Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 3-bromo-1-phenylpropane. The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 4:1) to provide 0.65 g of 4-[(3-phenylpropyl)oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:16][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)=[CH:7][C:2]=2[Cl:1])=[CH:20][CH:19]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Oc1ccc(Oc2cccc(F)c2)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(Oc2ccc(OCc3ccc(Cl)cc3)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A mixture of 0.88 g of 2-chloro-4-(3-fluorophenoxy)phenol, 0.54 g of p-chlorobenzyl alcohol, 1.01 g of triphenylphosphine, 0.65 g of diethylazadicarboxylate and 90 ml of tetrahydrofuran was stirred at room temperature. After 48 hours, the reaction mixture was concentrated, and 50 ml of diethyl ether was added thereto. The precipitates were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to give 0.83 g of 4-chloro-1-[2-chloro-4-(3-fluorophenoxy)phenoxy]methylbenzene. Yield, 62%. m.p., 47.3° C.
Reaction SMILES: C([S@]([NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1)=O)(C)(C)C.N[C@@H](C1C=CC=CC=1Cl)C1SC(NC(C2(C3C=CC4OCOC=4C=3)CC2)=O)=NC=1>CC#N>[NH2:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Agent: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Solvent: CC#N
Product: N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl

Procedure:
(R)-N-(5-(Amino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide was prepared from (R)-N-(5-((R)-t-butylsulfinylamino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide using the same protocol described for (S)-N-(5-(amino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. 1H-NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.60 (dd, J=7.7, 1.7 Hz, 1H), 7.33 (dd, J=7.9, 1.3 Hz, 1H), 7.27 (td, J=7.4, 1.5 Hz, 1H), 7.20 (td, J=7.6, 1.8 Hz, 1H), 7.16 (d, J=1.0 Hz, 1H), 6.89 (td, J=8.2, 1.7 Hz, 2H), 6.81 (d, J=7.9 Hz, 1H), 6.01 (s, 2H), 5.79 (s, 1H), 1.89 (s, 2H), 1.72-1.70 (m, 2H), 1.22-1.19 (m, 2H). HPLC ret. time 2.52 min, 10-99% CH3CN, 5 min run; ESI-MS 428.2 m/z (MH+).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]([F:43])([F:42])[C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:36](=[O:37])/[CH:35]=[CH:34]/[C:33]4[CH:39]=[CH:40][CH:41]=[C:31]([C:30]([F:42])([F:43])[F:29])[CH:32]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J (142 mg, 0.333 mmol), and trans-3-(trifluoromethyl)-cinnamic acid, by the method of Example 1, step K, giving a gold solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H35F3N4O2: 553 (M+H). Found: 553.2.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]1([PH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(=O)C=C>>[C:1]([CH2:2][CH2:3][P:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CC(=O)OC
Agent: C=CC(=O)[O-]
Product: COC(=O)CCP(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 8.6 g (0.1 mole) methyl acrylate and 19.5 g (0.105 mole, 5% excess) of diphenyl phosphine was reacted at 15° C. in the routine manner of Example 1. U.V. irradiation resulted in a rapid reaction. After 1 hour, there was no acrylate left unconverted. The expected mono- and diadducts were formed in a weight ratio of about 95° to 5. (A sample of the reaction misture which was not irradiated also showed a complete conversion after 22 hours but not after 1 hour.) On distillation of the reaction mixture in vacuo, the monoadduct, i.e. 2-carbomethoxyethyl diphenyl phosphine, was obtained as an almost colorless, liquid distillate having a slight yellow tint (Table 3).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]3[C:12](=[C:13](Br)[CH:14]=2)[N:11]=[CH:10][CH:9]=[CH:8]3)[CH2:3][CH2:2]1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]1([CH2:4][C:5]2[CH:6]=[C:7]3[C:12](=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:14]=2)[N:11]=[CH:10][CH:9]=[CH:8]3)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cc(CC2CC2)cc2cccnc12
Product: c1ccc(-c2cc(CC3CC3)cc3cccnc23)cc1

Procedure:
6-(cyclopropylmethyl)-8-bromoquinoline and benzene boronic acid can be combined to form 6-(cyclopropylmethyl)-8-phenylquinoline,
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(C)c2)c2ccccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(m-tolyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(NCCN(C)C)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(NCCN(C)C)nc1
Yield: 33.2 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridine-3-ylamino)quinolin-3-yl)ethanone (100 mg, 0.23 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (101 mg, 0.35 mmol) to afford the desired product (39 mg, 33%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.28 (s, 1H), 8.26-8.17 (m, 2H), 8.04-7.99 (m, 2H), 7.67 (dd, J=9.0, 2.7 Hz, 1H), 7.28 (s, 2H), 6.93 (d, J=9.0 Hz, 1H), 3.86-3.82 (m, 2H), 3.44-3.36 (m, 2H), 2.96 (s, 6H), 2.81 (s, 3H); ESI MS m/z 510 [C26H25Cl2N5O2+H]+; HPLC 96.6% (AUC), tR=10.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1O[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[S:24][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:10]1
Reactant: O=[N+]([O-])c1ccc(C2=NOC(c3c(Cl)cccc3Cl)C2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: O=[N+]([O-])c1ccc(C2=NSC(c3c(Cl)cccc3Cl)C2)cc1

Procedure:
By the method of Asian. J. Chem., 2000, 12, 1358-1360, (±)-5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)-2-isoxazoline can be treated with diphosphorus pentasulfide followed by aqueous quench to produce (±)-5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)-2-isothiazoline. The nitrophenyl group can be reduced to the corresponding aniline with tin dichloride or iron powder and ammonium chloride. The aniline, in turn, can be treated with 2,2-dichloroacetyl chloride and triethylamine to yield (±)-2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-3-(2-isothiazolinyl)]phenyl acetamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21](C(OCC)=O)[CH2:20][CH2:19]1.[BrH:29]>O>[BrH:29].[BrH:29].[BrH:29].[NH:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:9]2[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)CC1
Agent: Br
Solvent: O
Product: c1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)nc1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
A mixture of 30 parts of ethyl 4-[[1-[(2-pyridinyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate and 300 parts of a hydrobromic acid solution 48% in water was stirred and heated for 3 hours at 80° C. The reaction mixture was evaporated and the residue was crystallized from methanol, yielding 41 parts (93.2%) of N-(4-piperidinyl)-1-[(2-pyridinyl)methyl]-1H-benzimidazol-2-amine trihydrobromide; mp. 295.9° C. (intermediate 80).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:15]C)=[C:8]([CH3:14])[C:9]=2[CH3:13])[C:4]1=[O:17])[CH3:2].Cl.N1C=CC=CC=1>O>[CH2:18]([C:3]1([CH2:1][CH3:2])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([OH:15])=[C:8]([CH3:14])[C:9]=2[CH3:13])[C:4]1=[O:17])[CH3:19]
Reactant: CCC1(CC)C(=O)c2cc(OC)c(C)c(C)c2C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC1(CC)C(=O)c2cc(O)c(C)c(C)c2C1=O
Temperature: 180 °C

Procedure:
A mixture of 2,2-diethyl-4,5-dimethyl-6-methoxy-indan-1,3-dione (5.5 g., 0.021 mole) and pyridine hydrochloride (50 g.) is heated at 180°C. for six hours then poured into water (1 l) affording 4.0 g. of 2,2-diethyl-4,5-dimethyl-6-hydroxy-indan-1,3-dione which melts at 141°-142°C. after recrystallization from methanol-water.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br[C:11]1C=C(C(F)(F)F)C=C2[C:19]=1NC=C2>>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]2[C:3]=1[NH:4][CH:19]=[CH:11]2
Reactant: Nc1ccc(Cl)cc1Br
Reactant: FC(F)(F)c1cc(Br)c2[nH]ccc2c1
Product: Clc1cc(Br)c2[nH]ccc2c1

Procedure:
Made from 2-bromo-4-chloroaniline using the method for 7-bromo-5-(trifluoromethyl)-1H-indole. 1H-NMR (CDCl3, 400 MHz) δ 8.32 (bs, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.27 (t, J=3.0 Hz, 1H), 6.56 (dd, J=3.3, 2.3 Hz, 1H). LC/MS (HPLC method 4): tR=3.07 min, 229.95(MH)+.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH2:9][CH3:10])[N:4](COCC[Si](C)(C)C)[C:3]=1[CH:19]=[O:20].C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:19]=[O:20]
Reactant: CCCOc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(Br)c(C=O)[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 102.3 %

Procedure:
5-Bromo-2-propoxy-3-(2-trimethylsilanylethoxymethyl)-3H-imidazole-4-carbaldehyde (43.6 g, 120 mmol) was cooled at 0° C. in ice. TFA (200 mL, 2 mol) was added and the mixture was stirred at 0° C. for 15 minutes, then warmed to room temperature. After 20 minutes, the mixture was concentrated under reduced pressure and redissolved in EtOAc (300 mL). The organic was washed with saturated bicarbonate (200 mL), saturated aqueous NaCl, dried over MgSO4 and concentrated under reduced pressure to produce the title compound (28.6 g) as a yellow solid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:10][C:5]2=[C:4]([O:22]C)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl>O>[N:24]1([C:2]2[NH:7][C:6]3[N:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]=[CH:14][CH:13]=4)[CH:9]=[N:10][C:5]=3[C:4](=[O:22])[CH:3]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: COc1cc(Cl)nc2c1ncn2Cc1cccc2ccccc12
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Product: O=c1cc(N2CCOCC2)[nH]c2c1ncn2Cc1cccc2ccccc12
Yield: 28.2 %

Procedure:
A mixture of 5-chloro-7-(methyloxy)-3-(1-naphthalenylmethyl)-3H-imidazo[4,5-b]pyridine (140 mg, 0.432 mmol) and morpholine (2.5 mL, 28.7 mmol) was irradiated in a microwave oven for 4 h at 200° C. The mixture was diluted with water and the pH was adjusted to ca. 7 by the addition of 1 N HCl. The precipitate formed was collected, washed with water and air dried. It was then dissolved in DMSO and purified by RP-HPLC (Gilson, 25-80% AcCN in water plus 0.1% TFA). The fractions containing product were collected, neutralized by the addition of aqueous NaHCO3 sat sol and the volume was reduced to ½-⅓ of the original. The precipitate was collected by filtration, washed with water and dried overnight in a vacuum oven at 45° C. to give 5-(4-morpholinyl)-3-(1-naphthalenylmethyl)-3,4-dihydro-7H-imidazo[4,5-b]pyridin-7-one (45 mg, 0.122 mmol, 28.3% yield). MS (ES+) m/e 361 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (br. s., 1H), 8.32-8.47 (m, 1H), 8.00 (s, 1H), 7.94-7.98 (m, 1H), 7.89 (d, J=8.08 Hz, 1H), 7.52-7.61 (m, 2H), 7.47 (dd, J=8.08, 7.07 Hz, 1H), 7.35 (d, J=6.32 Hz, 1H), 6.07 (s, 1H), 5.77 (s, 2H), 3.65-3.75 (m, 4H), 3.35-3.43 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][F:11])=[CH:4][CH:3]=1.[Br:17]Br.O>C(Cl)Cl>[Br:17][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=1)[C:8](=[O:14])[C:9]([CH3:12])([CH3:13])[CH2:10][F:11]
Reactant: BrBr
Reactant: CC(C)(CF)C(=O)COc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Yield: 78.3 %

Procedure:
175 g (0.71 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 500 ml of methylene chloride, and 114 g (0.71 mol) of bromine were added dropwise at 20° to 30° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, 200 ml of water were added carefully and the methylene chloride phase was washed several times with ice-water and dried over sodium sulphate. After distilling off the solvent in vacuo, the residue was recrystallized from cyclohexane. 180 g (78% of theory) of 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone of melting point 73° to 75° C. were obtained. ##STR16##
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][N:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=2)=[O:13])[CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (108.0 mg, 0.18 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid (101.2 mg, 95.9%). FIRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.1627; Found: 600.1629.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].NC1N=C(O)C=C(O)N=1.Br[C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1>C(O)=O.O.CN1C(=O)CCC1>[S:30]1[CH:26]=[CH:27][CH:28]=[C:29]1[C:31]([OH:33])=[O:32].[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C(O)c1ccc(Br)s1
Agent: Nc1nc(O)cc(O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=CO
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccs1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Charged benzimidazole (III) (28.98 mmoles), cesium carbonate (33.81 mmoles), cuprous oxide (0.918 mmoles), 2-amino-4,6-dihydroxypyrimidine (3.62 mmoles), PEG (28.98 mmoles), 5-bromo-thiophen-2-carboxylic acid (IV)(24.15 mmoles) and NMP (10 ml) to the 100 ml RB flask fitted with thermo well and condenser. The reaction mixture was heated to 160° C. and maintained for 18-20 hrs. After completion of reaction, cooled the reaction to room temperature, added water (100 ml) and adjusted the pH to ˜4.5-5 using formic acid. Filtered off the precipitated solid and washed with water (2×25 ml). The solid was then dissolved in methanol (250 ml), filtered through a celite bed, distilled of the solvent completely under reduced pressure. To the residue IPA (25 ml) was added to precipitate the product, stirred for 30 min, filtered and dried to get the compound (V).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][O:7][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CO)cc(OC)c1
Agent: c1c[nH]cn1
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A mixture of 3,5-dimethoxybenzyl alcohol (4.0 g), t-butyl-diphenylsilyl chloride (6.54 g) and imidazole (3.28 g) in DML (60 mL) was stirred at room temperature for 24 h. DMF was evaporated and the residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 20%) to yield 8.5 g of 3,5-dimethoxy-1-[(t-butyldiphenylsilyloxy)methyl]benzene. ESMS: m/z 407 (MH+).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[C:5]([CH3:14])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])#[N:2].[NH2:18][C:19]12[CH2:25][C:22]([C:26]([NH2:28])=[O:27])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>C(O)C.CN(C)C1C=CN=CC=1>[C:1]([N:3]=[C:4]([NH:18][C:19]12[CH2:25][C:22]([C:26]([NH2:28])=[O:27])([CH2:21][CH2:20]1)[CH2:23][CH2:24]2)[C:5]([CH3:6])([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:14])#[N:2]
Reactant: NC(=O)C12CCC(N)(CC1)C2
Reactant: CCOC(=NC#N)C(C)(C)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C(N)=O)(CC1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of ethyl N-cyano-2-methyl-2-phenoxypropanimidoate (CI-1) (300 mg, 1.29 mmol) and 4-aminobicyclo[2.2.1]heptane-1-carboxamide (BA-7) (217 mg, 1.29 mmol) in ethanol (3 mL) was added 4-(dimethylamino)pyridine (47 mg, 0.387 mmol). The mixture was stirred at room temperature for 5 hours and then heated to 75° C. and stirred overnight. After concentration, the residue was purified by preparative reverse phase HPLC [Waters 2767; Benetnach 10-C18 20×250 mm, 10 μm; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/minute; detection at 214 and 254 nm] to give the titled compound. 1H NMR (400 MHz, CD3OD) δ ppm 7.34 (t, J=7.8 Hz, 2H), 7.14 (t, J=7.4 Hz, 1H), 7.0 (d, J=8.4 Hz, 2H), 2.10-2.15 (m, 4H), 2.01-2.03 (m, 4H), 1.79-1.83 (m, 2H), 1.72 (s, 6H); LCMS (ESI+) m/z 341.7 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:45]=[CH:46][CH:47]=1)[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>O1CCOCC1>[F:38][C:36]([F:37])([F:39])[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:20]3[CH:19]=[C:18]([NH:17][C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:16])[CH:47]=[CH:46][CH:45]=3)[CH2:27][CH2:26]2)=[CH:30][CH:31]=1)([OH:44])[C:40]([F:43])([F:42])[F:41]
Reactant: Nc1cccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1cccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 100 °C
Yield: 22.5 %

Procedure:
A mixture of phenyl pyridin-4-ylcarbamate (1.173 mmol, 251 mg) and 2-(4-((4-(3-aminobenzyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.782 mmol, 350 mg) in dioxane was heated in a Reactivial at 100° C. for 3 days. The reaction was then concentrated under reduced pressure. Chromatography on silica eluting with a gradient of dichloromethane to dichloromethane/methanol gave the title compound (100 mg). MS (ESI) m/z 568.5 [M+H]+