Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: COCCNS(=O)(=O)c1cccc(Br)c1
Yield: 96.9 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 2-methoxyethyl amine (1.62 g, 22 mmol) to give the title compound (5.7 g, 99%) as light-yellow liquid. MS (ISP) 294.0[(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:14][C:13]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1
Reactant: O=Cc1ccc(Cl)c(-n2cccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(-n2cccc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-(1H-pyrrol-1-yl)benzaldehyde in an analogous manner to that described in Example 1 gave 9-[4-chloro-3-(1H-pyrrol-1-yl)phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. This product was recrystallized from dimethylformamide/water and gave a yellow crystalline solid of melting point 282-283° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: O=C1CCCCN1
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure I using 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.01 mmol) and piperidin-2-one to give 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one. Mass Spectrum (ESI) m/e=311.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:23]([O:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH:23]([CH3:25])[CH3:24])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)Oc1cccc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(OC(C)C)c2)CC1
Yield: 93 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-isopropoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16]=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:10]=[CH2:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=O
Reactant: CN(C)C(=O)N(N)c1ccc(F)c(Cl)c1
Solvent: c1ccccc1
Product: C=NN(C(=O)N(C)C)c1ccc(F)c(Cl)c1
Reaction time: 18 h
Yield: 7.9 %

Procedure:
To a solution of 54.3 g of 2-(3-chloro-4-fluorophenyl)-4,4-dimethylsemicarbazide in 300 ml of benzene was added rapidly 40.5 g of 37% formaldehyde, followed by 240 g of Mg2SO4 at ambient temperature. After several days, an additional 40 g of 37% formaldehyde was added and the mixture was stirred for 18 hours. The resulting product was filtered and the filtrate was concentrated to dryness leaving an amber syrup which was purified by silica chromatography to yield 4.5 g of formaldehyde 2-(3-chloro-4-fluorophenyl)-4,4-dimethylsemicarbazone as a viscous oil.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[CH:26][CH:27]=1)=[S:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a stirred near solution of tert-butyl N-(4-{[(benzoylamino)carbothioyl]amino}benzyl)carbamate (10.4 g, 27.0 mmol) in MeOH (150 ml) was added a solution of K2CO3 (8.5 g, 61.5 mmol) in 15 ml water. The solution was stirred at room temperature for 24 hours and filtered to remove a white precipitate. The filtrate was evaporated in vacuo to yield 100% (7.6 g) of the desired product as an off-white solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Oc1cccc(F)c1
Product: Nc1nnc(Oc2cccc(F)c2)c(-c2ccccc2)n1
Yield: 23.2 %

Procedure:
6-(3-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (78 mg, 23%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-fluoro phenol (0.27 g, 2.39 mmol) according to the general procedure of Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:26][CH:27]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: CCOC(=O)C(C)(C)Cc1nc2ccc(O)cc2n1Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1nc2ccc(OCc3ccc(C)cn3)cc2n1Cc1ccc(Br)cc1
Reaction time: 12 h

Procedure:
To a 10 mL round-bottomed flask were added a stir bar, ethyl 3-(1-(4-bromobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (100 mg, 0.23 mmol), cesium carbonate (227 mg, 0.69 mmol), DMF (2 mL), and 2-(chloromethyl)-5-methylpyridine hydrochloride salt (41 mg, 0.23 mmol). After 12 h, the mixture was partitioned between water (50 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (2×20 mL). The combine organic layers were dried with sodium sulfate, filtered, and concentrated to dryness (124 mg, 99%). MS (ESI): mass calcd. for C28H30BrN3O3, 535.15; m/z found, 536.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[CH3:8][N:9]([CH3:34])[C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[C:24]3[CH:25]=[C:26]([CH3:28])[O:27][C:23]=3[CH:22]=[C:21]([C:29](OCC)=[O:30])[CH:20]=2)=[CH:14][N:13]=1)=[O:11]>>[CH3:34][N:9]([CH3:8])[C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[C:24]3[CH:25]=[C:26]([CH3:28])[O:27][C:23]=3[CH:22]=[C:21]([C:29](=[O:30])[NH:7][C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)[CH:20]=2)=[CH:14][N:13]=1)=[O:11]
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Product: Cc1cc2c(Oc3cnc(C(=O)N(C)C)nc3)cc(C(=O)Nc3ccn(C)n3)cc2o1

Procedure:
The title compound (4) was prepared by a method analogous to that described in Example 1 using 1-methyl-1H-pyrazol-3-amine and ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a)
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:34])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:17]=2)=[C:10]([Cl:35])[CH:9]=1)=[O:6].[OH-].[Na+]>CO.O.[OH-].[K+]>[Cl:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:36])=[O:2])[CH:9]=[C:10]([Cl:35])[C:11]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:34])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:17]=1
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(NC(=O)CC(=O)OC)cc2Cl)ccc1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(NC(=O)CC(=O)O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[3,5-Dichloro-4-(4-hydroxy-3-nonylcarbamoyl-phenoxy)-phenyl]-malonamic acid methyl ester (78 mg, 0.14 mmol) was dissolved in a mixture of MeOH (2 ml), water (1.5 ml), and 1 M NaOH (0.5 ml, 0.5 mmol). The resulting solution was stirred at RT for 2 h then diluted with 15 ml 0.1 M KOH. The solution was washed with a 1:1 mixture of Et2O and EtOAc (3×10 ml) and the combined organic washings were extracted with 0.1 M KOH (2×10 ml). The combined basic solutions were acidified with concentrated HCl and extracted with EtOAc (3×15 ml) and the combined organic extracts washed with brine. The dried extracts were filtered and concentrated to give the title compound of Step G and Example 3, (64 mg). MS (APCl+) Calc.: 524.1, Found: 525.1 (M+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=C(C(C3N=CC4CCCCC=4C=3)=O)[NH:22]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:2]([C:3]([C:5]3[CH:14]=[CH:13][C:8]4[O:9][CH2:10][CH2:11][O:12][C:7]=4[CH:6]=3)=[O:4])[NH:22]2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Product: COC(=O)Cc1c(C(=O)c2ccc3c(c2)OCCO3)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 6-bromoacetyl-2,3-dihydro-1,4-benzodioxine (J. Med. Chem. 1972, 15, 49) and methyl trans-4-chloro-2-[(phenylsulfonyl)amino]cinnamate (Example 1, step 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].C[Si](C)(C)[O:16][CH2:17][CH2:18]O[Si](C)(C)C.C(Cl)Cl>FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:8]2[O:16][CH2:17][CH2:18][O:9]2)[CH:10]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1
Temperature: -78 °C
Yield: 99.2 %

Procedure:
5-Methoxy-2-nitro-benzaldehyde (30.00 g, 0.1656 mol) and 1,2-bis-trimethylsilanyloxy-ethane (40.6 mL, 0.166 mol) were placed in a 40 mL vial, followed by Methylene chloride (1000 mL, 20 mol). The reaction mixture was then cooled to −78° C., and trimethylsilyl trifluoromethanesulfonate (1 mL, 0.008 mol) was added dropwise under N2. The reaction mixture was allowed to warm up to at 23° C. for 1 day. A solution of saturated K2CO3 (50 mL) was added to quench the reaction, and organic layer was separated. Removal of solvent gave a oily product, which was treated with ether/hexanes to give a pure solid product (37.0 g, 99%). NMR (MeOD) δ: 8.01 (d, J=9.0 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.05 (dd, J=8.9, 2.9 Hz, 1H), 6.49 (s, 1H), 4.85 (s, 3H), 3.91 (s, 4H). MS (M+1): 226.10.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:42]>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:25])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:41]([O:43][C:44]3[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=3)=[O:42])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCCCCO)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A solution of the alcohol (40.0 g, 88 mmol) produced in Example 4 and pyridine (7.1 ml, 88 mmol) in 300 ml of methylene chloride was added under nitrogen dropwise over one hour to a solution of 4-nitrophenyl chloroformate (17.7 g, 88 mmol) in 300 ml of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for two hours and overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 54.9 g of an off-white solid. Recrystallization from 1:1 ethyl acetatehexane gave 51.6 g (95%) of the title compound as a white crystalline solid, mp 117-120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](O)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B.CSC.Cl.C1C[O:22]CC1>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([OH:22])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Product: CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 g of 3-nitrophenylacetic acid was added to a solution of 26 ml of 10 M borane-methyl sulfide in 200 ml of THF, and the mixture was stirred at 25° C. for 3 hr. The solution was then acidified with HCl in methanol, followed by evaporation of the solvent. The product 3-nitrophenylethanol (IV, A=H) was partitioned between diethyl ether (Et2O) and aqueous sodium carbonate, and the Et2O layer dried over sodium sulfate. Evaporation of the Et2O afforded 34.8 g of 3-nitrophenylethanol (IV, A=H) as an oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:63]5[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:33])([F:34])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-(trifluoromethyl)benzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34-1.67 (m, 9 H) 1.70-1.85 (m, 3 H) 2.13 (br. s., 1 H) 2.27 (s, 3 H) 2.84-2.93 (m, 1 H) 3.32 (s, 3 H) 3.74-3.86 (m, 1 H) 4.00 (t, J=14.0 Hz, 1 H) 4.50 (quin, 1 H) 7.96 (d, J=8.6 Hz, 1 H) 8.12 (dd, 1 H) 8.20 (s, 1 H) 8.21 (s, 1 H) 8.48 (d, J=7.8 Hz, 1 H) 8.52 (s, 1 H). [M+H] calc'd for C27H32F5N7O2, 582; found 582.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:34])[OH:33])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH3:39][C:40]([CH3:58])([CH2:43][N:44]1[CH:48]=[C:47]([B:49]2[O:53][C:52]([CH3:55])([CH3:54])[C:51]([CH3:57])([CH3:56])[O:50]2)[CH:46]=[N:45]1)[CH2:41]O.CN1C=CN=C1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:33])[O:34][CH2:39][C:40]([CH3:58])([CH3:41])[CH2:43][N:44]4[CH:48]=[C:47]([B:49]5[O:53][C:52]([CH3:55])([CH3:54])[C:51]([CH3:57])([CH3:56])[O:50]5)[CH:46]=[N:45]4)=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CC(C)(CO)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cn1ccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
A suspension of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinic acid (Compound 74B, 0.500 g, 0.810 mmol) and 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 47B, 227 mg, 0.809 mmol) in 1,2-dichloroethane (24.4 mL) and 1-methylimidazole (0.967 mL, 12.1 mmol) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (2530 mg, 4.85 mmol). After stirring at 60° C. for 16 hours, the reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an off-white foam (318.1 mg, 45%). MS (ESI): m/z 879.93/881.94 [M+H]+. UPLC: tR=1.67 min (UPLC-TOF: polar—2 min).
Reaction SMILES: O([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])C1C=CC=CC=1.[CH3:16][C:17]1(C=O)[C:22]([CH3:23])=[CH:21][CH:20]=[C:19](C2C=CC=CC=2)[CH2:18]1>>[CH3:16][C:17]1[CH:18]=[C:19]([C:15]2[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][CH:14]=2)[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1=CC=C(c2ccccc2)CC1(C)C=O
Product: Cc1ccc(-c2ccc(C=O)cc2)cc1C

Procedure:
3-phenoxybenzaldehyde for 3,4-dimethylbiphenyl-3-carbaldehyde, the following compounds were generated:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1/[CH:6]=[CH:7]/[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:37])=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2/[CH:6]=[CH:7]/[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: CCOC(=O)c1ccc(/C=C/C2CCCN2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(/C=C/C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)cc1
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of ethyl (E)-4-[2-(2-pyrrolidinyl)ethenyl]benzoate (434 mg, 1.77 mmol), pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (797 mg, 1.77 mmol), Et3 N (0.37 mL, 2.66 mmol) in DMF (15 mL) was stirred for 15 hr. The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2×200 mL), dried over MgSO4, and evaporated off in vacuo. The residue was chromatographed on silica-gel with CHCl3-EtOAc (4:1) as eluent to give 906 mg (q.y.) ethyl (E)-4-[2-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate as a brown oil. 1H-NMR (CDCl3) δ 1.39 (3 H, t, J=7.3 Hz), 1.83–2.20 (4 H, series of m), 2.24 (3 H, d, J=4.9 Hz), 3.63 (4 H, m), 4.36 (2 H, q, J=7.3 Hz), 4.62 and 4.84 (total 1 H, m), 6.18–6.47 (2 H, m), 7.03–8.02 (14 H, series of m).
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH3:28][C:29]1[NH:30][C:31]([CH3:40])=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>CCCCCC.CCOCC>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:36]3[N:35]=[C:34]([C:33]4[CH:32]=[C:31]([CH3:40])[NH:30][C:29]=4[CH3:28])[CH:39]=[CH:38][CH:37]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(-c2ccccn2)c(C)[nH]1
Reactant: Brc1ccc(C2CCN(Cc3ccccc3)CC2)cc1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(-c2cccc(-c3ccc(C4CCN(Cc5ccccc5)CC4)cc3)n2)c(C)[nH]1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 32.3 %

Procedure:
To a 125 mL three-necked round-bottomed flask equipped with septum and N2 inlet were added 2.93 g (8.88 mmol) N-benzyl-4-(4-bromophenyl)piperidine and 30 mL dry ether. The solution was cooled to −70° C., and 6.66 mL (10.65 mmol) of a 1.6 N solution of butyl lithium in hexane added dropwise over 5 minutes. After stirring a further 5 minutes at −70° C., the solution was warmed slowly to room temperature over 25 minutes. A solution of 1.83 g (10.65 mmol) 2-(2,5-dimethylpyrrolyl)pyridine in 10 mL dry ether was then added dropwise over 5 minutes, and the reaction, which turned slowly dark red, stirred at room temperature for 3 hours. The reaction was quenched with aqueous ammonium chloride solution, partitioned between ethyl acetate and water, and the organic layer separated, washed with brine, and dried over sodium sulfate, allowing it to stand overnight to effect rearomatization of the pyridine ring. After evaporation of the solvent, the residue was chromatographed on silica gel using ethyl acetate/hexane followed by methanol/methylene chloride as eluant to afford 1.21 g (32%) of an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([O:10][CH3:9])=[O:20])[CH:13]=2)[N:3]=1
Reactant: C#Cc1cccc(C(=O)OC)c1
Reactant: Brc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C#Cc2cccc(Br)n2)c1
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A solution of 15.1 g of 2,6-dibromopyridine in 500 ml of triethylamine is mixed under ice cooling with 10.2 g of 3-ethinylbenzoic acid methyl ester, 1.1 g of bis-(triphenylphosphine)-palladium(II) chloride ad 150 mg of copper(I) iodide and the mixture is stirred for 1 hour. Then, the ice bath is removed and it is stirred for 48 hours at room temperature. The precipitate is filtered off, the filtrate is evaporated to dryness, mixed with water and shaken out with ethyl acetate. The organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-12% ethyl acetate. 4.8 g of 2-bromo-6[2-(3-methoxycarbonylphenyl)-ethinyl]-pyridine of melting point 124°-126° C. is obtained.