Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:48]=[CH:49][CH:50]=1)[C:34]([NH:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][N:43]([CH3:47])[CH2:44]2)=[CH:39][CH:38]=1)=[O:35]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH:29][CH2:30][C:31]1[CH:50]=[CH:49][CH:48]=[C:33]([C:34](=[O:35])[NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][N:43]([CH3:47])[CH2:44]3)=[CH:39][CH:38]=2)[CH:32]=1)=[O:9]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(C)CC4)c2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-chloro-4-methoxybenzoic acid dihydrochloride (29 mg, 150 mmol), EDC (30 mg, 150 mmol), HOBt (22 mg, 150 mmol), and TEA (0.057 mL, 408 mmol) in anhydrous DMF (5 mL) was stirred at room temperature for 30 min. To this was added 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide. (50 mg, 136 mmol) and the solution stirred at room temperature for 24 h. The reaction was diluted EtOAc (100 mL) and quenched with sat. NH4Cl (100 mL). The organic fraction was dried (Na2SO4). The residue was purified by flash chromatography using a methanol/methylene chloride gradient to provide 31 mg of 3-chloro-4-methoxy-N-[3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray, 464 (M+H).
Reaction SMILES: [C:1]1([CH2:7]C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC=O)C=CC=CC=1.C1([CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C=CC=CC=1>>[C:1]1([CH2:7][CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Reactant: NC(=O)Cc1ccccc1
Agent: O=CCCc1ccccc1
Product: O=C(Cc1ccccc1)NC(CCc1ccccc1)NC(=O)Cc1ccccc1
Yield: 92 %

Procedure:
Compound 45 was prepared from 2-phenylacetamide and 3-phenylpropanal using the procedure for compound 44. Yield: 92%. 1HNMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.6 Hz, 2H), 7.10-7.31 (m, 15H), 5.26 (t, J=7.6 Hz, 1H), 3.38-3.46 (m, 4H), 2.47-2.53 (m, 2H), 1.88-1.94 (m, 2H). LCMS (ESI): m/z 387.3 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]([F:23])=[C:21]3[C:17]([C:18]([NH2:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:22]([F:23])=[C:21]3[C:17]([C:18]([NH2:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A suspension of 3 g of tert-butyl[4-(3-amino-7-fluoro-1H-indazol-6-yl)phenyl]carbamate in 60 mL of dichloromethane is admixed at ambient temperature with 6 mL of trifluoroacetic acid. The reaction mixture is stirred at ambient temperature for 18 h and concentrated to dryness under reduced pressure. The solid obtained is taken up in ethyl acetate and the solution is treated with 4N aqueous sodium hydroxide solution and then decanted. The organic phase is subsequently washed with distilled water, then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The yellow solid obtained (2.08 g) is chromatographed on a silica column (eluent: ethyl acetate). Evaporation to dryness under reduced pressure of the fractions containing the expected product gives 1.88 g of 6-(4-aminophenyl)-7-fluoro-1H-indazol-3-ylamine in the form of a yellow solid, whose characteristics are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][C:26](Cl)=[O:27].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[N:15]1[CH:24]=[CH:25][C:26]([OH:27])=[N:16]1
Reactant: O=C(Cl)CCBr
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(-n2ccc(O)n2)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.2 %

Procedure:
12 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 200 mL of tetrahydrofuran, and 100 mL of water was added. To this solution, 16 g of potassium carbonate and 8.1 g of 3-bromopropionyl chloride were added, followed by stirring at room temperature for 5 hours. The aqueous layer was neutralized to the vicinity of pH 2 with 6N hydrochloric acid. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid, which was washed with hexane. Then, this solid was dissolved in 200 mL of toluene, and 100mL of water was added. Then, 3.7 g of potassium permanganate and tetra n-butyl ammonium bromide in a catalytic amount were added, followed by stirring at room temperature for 10 minutes. Then, an insoluble solid was removed by filtration, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the solid was washed with hexane to obtain 8.7 g of pale yellow crystals (melting point: 166-168° C.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].C(N(CC)CC)C.[CH2:14]([NH:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].Cl>COC1CCCC1>[CH2:14]([N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:2](=[O:3])[O:4][CH2:5][Cl:6])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNCCCC
Reactant: O=C(Cl)OCCl
Agent: Cl
Solvent: COC1CCCC1
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)OCCl
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Chloromethyl chloroformate (5.0 ml) was added dropwise to 100 ml of a solution of 11.7 ml of triethylamine and 11.3 ml of N,N-di-n-butylamine in cyclopentyl methyl ether under ice cooling, and the mixture was stirred at room temperature for 13 hr. 2 N hydrochloric acid (100 ml) was added thereto, followed by separation. The organic layer was washed with 100 ml of a 5% aqueous sodium hydrogencarbonate solution and 100 ml of semi-saturated brine, was dried over anhydrous magnesium sulfate, and was filtered, and the solvent was removed by distillation under the reduced pressure to give 12.7 g of chloromethyl N,N-di-n-butylcarbamate.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH:22][CH2:21][CH:20]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:19]2>C1COCC1>[CH2:25]([N:24]([CH2:28][CH2:29][CH3:30])[CH:20]1[CH2:19][C:18]2[C:23]3=[C:14]([O:13][C:1](=[O:2])[N:22]3[CH2:21]1)[CH:15]=[CH:16][CH:17]=2)[CH2:26][CH3:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCN(CCC)C1CNc2c(O)cccc2C1
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cccc3oc(=O)n(c23)C1
Reaction time: 0.08 h
Yield: 86.6 %

Procedure:
Carbonyldiimidazole (0.46 g, 2.8 retool) was added to a stirred solution of 1,2,3,4-tetrahydro-8-hydroxy-N, N-dipropyl-3-quinolinamine (0.59 g, 2.4 mmol) in THF (10 mL). After 5 minutes, the solvent was removed and the residue was dissolved in ethyl acetate and chromatographed on silica gel using 5% ethyl acetate in hexane as the initial eluant to give 0.57 g of 5-(dipropylamino)-5,6-dihydro-2H,4H-oxazolo(5,4,3-ij)quinolin-2-one as an oil.
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:19][S:20][C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)[C:13]=3[CH3:30])[CH2:6][O:5]2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH2:3]1[C:4]2([O:5][CH2:6][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:19][S:20]([C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[O:39])[C:13]=3[CH3:30])[CH2:8][O:9]2)[CH2:1][CH2:2]1
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC2(CCC2)OC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC2(CCC2)OC1
Reaction time: 0.92 h
Yield: 86.1 %

Procedure:
To a toluene (20 ml)-methanol (2 ml) solution of the 2-(((4-(5,9-dioxaspiro[3.5]non-7-ylmethoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (499 mg, 1.17 mmol) obtained in the step (13d), a toluene (1 ml)-methanol (1 ml) solution of 3-chloroperbenzoic acid (280 mg, 1.05 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred in the same conditions for 55 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing the title compound were collected with ethyl acetate, and concentrated. To the residue, diethyl ether was added and then the mixture was concentrated to obtain the title compound (445 mg, yield: 86.1%) as a colorless foam.
Reaction SMILES: [C:1](CCSCCC#N)#[N:2].[C:10]([NH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[N:32]=[N:33][C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([N+:43]([O-:45])=[O:44])=[CH:36][C:35]=1Br)[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C-]#N.[Na+]>O>[C:10]([NH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[N:32]=[N:33][C:34]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][C:37]([N+:43]([O-:45])=[O:44])=[CH:36][C:35]=1[C:1]#[N:2])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCSCCC#N
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(=O)C=Cc2ccccc2)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(=O)C=Cc2ccccc2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85.5 %

Procedure:
Into a solution composed of 6.8 parts of cuprous bromide in 300 parts by volume of bis(β-cyanoethyl) sulfide, there are introduced 26 parts of 3-cinnamoylamino-4-(2'-bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline. The mixture is heated to 100° C. and, during several minutes, a solution of 2.6 parts of sodium cyanide in 16 parts of water is allowed to flow in. Stirring is continued for 1 to 2 hours more, at 115° C. After cooling to 30° C., the 3-cinnamoylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline formed is separated, under the same conditions as in example 1. The yield is 85.5%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.Cl[C:32]1[N:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=1)[O:1][C:32]1[N:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 75.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (200 mg, 0.464 mmol) synthesized in Example (38d) and methyl 5-chloropyrazine-2-carboxylate (120 mg, 0.695 mmol) synthesized in Example (62b) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (257 mg, 1.86 mmol) was added, followed by stirring at 80° C. for 7 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%). The resulting yellow solid was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (4 mL) was added, followed by stirring at room temperature for 1.5 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%) to afford the desired compound (164 mg, yield 93%) as a yellow solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH:12]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A mixture of dry DMSO (223.26 mmol, 4.0 eq.) and dry methylene chlloride (100 ml) was added dropwise to a solution of oxalyl chloride (111.63 mmol, 2.0 eq.) in dry methylene chloride (100 ml) at −78° C. A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (55.81 mmol, 1.0 eq.) in dry methylene chloride (100 ml) was added dropwise to the reaction mixture at same temperature and it was then stirred for 30 min. Et3N (279.07 mmol, 5.0 eq.) was added at −78° C. and the reaction mixture allowed to slowly warm to 25° C. and stir for another 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (200 ml), diluted with methylene chloride (100 ml) and the layers were separated. The organic layer was washed with brine (200 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude desired product as light orange oil which is used in the next step without purification. Yield: 95%
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=[N:3]1.O.[NH2:25]N.O.C([O-])(O)=O.[Na+]>Cl.C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:4](=[O:5])[NH:3][N:25]=[C:15]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NN
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(=O)[nH]nc(-c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 21.6 %

Procedure:
A suspension of [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-phenyl-methanone (34 g, 11 mmoles), prepared as described in example 12, in 3N HCl (45 ml) was refluxed under stirring for 2 days, then added with 36% HCl (10 ml). After 20 hours the mixture was cooled and extracted more times with CHCl3. The organic phases were anhydrified and brought to dryness. The residue was dissolved in acetic acid and treated with hydrazine monohydrate (0.96 g, 19.24 mmoles) in acetic acid (7 ml). The mixture was heated to 80° C. under dry N2 and stirring for 20 hours, then brought to small volume, poured into water, neutralised with NaHCO3 in excess and extracted with CHCl3. The organic phases anhydrified and brought to dryness yielded 0.6 g of the title compound (yield: 37%). m.p.: 230-235° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][O:26][C:27]1[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:28]=1[CH2:29][N:30]1[C@H:33]([CH2:34][CH:35]=O)[C@H:32]([N:37]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:38](=[O:47])[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:31]1=[O:57]>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:35][CH2:34][C@@H:33]1[C@H:32]([N:37]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:38](=[O:47])[O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:31](=[O:57])[N:30]1[CH2:29][C:28]1[CH:58]=[CH:59][C:60]([O:62][CH3:63])=[CH:61][C:27]=1[O:26][CH3:25]
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2CC=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2CC=C(Br)Br)cc1
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of PPh3 (302.4 mg, 1.15 mmol) in DCM (1 mL) at 0° C. was added CBr4 (192 mg, 0.58 mmol). After 10 min, a solution of benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-(2-oxoethyl)azetidin-3-yl)(4-methoxybenzyl)carbamate (152.7 mg, 0.29 mmol) in DCM (800 μL) was added dropwise followed by DCM (800 μL) wash. After 20 min, the reaction mixture was diluted with DCM and water, and the layers were separated. The aqueous layer was extracted with DCM (2×). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (0-40% EtOAc-Hept) to afford the title compound (162 mg, 82%). LCMS: Rt=1.2 min, m/z=689.1 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:33])=O.C1(C)C=CC=CC=1>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Yield: 89.4 %

Procedure:
A mixture of 4-hydroxy-1-oxo-6-(4-propoxy-phenoxy)-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester (495 mg, 1.20 mmol), POBr3 (379 mg, 1.32 mmol), and toluene was microwaved at 110° C. for 25 min. Subsequently, the mixture was diluted with EtOAc, washed with aqueous NaHCO3 and saturated NaCl solution before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title product (509 mg) that was used in the next step without further purification. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.74 (s, 1H), 8.19 (d, 1H, J=9.2 Hz), 7.60-7.46 (m, 2H), 7.07-6.92 (m, 4H), 4.46 (t, 2H, =7.1 Hz), 3.94 (t, 2H, J=6.6 Hz), 1.83 (m, 4H), 1.45 (m, 2H), 1.10-0.94 (m, 6H).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][C:28]=2[Cl:33])=[C:23]([F:34])[CH:22]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][C:28]=2[Cl:33])=[C:23]([F:34])[CH:22]=1)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1ncc(Cl)c1-c1ccc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)NC(CN)Cc2ccccc2)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl]carbonyl}amino)-3-phenylpropyl]carbamate in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[Cl:25]>ClCCl>[Cl:25][C:19]1[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:14]([C:10]1[CH:9]=[C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:13]=[CH:12][N:11]=1)=[O:16]
Reactant: Nc1ccc(O)cc1Cl
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1Cl)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-chlorophenol (Chontech), the title compound was obtained as a white solid after trituration in dichloromethane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:24][C:25]1[N:26]=[CH:27][NH:28][C:29]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:24][C:25]1[N:26]=[CH:27][NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1[nH]cnc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Br)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (36.1 mg, 0.105 mmol), 4-bromo-1H-imidazole-5-carboxylic acid (20.0 mg, 0.105 mmol) and diisopropylethyl amine (0.0366 mL, 0.210 mmol) in DMF (5 ml) was added HATU (39.8 mg, 0.105 mmol) and the mixture was stirred at rt for 30 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-bromo-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (11.0 mg, 0.021 mmol, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27-8.50 (m, 1H), 8.11 (s, 1H), 7.76-7.89 (m, 2H), 7.74 (s, 1H), 7.50 (dd, 1H), 7.37 (t, 1H), 4.50 (d, 2H). LC-MS (ES+) m/z 516.90, [M+H].