Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20].[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O.CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(Cl)cc1Cl
Yield: 91.5 %

Procedure:
Dimethyl 2-(2,4-dichlorophenyl)piperidine-1,4-dicarboxylate (2.78 g, 8.03 mmol) was dissolved in acetonitrile (27.1 mL) and water (0.542 mL). Lithium bromide (5.58 g, 64.24 mmol) and triethylamine (4.48 mL, 32.12 mmol) were added and the resulting mixture heated under reflux for 4 h, diluted with Water and MTBE and the organic layer extracted with water. The combined aqueous layers were acidified with 3 M HCl, extracted with MTBE, dried over MgSO4, filtered and evaporated to give 2-(2,4-dichlorophenyl)-1-(methoxy-carbonyl)piperidine-4-carboxylic acid (2.440 g, 91%) as a foam. MS m/z 332 (M+H)+
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2].C(N(CC)CC)C.[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:42]2[CH2:43][CH2:44][C@H:40]([N:39]([CH3:45])[CH3:38])[CH2:41]2)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2]
Reactant: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)CC1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Ethyl 1-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)piperidine-4-carboxylate (I-161) (0.27 g, 0.66 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([OH:12])[CH2:9][CH:8]=[C:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH3:4]>[Pd]>[CH3:4][N:3]([CH2:5][CH:6]1[CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:8][CH2:9][CH:10]([OH:12])[CH2:11]1)[CH3:2]
Reactant: COc1cccc(C2=CCC(O)CC2CN(C)C)c1
Agent: [Pd]
Agent: Cl
Product: COc1cccc(C2CCC(O)CC2CN(C)C)c1

Procedure:
When producing [5-(4-methoxybenzyloxy)-2-(3-methoxyphenyl)cyclohexylmethyl]-dimethylamine, the cyclohexene derivative [5-(4-methoxybenzyloxy)-2-(3-methoxyphenyl)cyclohex-2-enylmethyl]dimethylamine was isolated as a secondary product, as the 3-dimethylaminomethyl-4-(3-methoxyphenyl)cyclohexanol hydrochloride used was contaminated by the preliminary stage 5-dimethylaminomethyl-4-(3-methoxyphenyl)-cyclohex-3-enol hydrochloride which was catalytically hydrogenated by palladium to produce 3-dimethylaminomethyl-4-(3-methoxyphenyl)cyclohexanol.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17])([O-:3])=[O:2].[NH4+:20].C(O)(=O)C>O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16]([NH2:20])(=[O:18])=[O:17])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 17 %

Procedure:
A mixture of 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% ammonium hydroxyde is stirred at a temperature between 5° C. and 10° C. for 3 hours and then allowed to stand for 16 hours. To the mixture 6 ml of acetic acid and 40 ml of water are added, the separated crystals are filtered off, washed with water and acetone, dried and dissolved in a slight amount of hot dimethyl sulfoxide. The product is precipitated from this solution with 2-propanol. Thus 1.40 g (17%) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: >330° C.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16](=[O:17])[C:15]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:14]([OH:29])[CH2:13][C:9]32[CH2:12][O:11][CH2:10]3)=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16](=[O:17])[C:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:14]([OH:29])[CH2:13][C:9]32[CH2:10][O:11][CH2:12]3)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)CC2(COC2)N(Cc2ccc(-c3ccccc3)cc2)C1=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)CC2(COC2)N(Cc2ccc(-c3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution in chloroform (20.0 mL) of the compound (2.60 g) obtained in step (1) above, trifluoroacetic acid (8.00 mL) was added and the mixture was stirred at room temperature for 12 hours. After concentrating under reduced pressure, ethyl acetate was added to the residue. With continued stirring, n-hexane was added and the precipitate was recovered by filtration to give the titled compound as a pale brown solid (2.18 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
Methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.120 g) was suspended in DCM (5 mL). Pyridine (0.885 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.180 g) were added. The mixture was stirred at room temperature for 5 hours then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5M aqueous hydrochloric acid solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-10% to give methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.208 g) as a colourless oil.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][C@H:13](O)[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:35])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([Cl:35])[C:14]2[C:15]([CH3:24])=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[O:18][CH2:17]3)[CH2:10][CH2:9][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[C@H](O)c1ccc2c(c1C)COC2=O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled with an ice bath solution of (S)-tert-butyl 3-(acetylthiomethyl)-4-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazine-1-carboxylate (573 mg, 1.23 mmol) in anhydrous toluene (12.3 mL) was added thionyl chloride (0.268 mL, 3.70 mmol). Then, anhydrous pyridine (0.399 mL, 4.93 mmol) was added dropwise. The reaction mixture was kept at 0° C. for 20 min, then warmed to room temperature and stirred for 3 hours. TLC showed the consumption of the starting material. The reaction was concentrated under reduced pressure and dried on high vacuum overnight. Used directly in the next step.
Reaction SMILES: CC(OC([N:8]([C:16]1[NH:17][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][C:34]3[CH:39]=[C:38]([CH:40]4[CH2:42][CH2:41]4)[CH:37]=[C:36]([C:43]#[N:44])[CH:35]=3)[C:27]=2[F:45])=[O:23])=[C:19]([Cl:21])[N:20]=1)C(OC(C)(C)C)=O)=O)(C)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[NH2:8][C:16]1[NH:17][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][C:34]3[CH:39]=[C:38]([CH:40]4[CH2:42][CH2:41]4)[CH:37]=[C:36]([C:43]#[N:44])[CH:35]=3)[C:27]=2[F:45])=[O:23])=[C:19]([Cl:21])[N:20]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C4CC4)c3)c2F)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)cc(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of bis(1,1-dimethylethyl)(4-chloro-5-{[({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (161 mg, 0.244 mmol) in DCM (5 ml) was added TFA (2.5 ml) and the reaction mixture was stirred at RT for 3 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 2-amino-4-chloro-N-({4-chloro-3-[(3-cyano-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide trifluoroacetate (59 mg, 0.103 mmol, 42% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:15][CH2:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 42 h
Yield: 127.1 %

Procedure:
A mixture of methyl 3-nitro-4-methylbenzoate (4.147 g), N-bromo-succinimide (7.12 g) and AIBN (0.40 g) in carbon tetrachloride (30 ml) was stirred at 70° C. for 42 hr. After cooling, the insoluble matter was filtered off and the filtrate was concentrated to give an oil (7.40 g) containing the object compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([O:33]C)=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:35][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:19])=[O:18])[C:5](=[O:36])[CH2:4]1)[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:35][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:18])=[O:19])[C:5](=[O:36])[CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CO
Product: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C(=O)C1
Yield: 64.6 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 173, 0.28 g) and lithium hydroxide monohydrate (0.126 g) in dioxane (9 mL) and water (3 mL) was irradiated in the microwave at 130° C. for 30 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated in vacuo. The residue was triturated with 20% methanol in DCM, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20%. The resultant solid was triturated with ether and filtered to give (1aRS,7bSR)-5-[2-(4-ethyl-2-oxo-piperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.176 g) as a white solid.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH:21](O)[OH:22])[O:19][CH:20]=2)[N:11]=1.[CH3:29][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:22])[CH3:29])[O:19][CH:20]=2)[N:11]=1
Reactant: O=C(Nc1cnn(Cc2coc(C(O)O)n2)n1)OCc1ccccc1Cl
Reactant: C[Mg]Br
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)co1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-dihydroxymethyl-oxazol-4-ylmethyl)-2H-[1,2,3]triazol-4-yl]-carbamic acid 2-chloro-benzyl ester (19 mg, 0.05 mmol) in THF (1.0 mL) was treated at −65° C. with methylmagnesium bromide (0.15 mL of a 1M solution in THF, 0.15 mmol). The reaction mixture was then stirred at −65° C. for 1 h. The reaction mixture was then slowly warmed to rt and stirred at this temperature for 45 min. Sat. aq. NH4Cl was then added and the aq. layer was extracted with EA (3×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The residue was purified by FC (EA) to give the title compound as a yellow oil. TLC: rf (EA)=0.30. LC-MS-conditions 02: tR=0.89 min, [M+H]+=378.30.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@H:4]([CH2:42][CH2:43][S:44][CH3:45])[NH:5][C:6](=[O:41])[CH2:7][N:8]([CH2:20][C@@H:21]([NH:26][C:27](=[O:40])[CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>CO>[N+:37]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][S:29][CH2:28][C:27]([NH:26][C@@H:21]([C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:20][N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:46])=[O:2])[CH2:42][CH2:43][S:44][CH3:45])=[O:41])=[O:40])=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)CSCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)O)Cc1cccc2ccccc12)NC(=O)CSCc1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
N-{2(S)-[(4-Nitrobenzylthio)acetamido]-3(S)-methylpentyl}-N-(1-naphthylmethyl)-glycyl-methionine methyl ester (from Example 1; 100 mg, 150 μmol) was dissolved in MeOH (1 mL) and 1.0N NaOH (300 μL, 300 μmol) was added. The mixture was stirred at 45° C. under argon for 45 minutes then the solution was partitioned between EtOAc (100 mL) and 5% citric acid (50 mL). The organic layer was washed with H2O (2×50 mL), dried (MgSO4), filtered and evaporated to give the title compound. 1H NMR; δ0.84 (t, 3H, J=7.5 Hz), 0.88 (d, 3H, J=7 Hz), 0.91-1.0 (m, 1H), 1.0-1.2 (m, 1H), 1.2-2.1 (m, 5H), 1.90 (s, 3H), 2.8-2.86 (m, 2H), 3.0-3.3 (m, 4H), 3.90 (s, 2H), 3.91-4.22 (m, 4H), 7.37-7.56 (m, 6H), 7.78-7.88 (m, 2H), 8.15 (d, 2H, J=8 Hz), 8.27 (d, 1H, J=8.3 Hz).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][N:10]=1)([F:4])[CH3:3].[H][H]>CO.[Pt]=O>[F:1][C:2]([CH:5]1[NH:10][CH2:9][CH2:8][NH:7][CH2:6]1)([F:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(F)(F)c1cnccn1
Agent: O=[Pt]
Solvent: CO
Product: CC(F)(F)C1CNCCN1

Procedure:
A 4.3 g portion of 3-(1,1-difluoroethyl)pyrazine in 25 ml of methanol was reduced with 50 psi hydrogen and 750 mg of platinum oxide at 20° C. for 5 hours. The resulting oil was purified by chromatography, giving about 700 mg of 3-(1,1-difluoroethyl)piperazine.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:22]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Reactant: CCCNCCC
Product: CCCN(CCC)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1

Procedure:
from trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol and dipropylamine. Colourless oil.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][C:12]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:13][CH:14]=1)([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 90 °C

Procedure:
To a solution of the product of Example 26A (370 mg, 1.16 mmoles) and 2-bromo-5-(trifluoromethyl)pyridine (341 mg, 1.51 mmoles) in N,N-dimethylformamide (10.0 ml) were added 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.48 mmoles) and the reaction mixture was heated under a nitrogen atmosphere to about 80° C. for about 1 hour. Another portion of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) was added and the mixture was heated to about 90° C. for about 2 hours. The solvent was evaporated in high vacuum, the residue was taken up in water (20.0 ml) and diethyl ether (20.0 ml), and was filtered through Celite. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2:1) as the mobile phase to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3[C:14]4[C:19]([C:20]([C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:30]=[CH:29][CH:28]=5)=[C:21]5[C:26]=3[CH:25]=[CH:24][CH:23]=[CH:22]5)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.CN1CCCC1=O>O>[C:27]1([C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[CH:12]4)=[CH:7][CH:8]=3)=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2ccc(-c3c4ccccc4c(-c4cccc5ccccc45)c4ccccc34)cc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1ccc2ccc(-c3c4ccccc4c(-c4cccc5ccccc45)c4ccccc34)cc2c1
Temperature: 200 °C
Reaction time: 6.5 h

Procedure:
Under the nitrogen atmosphere, 9-(7-methoxynaphthalen-2-yl)-10-(naphthalen-1-yl)anthracene (17.5) as the third intermediate compound, pyridine hydrochloride (22.0 g) and N-methylpyrrolidone (35 ml) were added to a flask and stirred for 6.5 hours at 200° C. Once the heating is completed, the reaction solution was cooled to 100° C. or less, added with water, and the precipitated solid was collected by suction filtration. The crude product obtained was purified by silica gel column chromatography (solvent: toluene) to give 7-(10-(naphthalen-1-yl)anthracen-9-yl)naphthalene-2-ol (16.0 g) as a fourth intermediate compound. The scheme is shown in the following “Reaction 5”.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: COc1ccc(CNc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)c(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)c(OC)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To [5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (122, 60 mg, 0.11 mmol) in 10.0 mL of methanol, potassium hydroxide (0.20 g, 3.6 mmol) was added. The reaction was stirred at 60° C. for 4 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-1496, 26.1 mg). MS (ESI) [M+H+]+=410.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([NH2:21])[N:6]=1.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Br:28][C:10]1[N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:21])[N:6]=[C:5]([O:4][CH2:3][CH:2]([CH3:22])[CH3:1])[N:13]=2
Reactant: BrBr
Reactant: CC(C)COc1nc(N)c2ncn(CC3CCOCC3)c2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)COc1nc(N)c2nc(Br)n(CC3CCOCC3)c2n1
Temperature: 25 °C

Procedure:
2-[(2-Methylpropyl)oxy]-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (88 mg) was dissolved in glacial acetic acid (1.5 mL) before adding sodium acetate (355 mg). The above was then cooled in an ice-bath before bromine (0.2 mL) which was added gradually. The reaction mixture was warmed to room temperature before being heated to 70° C. (external temperature) for 4 hours. The reaction mixture was quenched with 10% (w/v) sodium thiosulphate solution (to a pale yellow colour with no further change) and then the pH was adjusted to 6-7 by the addition of 2M sodium hydroxide. This was then extracted into ethyl acetate (20 mL, 3 times). The organic layer was separated, combined and dried by passing through a hydrophobic frit. The organic layer was evaporated under reduced pressure and then azeotroped with toluene to give the title compound as a pale yellow solid (0.10 g). This material then used in the next stage without the need for purification
Reaction SMILES: C[C@H]1[C@]23C[C@H](C(C)(C)[C@@H]2CC1)[C@@](O)(C)CC3.O=CC1C=CC(O)=C(OC)C=1.C[CH2:29][C:30]([O:32][CH:33]1[CH:37]2[CH:38]3CC=C[CH:39]3[CH:35]([CH2:36]2)[CH2:34]1)=[O:31].C1(CCO)C=CC=CC=1>>[O:32]1[C:33]2[C:37](=[CH:38][CH:39]=[CH:35][CH:34]=2)[CH:36]=[CH:29][C:30]1=[O:31]
Reactant: CCC(=O)OC1CC2CC1C1CC=CC21
Agent: COc1cc(C=O)ccc1O
Agent: C[C@@H]1CC[C@H]2C(C)(C)[C@H]3C[C@@]12CC[C@@]3(C)O
Solvent: OCCc1ccccc1
Product: O=c1ccc2ccccc2o1

Procedure:
cedrol; vanillin; cyclopentadecanolide tricyclodecenyl acetate; tricyclodecenyl propionate; phenylethyl alcohol