=[N:15][C:16]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[N:17][CH:18]=2)[CH2:9][CH2:10]1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Sodium hydride (0.93 g, 23.37 mmol, 60% in mineral oil) was added to MeSO2NH2 (2.22 g, 23.37 mmol) in dry DMF (30 mL) at 0° C. over 15 min. The mixture was stirred at 0° C. for 1 h and the title compound of step 5 (3.00 g, 7.79 mmol) was added. The mixture was heated at 60° C. for 6 h. After cooling, ice water was added and the pH was adjusted to 5 with acetic acid. The suspended solids were collected and washed with MTBE (50 mL) to afford the title compound (3 g, yield: 96.7%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 9.80 (s, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.42 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.70 (m, 2H), 7.56 (t, J=7.6 Hz, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.70 (s, 3H), 3.39 (s, 3H), 1.12 (m, 1H), 0.58 (m, 2H), 0.24 (m, 2H). LCMS: 401.1 (M+1)+
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].CC(C)([O-])C.[K+].CS(O[CH2:21][CH:22]1[C:26]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=2[O:24][CH2:23]1)(=O)=O.O>CN1C(=O)CCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][CH:22]([CH2:21][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[C:26]=2[CH:27]=1
Reactant: CS(=O)(=O)OCC1COc2ccc(F)cc21
Reactant: COC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C(CC1COc2ccc(F)cc21)C(=O)OC
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Dimethyl malonate (262 g) was dissolved in NMP (2 l) and potassium tert-butoxide (202 g) was added portionwise keeping the temperature at 15-20° C. The mixture was heated to 60° C. and a solution of 2,3-dihydro-5-fluorobenzofuran-3-ylmethyl methanesulfonate (155 g) in NMP (150 ml) was added dropwise. The mixture was stirred for 4 h at 70-75° C. followed by addition of cold water. Extraction with ether, drying the ether phase over magnesium sulfate, followed by removal of solvent in vacuo gave dimethyl 2-(2,3-dihydro-5-fluorobenzofuran-3-ylmethyl)malonate (160 g) as an oil, which was sufficiently pure for the further synthesis.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)[CH3:3].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>N1C=CC=CC=1.CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:2]([CH3:3])[NH:1][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C)N)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(C)NCc2ccccc2)cc1OC
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture containing 18.1 g of 1-amino-1-(3,4-dimethoxyphenyl)-ethane (J. Chem. Soc. 1963, 4289), 10,6 g of benzaldehyde and 1 drop of pyridine in 100 ml of methanol is let stand at 20° C. for 2 days, then 3.8 g of sodium borohydride are added during 30 minutes and stirred for additional 3 hours. After evaporation of the solvent, the residue is diluted with water, extracted with chloroform, the organic phase is dried and evaporated to give 27.1 g of the crude title compound, which can directly be used in the process described in Example 6.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:13]([N+:14]([O-])=O)=[C:12]([O:17][CH:18]([F:20])[F:19])[N:11]([CH3:21])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O1CCCC1.[H][H]>[Ni].C(O)C>[F:1][C:2]1[C:3]([C:9]2[C:13]([NH2:14])=[C:12]([O:17][CH:18]([F:19])[F:20])[N:11]([CH3:21])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [H][H]
Reactant: Cn1nc(-c2ncc(Cl)cc2F)c([N+](=O)[O-])c1OC(F)F
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1nc(-c2ncc(Cl)cc2F)c(N)c1OC(F)F

Procedure:
4.2 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-nitro-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H47) are initially introduced into the reaction vessel together with 40 ml of tetrahydrofuran, and 5.8 g of Raney nickel in ethanol are added. Hydrogenation is carried out under normal pressure and at a temperature of 30-35° C. After uptake of 728 ml of hydrogen, the hydrogenation is interrupted and the reaction mixture is filtered over Hyflo. After removal of the solvent in vacuo, 3.15 g of the desired title compound are obtained as a brown solid of melting point 92-94° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[CH2:7]([NH:14][C:15](=[O:37])[N:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][C:25]=2[OH:36])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:36][C:25]1[CH:26]=[C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:16]([CH3:17])[C:15]([NH:14][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:37])[CH:19]=1)[CH3:2]
Reactant: CCOCCBr
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCOCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (4.43 mmol, 5.4 eq) of 2-bromoethyl ethyl ether and 350 mg (0.82 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 4.4 eq) of potassium carbonate at 90° C. for 12 hours, methyl 3-[2-(2-ethoxyethoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:31]([CH3:40])[C@H:32]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:34][CH2:35][CH3:36].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([N:31]([CH3:40])[C@H:32]([C:37]([NH2:39])=[O:38])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])[CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC[C@H](NC)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
Condensation of BocDTrp-LeuOH (Example 38, 2.09 g.) and MeNleNH2 (1.00 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocDTrp-Leu-MeNleNH2 in 99% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MeNleNH2 (2.50 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-Leu-MeNleNH2 in 37% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:31][C:17]1[CH:16]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:14]2[C:23]3=[C:22]4[C:11]([CH:10]=[CH:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[C:21]4[CH:20]=[CH:19][C:18]=13)=[CH:12][CH:13]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)ccc5ccc2c3c54)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)cc(Br)c5ccc2c3c54)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
Next, a mixed solution of 2.6 g of 1,6-bis(4-methylphenyl)pyrene, 1.2 g of N-bromosuccinimide and 60 ml of dimethylformamide was stirred under a nitrogen gas stream at 60° C. for 5 hours. The solution was cooled to room temperature and 60 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The resulting solid was recrystallized from toluene and then vacuum-dried to obtain 1.4 g of 3-bromo-1,6-bis(4-methylphenyl)pyrene.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[F:15][C:16]([F:25])([F:24])[CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>C1COCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([C:20]2([OH:23])[CH2:19][CH2:18][CH:17]([C:16]([F:24])([F:25])[F:15])[CH2:22][CH2:21]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(C(F)(F)F)CC1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC(C(F)(F)F)CC2)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (3 mL of a 2.5 M solution in hexanes, 7.5 mmol) was added dropwise to 5-bromo-2-methoxy pyridine (6.0 mmol, 0.78 mL) in 40 mL of THF cooled in a dry ice/acetone bath. After aging for 15 min, 4-trifluoromethylcyclohexanone (6.0 mmol, 1 g) was added and the reaction mixture was allowed to slowly warm to 0° C. over 2 h. The reaction was cooled in a dry ice/acetone bath and the reaction was quenched by addition of sat. ammonium chloride (aq), then saturated sodium bicarbonate (aq). The reaction mixture was extracted with hexanes/EtOAc. The organic phase was concentrated and the resultant residue was purified by flash chromatography on silica gel using a step gradient of 4:1, 2:1 and 1:1 (v/v) EtOAc/hexanes to give the title compound as a mixture of isomers. LC-MS (ESI): m/z=276.2 [M+1]+.
Reaction SMILES: CC1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9](CCOC3C=CC=CC=3)C2=O)[S:4][C:3]=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.Cl.CC1SC=C(CN)N=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:9][CH2:10][C:11]4[N:7]=[C:5]([CH3:6])[S:4][CH:3]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(CN)cs1
Agent: Cl
Product: Cc1nc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)cs1
Yield: 71 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (2-methylthiazol-4-yl)methanamine dihydrochloride, the title compound was obtained as a colorless solid in 71% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 3H), 6.28 (t, J=5.2 Hz, 1H), 6.10 (s, 1H), 4.63 (d, J=5.2 Hz, 2H), 4.43 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.71 (s, 3H), 2.49 (s, 3H); MS (ES+) m/z 445.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:16]4[O:17][CH2:18][CH2:19][NH:20][C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:21]=1.Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=1.ClC1C(Cl)=CC=CN=1>>[Cl:31][C:30]1[C:25]([N:20]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:9]4[NH:8][C:7]5[CH:21]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=[CH:5][C:6]=5[N:10]=4)[C:16]=3[O:17][CH2:18][CH2:19]2)=[N:26][CH:27]=[C:28]([Cl:32])[CH:29]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4)[nH]c2c1
Agent: Clc1cccnc1Cl
Product: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4c3ncc(Cl)cc3Cl)[nH]c2c1
Yield: 89 %

Procedure:
The procedure of Example 6 was repeated except for using 8-(6-(trifloromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine and 2,3,5-trichloropyridine instead of 4-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)benzenamine and 2,3-dichloropyridine in Example 6 respectively to obtain the title compound (4.1 g, yield: 89%).
Reaction SMILES: CCN(CC)CC.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)=[CH:20][CH:19]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH:14]([C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:57])([CH3:56])[CH3:58])[CH2:49][CH2:50][CH2:51]3)=[CH:44][CH:43]=2)=[CH:22][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(=O)Nc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Et3N (36.6 μL, 0.263 mmol) and phenyl isocyanate (10.4 μL, 0.0964 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.0876 mmol) in DCM (1 mL) at 0° C., and stirred at room temperature. After reaction was completed, the mixture was diluted with sat. NaHCO3 and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1). The fractions were concentrated and solidified with CHCl3. The precipitated solids were collected by filtration and washed with CHCl3 to afford desired product (33.5 mg, 55.4%) as cream colored solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.16-8.11 (m, 1H), 8.03-7.99 (m, 1H), 7.54-7.48 (m, 2H), 7.38-7.21 (m, 9H), 7.16-7.05 (m, 4H), 6.95 (d, J=8.2 Hz, 1H), 6.89-6.73 (m, 3H), 6.59 (dd, J=8.0, 4.8 Hz, 1H), 6.29 (s, 1H), 5.19 (s, 1H), 2.61-2.23 (m, 4H), 2.20-2.06 (m, 1H), 1.95-1.80 (m, 1H), 1.49-1.16 (m, 9H).
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O.[OH-].[Na+]>C(C(C)=O)C(C)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: [Na+]
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 85 °C
Yield: 100.1 %

Procedure:
A mixture of methyl isobutyl ketone (60 ml), diphenyl phosphite (13.1 g), imidazole (5.44 g) and o-chlorophenyldiphenylmethanol (11.78 g) obtained in Example 1 (B) was heated at 85° C. for 4 hours. To the reaction mixture, a 10% aqueous sodium hydroxide solution (110 g) was added, and the mixture was refluxed for 1 hour. After cooling to room temperature, the organic layer was separated, washed with water and concentrated to dryness under reduced pressure to give 13.8 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 100%. M.P., 138°-142° C. Recrystallization from methyl isobutyl ketone gave 12.3 g of the pure compound. Yield, 89%. M.P., 142°-143° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH2:8])[CH2:4][O:3]1.N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(OCC)C>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(CN)O1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)OCC(CNS(C)(=O)=O)O1
Reaction time: 2 h
Yield: 11.9 %

Procedure:
To a solution of the (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (4.616 g, 35.19 mmol) in diethylether (100 mL) was added pyridine (2.90 mL, 35.9 mmol). A solution of methanesulfonyl chloride (2.75 mL, 35.4 mmol) in diethylether (50 mL) was added to the amine solution over 30 minutes. After stirring for 2 h, the reaction was washed once with 25 mL water then twice with 25 mL brine. The organic layer was separated, dried over MgSO4, filtered, and evaporated to a residue. The residue was chromatographed over silica gel with 0-100% EtOAc in hexanes. The product fractions were evaporated in vacuo to give N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methanesulfonamide as a near-colorless oil (0.875 g, 4.18 mmol, 12% yield). 1H NMR (400 MHz, DMSO-d6): 7.17 (1H, t, J=6.4 Hz), 4.13-4.06 (1H, m), 3.98 (1H, dd, J=8.3 Hz, 6.4 Hz), 3.66 (1H, dd, J=8.3 Hz, 5.7 Hz), 3.09-2.98 (2H, m), 2.91 (3H, s), 1.33 (3H, s), 1.26 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH:11]([CH3:30])[C:12]([OH:29])([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)[C:13]([F:16])([F:15])[F:14].[CH3:31][O:32][C:33](=[O:41])[CH2:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:31][O:32][C:33](=[O:41])[CH2:34][CH:35]1[CH2:36][CH2:37][N:38]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:11]([CH3:30])[C:12]([OH:29])([C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=4[CH:28]=3)[C:13]([F:15])([F:14])[F:16])[CH:4]=2)[CH2:39][CH2:40]1
Reactant: CC(c1cc(C(=O)O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)CC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(C(=O)c2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a solution of 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-benzoic acid (74 mg) in tetrahydrofuran (0.63 ml) were added 4-piperidine acetic acid methyl ester (32 mg), N-ethyldiisopropylamine (65 mg) and benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 113 mg). The mixture was stirred at room temperature for 18 h and then concentrated to dryness. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (82 mg) as colorless foam. MS (m/e)=583.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([Li])(CC)C.[C:15](=[O:17])=[O:16].Cl>C1COCC1.CCCCCC>[OH:6][CH:5]1[C:4]2[C:3](=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=2)[C:15](=[O:16])[O:17]1
Reactant: O=Cc1cccc(F)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OC(O)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a -70° C. solution of the dimethylacetal of 3-fluorobenzaldehyde (5.3 g, 31 mmol) in THF (35 ml) was added dropwise sec-butyllithium (22.2 ml of a 1.4 M solution in hexane), and the red solution was stirred for 0.5 h. The solution was saturated with CO2 for 5 min with tne red color dissipating to yield a light yellow solution. After 10 min the reaction was allowed to warm to room temperature, and after 30 min HCl (3.5 ml) was added. After concentration the solution was made basic with 5% KOH (25 ml), the neutral material extracted with Et2O (2×40 ml), the base layer acidified to pH 1 witn HCl, and the product extracted with EtOAc (2×75 ml). Work up as usual afforded 4.5 g (86%) of the title compound, mp 11°-119°, suitable for use in the next step. Recrystallization of this material from EtOAc/PE gave analytically pure material: mp 126°-127° C.; IR 3400 (br s), 1740-1760 (structured s), 1630 (m), 1485 (m), 1300 (m), 1085 (s), 910 (m), 760 (m); 1H NMR 7.8-7.1 (highly structured m, 3 H), 6.60 (br s, 1H); exact mass calcd for C8H5O3F m/e 168.0227, obsd 168.0226.