Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O-])(O)=O.[Na+]>CO>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)OC
Yield: 95 %

Procedure:
a-Benzylacrylic acid (1.00 g, 6.17 mmol) in methanol (20 ml) was treated with BF3 ·Et2O (2 ml). The mixture was heated to reflux for 14 h, cooled, and poured into saturated NaHCO3 solution. Extraction with ether followed by drying over Na2SO4 and evaporation afforded 1.03 g (95%) of a mobile oil. 1H NMR (CDCl3) δ 7.17-7.35 (m, 5H), 6.23 (m, 1H), 5.47 (m, 1H), 3.74 (s, 3H), 3.63 (s,2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1Cl>C1(C)C=CC=CC=1>[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1
Reactant: NCC1CCNCC1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1c(N2CCC(CN)CC2)nc2ccccc21

Procedure:
27 g of 4-aminomethylpiperidine are placed in 300 ml of anhydrous toluene in the presence of 33 g of potassium carbonate and of 33 g of 1-methyl-2-chlorobenzimidazole. The mixture is subjected to reflux for 48 hours. After evaporation, the residue is taken up in ether and an excess of hydrochloric ether. The precipitate formed is spun down, washed with ether, and then taken up in 750 ml of water and 30% caustic soda is added to give a basic pH.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][O:16][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Reactant: BrCCCOC1CCCCO1
Product: COC(=O)c1cc(COCCCOC2CCCCO2)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate (3.5 g) was reacted with 2-(3-bromopropoxy)-tetrahydropyran analogously to O5.063 to give methyl 3-tert-butyl-5-[3-(tetrahydropyran-2-yloxy)propoxymethyl]benzoate, and the latter was subsequently converted to the title compound according to the sequence O4.059 to O2.059. 1.75 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH:19]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:28])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[CH:7]1[C:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[S:10](=[O:28])[C:9]=2[CH:19]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1CC2

Procedure:
540 Mg. methyl-10,11-dihydrodibenzo[b,f]-thiepin-3-carboxylate is dissolved in 40 cc methylene chloride and m-chloroperbenzoic acid is added in small portions until TLC shows very little starting material left. Excess calcium hydroxide powder is added and the mixture filtered through celite. The organic layer is evaporated and the residue chromatographed on silica gel to afford 570 mg. (94.7%).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[OH:10][C:9]1[N:11]=[CH:12][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)NNc1ccccc1
Solvent: COC(OC)OC
Product: Oc1ncn(-c2ccccc2)n1

Procedure:
One hundred g of 1-phenylsemicarbazide was added to 500 ml of trimethyl orthoformate, and about 400 mg of p-toluenesulfonic acid was added to the mixture. It was heated on a steam bath with strong agitation for 2 hours, and was then transferred to a large flask, cooled and evaporated under vacuum. The residue was recrystallized from about 1600 ml of acetic acid to obtain 97 g of the desired intermediate, m.p. 277°-280°.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:30]N)=[CH:24][C:23]=2[O:22]1>C(O)(=O)C>[O:29]1[C:28]2[CH:27]=[CH:26][C:25]([N:30]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:24][C:23]=2[O:22][CH2:21]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccc2c(c1)OCO2
Yield: 301.7 %

Procedure:
3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) (0.2 g; 0.74 mmol) and 3,4-methylenedioxyphenylhydrazine (0.136 g; 0.89 mmol) are dissolved in a sealed tube in acetic acid (4 ml) and irradiated at 180° C. for 10 min. The solvent of the reaction mixture is removed and the crude product is purified by preparative HPLC yielding 0.80 g (30%) of the final product. MS: M=359.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10](OC(OCC)OCC)C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(F)cnc1N
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: Fc1cnc2[nH]cnc2c1
Temperature: 100 °C
Yield: 36 %

Procedure:
A stirred mixture of 5-fluoropyridine-2,3-diamine (1.13 g) from Step 1 of this Example, formic acid (0.5 mL), and triethylorthoformate (15 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-fluoro-3H-imidazo[4,5-b]pyridine (760 mg, 36% over two steps) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.09 (br s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 7.97 (d, J=7.9 Hz, 1H). LCMS (ESI) m/z 138 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([C:13]([C:16]([O:18]CC)=[O:17])([CH3:15])[CH3:14])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3].Cl>>[CH2:1]([C:4]1([C:13]([C:16]([OH:18])=[O:17])([CH3:14])[CH3:15])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCC1(C(C)(C)C(=O)OCC)C(=O)NC(=O)NC1=O
Agent: Cl
Product: C=CCC1(C(C)(C)C(=O)O)C(=O)NC(=O)NC1=O
Reaction time: 8 h

Procedure:
A mixture of 50 g. of 5-allyl-5-(1-ethoxycarbonyl-isopropyl)barbituric acid and 400 ml. of 1 N hydrochloric acid was heated under reflux for 4 hours. The solution was allowed to stand at room temperature overnight and the precipitate was collected to yield 42.5 g. (94%) of the acid, m.p. 202°-203°.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33].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>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1
Reactant: NCC(O)C(F)(F)F
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(O)C(F)(F)F)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 3-amino-1,1,1-trifluoropropan-2-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=487.4 [M+H]+.
Reaction SMILES: N[CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BrH:13].N([O-])=O.[Na+]>O>[Br:13][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: Br
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Br)Cc1ccccc1
Temperature: -10 °C

Procedure:
15.0 g (165 mmol) of DL-phenylalanine and 37.8 g (317 mmol) were dissolved in 80 ml of water. 25 ml of conc. HBr in water were added at room temperature, and the reaction solution was then cooled to −10° C. While stirring at −10° C., 7.77 g (112 mmol) of sodium nitrite were added in portions over a period of 1 h, and the reaction solution was then stirred at 0° C. for 6 h. The reaction solution was extracted with diethyl ether (4×60 ml), the combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 18.0 g (86%) of yellow oil
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.CO.O.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:27])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CO
Solvent: O
Product: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.5 g of (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of methanol is added 0.125 g of p-toluenesulfonic acid monohydrate. The solution is stirred at room temperature for 2 days and then concentrated to a small volume, and the residue partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to give methyl (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([Br:30])=[CH:25][C:24]=2[O:31][CH3:32])=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([Br:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(C)c(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate (5.12 g, 9.99 mmol) and MeOH (50.0 ml) to give a yellow suspension. Sodium methoxide (25 wt % in MeOH) (0.432 ml, 1.998 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 70° C. heating bath. After 1 h, additional portions of MeOH (25 mL) and sodium methoxide solution (ca. 0.85 mL) were added in sequence. After 7 h, the mixture was cooled and concentrated under vacuum. The residue was purified by chromatography on silica gel (80-g Redi-Sep column, 25-g silica gel loading column, loaded as a solution in MeOH-DCM, then eluted with 25-75% EtOAc/Heptane containing 10% DCM). The fractions containing product were combined and concentrated to give 6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2(1H)-one (4.233 g, 9.08 mmol, 91% yield) as a tan solid. m/z (ESI) 466.1 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:42])[C:6]([NH:8][C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])=[O:7])(=[O:3])[CH3:2].[C:43]([O:46][CH2:47][CH2:48]Br)(=[O:45])[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:43]([O:46][CH2:47][CH2:48][N:8]([C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:42])[C:9]1[C:10]([I:41])=[C:11]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C:12]([I:35])=[C:13]([C:33]=1[I:34])[C:14]([NH:16][CH:17]([CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:15])(=[O:45])[CH3:44]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(C)OC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)OCCN(C(=O)C(C)OC(C)=O)c1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I

Procedure:
5-(2-Acetoxypropionylamino)-3-acetoxymethyl-N-(1,3,4-triacetoxybut-2-yl)-2,4,6-triiodobenzamide (Example 37a) was N-alkylated using 2-bromoethyl acetate and cesium carbonate according to the procedure in Example 30a. The yield of isolated product was 82.4%.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN1CCN(c2cc(CO)ccc2C2CCC(C(C)(C)C)CC2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCN1CCN(c2cc(C=O)ccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 85.1 %

Procedure:
A mixture of the crude product of [4-(4-t-butylcyclohexyl)-3-(4-butylpiperazin-1-yl)phenyl]methanol produced in Example (101a) (294 mg), manganese (IV) oxide (1.3 g, 14.95 mmol) and chloroform (15 mL) was refluxed for 40 minutes. The reaction mixture was filtered and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure to give 249 mg of a crude product of the title compound as an ochre oil. This product was directly used without purification for the following reaction.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[F:17][C:18]1([F:38])[CH2:25][C@H:24]2[C@H:20]([CH2:21][NH:22][C@@H:23]2[CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH2:19]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:7]([N:22]2[CH2:21][C@H:20]3[C@H:24]([CH2:25][C:18]([F:17])([F:38])[CH2:19]3)[C@H:23]2[CH2:26][N:27]2[C:28](=[O:37])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]2=[O:36])=[O:9])[N:6]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1NC[C@@H]2CC(F)(F)C[C@@H]21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A mixture of 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid (208 mg), (1S,2S,5R)-2-(7,7-difluoro-3-azabicyclo[3.3.0]oct-2-ylmethyl)-isoindole-1,3-dione (273 mg), DIPEA (0.41 mL) in dry DMF (6 mL) was stirred at RT for 4 h. The reaction mixture was directly purified by preparative HPLC to give the title compound (130 mg, 28%) as an oil. LC-MS: tR=1.02 min; [M+H]+=521.99
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Oc1ccc(-n2cccn2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: c1cnn(-c2ccc(OCCN3CCCCC3)cc2)c1
Yield: 47 %

Procedure:
The title compound was prepared from 4-Pyrazol-1-yl-phenol (0.1 g, 0.62 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.23 g, 1.25 mmol) using the general procedure C with a yield of 47% (80 mg); 1H NMR (400 MHz, CDCl3) 7.82 (dd, J=2.4, 0.4 Hz, 1H), 7.69 (br, dd, J=1.6, 0.4 Hz, 1H), 7.57 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 6.43 (dd, J=2.4, 2 Hz, 1H), 4.14 (t, J=12, 6 Hz, 2H), 2.79 (t, J=12, 6 Hz, 2H), 2.52 (br, 4H), 1.61-1.47 (m, 6H);
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:7]([NH2:9])=[O:8])[NH:2]2.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][C:27]([OH:35])([CH2:28]3)[CH2:26]1)[CH2:32]2)[C:22](O)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:7]([C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][C:27]([OH:35])([CH2:28]3)[CH2:26]1)[CH2:32]2)(=[O:8])[NH2:9]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Product: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
Path B: Coupling reaction of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide or its salts of Formula-III with (2S)-2-{[(benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of formula-XIV to give benzyl N-[(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate of formula-XV, can be carried out in a suitable solvent, for example, tetrahydrofuran, N,N-dimethyl formamide, 1,4-dioxane or ethyl acetate using a coupling agent for example, 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminoporpyl)carbodiimide (EDAC), 1-propane phosphonic acid cyclic anhydride or N-[(dimethyl amino)-1H-1,2,3-triazolo[4,5-b]pyridylmethylene]-N-methyl methanaminium hexafluoro phosphate N-oxide (HATU) and optionally a catalyst, for example, 1-hydroxybenzotriazole (HOBT) or 7-aza-1-hydroxy benzotriazole (HOAt) and optionally, with a base, for example, N,N-dimethylamino pyridine (DMAP), triethylamine, N,N-diisopropyl ethyl amine, or N-methyl morpholine.
Reaction SMILES: COP([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)OC.[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29](/[CH:30]=[CH:7]/[C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:32]=[CH:33][CH:34]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCCCCCCCC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.33 h

Procedure:
For Wittig-Horner olefination, 3.64 g of potassium-tertbutylate is added at -20° C. to a solution of 9.41 g of-2-oxo-decyl-phosphonic acid dimethyl ester in 280 ml of tetrahydrofuran and stirred for 20 minutes at this temperature. Then, a solution of 4.5 g of 3-tert-butyldimethylsilyloxymethylbenzaldehyde (see example 18A) in 150 ml of tetrahydrofuran is instilled in this solution and stirred for one hour at -20° C. It is poured on 500 ml of saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase is washed neutral with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue thus obtained is chromatographed on silica gel. With hexane/5-20% ethyl acetate, 6.5 g of 1-[3-(tert-butyldimethylsilyloxymethyl)-phenyl]-(1E)-undecen-3-one is obtained as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:31]1([CH2:30][O:29][C:5]2[CH:4]=[CH:3][C:2]([C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[CH:7][C:6]=2[C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH2:33][CH2:32]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(Br)ccc4OCC4CC4)cn(C)c(=O)c32)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(-c3cccnc3)ccc2OCC2CC2)c2cc[nH]c2c1=O
Temperature: 120 °C
Yield: 75.1 %

Procedure:
A suspension of Example 314b (100 mg, 0.190 mmol), pyridin-3-ylboronic acid (23.31 mg, 0.190 mmol), sodium carbonate (60.3 mg, 0.569 mmol), and tris(dibenzylideneacetone)-dipalladium(0) (15.48 mg, 0.019 mmol) in 4 mL dioxane-water (3:1) was heated under nitrogen under microwave conditions (Biotage Initiator) at 120° C. for 30 minutes. The reaction mixture was the treated with 1 mL aqueous 4 N NaOH and heated at 120° C. under microwave conditions again for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate (2×), washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 0-10% methanol/dichloromethane gradient) to give the title compound (53 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.95 (s, 1H), 8.90 (dd, J=2.4, 0.7 Hz, 1H), 8.56-8.49 (m, 1H), 8.07 (ddd, J=8.0, 2.4, 1.7 Hz, 1H), 7.71-7.64 (m, 2H), 7.45 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.34 (s, 1H), 7.26 (t, J=2.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.18 (dd, J=2.6, 2.2 Hz, 1H), 3.91 (d, J=6.7 Hz, 2H), 3.58 (s, 3H), 1.15-1.04 (m, 1H), 0.49-0.42 (m, 2H), 0.28-0.21 (m, 2H). MS (ESI+) m/z 372.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N+:26]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:12][CH2:13]3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([NH2:26])[CH:3]=1
Reactant: Cc1c(Cn2c(C3CC3)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1c(Cn2c(C3CC3)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To a 250 mL round-bottom flask containing MeOH (70 mL) was added crude 4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (5.87 g, 12.92 mmol), tin(II) chloride dihydrate (8.75 g, 38.8 mmol) and hydrochloric acid (5.38 mL, 64.6 mmol). The resultant suspension was heated to 50° C. and monitored by LC/MS. By LC/MS analysis the reaction was complete in 30 minutes. After the reaction had cooled to rt, the majority of the MeOH was removed in-vacuo and sodium carbonate (64.6 mL, 64.6 mmol) was added slowly to adjust the pH to about 10 and the mixture was extracted with Et2O (3×100 mL) and the organic was washed with H2O and brine and dried over MgSO4 and filtered. The solvent was removed in-vacuo leaving the desired compound (3.42 g, 8.06 mmol, 62.4% yield) as crude brown solid that by LC/MS was sufficiently pure to use in the next step. NMR was consistent with desired product. MS (ES+) m/e: 423.1, 423.8 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.57 (d, J=7.83 Hz, 1H), 7.19 (t, J=7.83 Hz, 1H), 6.84-6.95 (m, 1H), 6.35-6.58 (m, 2H), 5.51 (s, 1H), 5.42 (s, 1H), 2.57 (s, 3H), 1.84-1.98 (m, 1H), 1.05-1.17 (m, 2H), 0.87-1.05 (m, 2H)