Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C@@H:2]([C@@H:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])[CH2:3][OH:4]
Reactant: CCOC(=O)[C@@H](C)[C@H](C)OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@H](CO)[C@H](C)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl (2S,3S)-2-methyl-3-tetrahydropyranyloxybutanoate (4) (8.18 g, 35.56 mmol) at 0° C. was added dropwise to a stirred suspension of LiAlH4 (2.70 g, 71.12 mmol) in THF/toluene (2:1) (178 ml). The reaction mixture is stirred at 0° C. for 30 minutes, and then at room temperature for 30 minutes. The reaction is neutralized by means of the “Fieser treatment”; the reaction was treated by successively adding dropwise 2.7 ml of ice-cold water, 2.7 ml of a 15% aqueous NaOH solution, and 3×2.7 ml of ice-cold water. After having stirred for at least 30 minutes, the mixture is filtered on Celite. The precipitated aluminum salts were then washed with EtOAc. The solvent was evaporated, the residual oil was purified by means of flash chromatography on a silica gel column (heptane/EtOAc=5:1 and then 2:1) in order to obtain (2R,3S)-2-methyl-3-tetrahydropyranyloxybutanol (5) in the form of a colorless oil (6.59 g, 99%): 1H NMR (250 MHz, CDCl3) δ 4.69 to 4.67 (m, 0.5H); 4.58 to 4.56 (m, 0.5H); 3.98 to 3.43 (m, 5H); 1.80 to 1.48 (m, 7H); 1.29 (d, J=6.3 Hz, 1.5H); 1.18 (d, J=6.1 Hz, 1.5H); 0.95 (d, J=7.0 Hz, 1.5H); 0.94 (d, J=7.0 Hz, 1.5H); 13C NMR (50 MHz, CDCl3) δ 99.9; 97.4; 78.4; 74.9; 65.2; 64.2; 62.7; 41.2; 40.6; 31.3; 31.0; 25.3; 25.1; 20.7; 19.8; 18.9; 17.5; 14.0; 13.0; MS (CI) m/z 189 [M+H]+. HRMS calculated for C10H21O3 (M+H), 189.14906; found, 189.14755.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH2:16][CH2:17][O:18][CH2:19][CH:3]12.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.O.C(OCC)(=O)C>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH2:16][CH2:17][O:18][CH2:19][CH:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)C1COCCN21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2cc(CO)cnc2N2CCOCC12
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Methyl 6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazine-3-carboxylate (1000 mg, 3.80 mmol) was taken up in tetrahydrofuran (47 mL) in an inert environment. To the stirred suspension at room temperature was added NaH (228 mg, 5.70 mmol, 60% dispersion in mineral oil) and stirred 30 minutes. The reaction was then cooled to −45° C. and lithium aluminum hydride (11.4 mL, 1M in THF) was added. The reaction was stirred at a temperature between −20 and −10° C. for 1 hour. The reaction was then cooled back to −78° C. and methanol (3 ml) followed by water (1 ml) was added. The reaction was allowed to stir at ambient temperature for 2 hours and then poured into ethyl acetate (400 ml) and water (100 ml). The biphasic mixture was stirred vigorously and then filtered through a medium frit. The filtrate was collected. The layers were separated and the aqueous phase was extracted with ethyl acetate (1×100 ml). The organic layers were combined, washed with brine (100 ml), and concentrated to yield 657 mg (73.5%) of the title compound as a white solid. [M+H] calc'd for C11H13N3O3, 236. found, 236.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([NH2:22])=O)=[CH:4][CH:3]=1.ClCCl.C(N(CC)CC)C.FC(F)(F)C(O)=O>O>[C:20]([C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=2)#[N:22]
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(N)=O)n2Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2c(c1)cc(C#N)n2Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a mixture of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carboxamide (100 mg) and dichloromethane (2 ml), triethylamine (0.09 ml) and anhydrous trifluoroacetic acid (0.09 ml) were added at 15 to 30° C. and the mixture was stirred at the same temperature for 2 hours. Water was added therto, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 68 mg of the desired product as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=1
Reactant: BrCc1cccnc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Br
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1cccnc1

Procedure:
The title compound, MS: m/e=309.3(M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[F:12])#[N:2].S(Cl)([Cl:15])=O>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Product: N#Cc1ccc(C(=O)Cl)cc1F
Reaction time: 2 h

Procedure:
0.66 g (4.0 mmol) 4-cyano-3-fluoro-benzoic acid were mixed with 10 mL thionyl chloride and boiled for 2 h. The mixture was evaporated to dryness and coevaporated twice with toluene. The residue was reacted further as the crude product.
Reaction SMILES: [CH2:1]([Si:3]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:4]#[C:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl.C[N:29]([CH3:32])C=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.O>[CH2:6]([C:5]1[C:8]2[C:32](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:29][C:4]=1[Si:3]([CH2:1][CH3:2])([CH2:13][CH3:14])[CH2:15][CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[Si](C#CCc1ccccc1)(CC)CC
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC[Si](CC)(CC)c1[nH]c2ccccc2c1Cc1ccccc1
Temperature: 103 °C
Reaction time: 6 h

Procedure:
3-Benzyl-2-triethylsilanyl-1H-indole2-Iodoaniline (5.48 g, 25.02 mmol), triethyl-(3-phenylprop-1-ynyl)silane (6.34 g, 27.51 mmol), lithium chloride (1.11 g, 26.19 mmol) and sodium carbonate (7.95 g, 75.01 mmol) were combined in dimethylformamide (absolute, 70 ml) in an argon atmosphere. The catalyst ([Pd(dppf)Cl2×CH2Cl2], 2.05 g, 2.51 mmol) was then added. The solution was stirred at 100-106° C. for 6 h. The black reaction mixture was cooled to room temperature and water (300 ml) and ethyl acetate (150 ml) were added in succession. After stirring for one hour, the mixture was filtered over Celite. The phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate. After filtration, the volatile constituents were removed completely in vacuo. The residue (10.5 g of brown oil) was purified by chromatography [silica gel 60 (300 g); cyclohexane/ethyl acetate 10:1 (2,200 ml)]. 3-Benzyl-2-triethylsilanyl-1H-indole was isolated as a brown oil (6.44 g, (80%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:20])=[CH2:19])=[CH:14][CH:13]=1)([CH3:11])=[CH2:10].Cl>C(O)(=O)C>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])([CH3:20])[CH3:19])=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: C=C(C)c1ccc(C(=C)C)cc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(c1ccc(C(C)(C)c2ccc(O)cc2O)cc1)c1ccc(O)cc1O
Temperature: 70 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
110.0 g Resorcinol, 15.8 g p-diisopropenylbenzene and 200 ml glacial acetic acid were added to a flask and heated to about 70° C. to dissolve the reactants. Anhydrous hydrogen chloride was condensed into the reaction mixture until saturated. The reaction was allowed to cool and stand at ambient temperature for 17 hours. The product was precipitated in water, washed with water and vacuum dried at 60° C. About 29.1g of product with a melting point of about 110° to 115° C. was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][C:22]([C:24]2([OH:36])[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]([CH3:35])[CH2:25]2)=[N:21][CH:20]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[NH2:5][C:4]1[CH:6]=[C:7]([C:19]2[S:23][C:22]([C:24]3([OH:36])[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]([CH3:35])[CH2:25]3)=[N:21][CH:20]=2)[CH:8]=[C:2]([CH3:1])[CH:3]=1
Reactant: CCOC(=O)C1CCC(O)(c2ncc(Br)s2)CC1C
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)C1CCC(O)(c2ncc(-c3cc(C)cc(N)c3)s2)CC1C
Temperature: 100 °C
Yield: 83.5 %

Procedure:
To a round bottom flask containing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (402 mg, 1.7 mmol), ethyl 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxylate (400 mg, 1.1 mmol), Pd2(dba)3 (105 mg, 0.11 mmol), X-phos (55 mg, 0.11 mmol) and Cs2CO3 (1.12 g, 3.45 mmol) was added 4.3 mL of degassed 10:1 1,4 dioxane/H2O. The reaction was heated to 100° C. for 16 h, then cooled and partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous phase was extracted once with EtOAc (50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification of the resulting residue on silica furnished ethyl 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2-methylcyclohexanecarboxylate (344 mg, 80%) as a colorless foam. MS ESI: [M+H]+ m/z 375.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][C:14]1([CH3:24])[O:18]/[C:17](=[CH:19]\[C:20](O)=[O:21])/[C:16](=[O:23])[O:15]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:20](=[O:21])/[CH:19]=[C:17]2\[O:18][C:14]([CH3:13])([CH3:24])[O:15][C:16]\2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Reactant: NCCCc1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC1(C)OC(=O)/C(=C/C(=O)NCCCc2ccc(Cl)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a cold (0° C.) solution of the hydrochloride salt of Intermediate 1 (7.1 g, 30 mmol), (Z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetic acid (5.6 g, 33 mmol), EDC (6.8 g, 36 mmol), and HOBt (5.4 g, 36 mmol) in DMF (200 mL) was added N-methylmorpholine (13 mL, 120 mmol). The reaction mixture was allowed to warm to rt, stirred for 16 h, diluted with EtOAc (500 mL), the solution washed with saturated aqueous NaCl:water (1:1), and the organic portion dried over MgSO4, filtered and evaporated to dryness in vacuo. The product was purified by silica gel chromatography (330 g silica gel) to obtain 9.68 g (89%) of Intermediate 5. HPLC/MS (Method C) RT=3.40 min; [M+H]+ 359; 1H NMR (500 MHz, chloroform-d) (δ ppm): 1.76 (s, 6H), 1.88 (quin, J=7.42 Hz, 2H), 2.64 (t, 2H), 3.37 (q, 2H), 5.86 (s, 1H), 6.37 (br. s., 1H), 7.01-7.07 (m, 1H), 7.28 (d, 1H), 7.35 (d, J=7.70 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Br:28].[OH-].[Na+].O>C(O)C>[Br:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[CH2:19][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:17])=[CH:11][N:12]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Br)c(CSc2ccc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 99 %

Procedure:
As described in Method A, N-(4-fluoro-phenyl)-6-mercapto-nicotinamide IIa (745 mg, 3 mmol, 1 eq.) and 2-bromomethyl-4-methoxyphenyl bromide (0.84 g, 3 mmol, 1 eq.) were suspended in ethanol (36 ml). To the suspension, 1 N sodium hydroxide (5.1 ml, 6 mmol, 2 eq.) was added, and the reaction mixture heated to gentle reflux for 2 hours, then water (200 ml) was added to the reaction mixture while still hot. Upon cooling, a white precipitate formed, and this was filtered, washed with 50% aqueous ethanol, then water and dried in the oven to afford 1.33 g (99% yield, >95% purity by LC-MS) of 6-(2-bromo-5-methoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide, intermediate VII, as an off-white solid. ESI-MS m/z=448.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=1>O1CCOCC1.C(OCC)(=O)C>[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]3)=[CH:6][CH:7]=2)[CH:27]=1)#[N:29]
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccnc(Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)c1
Temperature: 125 °C
Yield: 54.8 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.36 g) and 2-chloro-4-cyanopyridine (0.14 g) in dioxane (1 mL) was heated at 125° C. in a sealed tube for 5 days. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (methylene chloride to 2% ethanol/methylene chloride gradient gave the above-named compound (0.22 g) mp 152-153° C. NMR (CDCl3) 8.45 (1H, m), 7.86 (3H, m), 7.48 (2H, d), 7.20 (1H, br s), 7.07 (1H, s), 6.91 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([CH3:35])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:28]([CH3:35])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(C)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and 4-methoxy-2-methylphenylboronic acid (166 mg, 1.0 mmol) to afford after chromatographic purification the title compound (105 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ 7.04 (d, 1H, J=8.5 Hz), 6.65–6.79 (m, 4H), 3.75–4.22 (m, 2H), 3.74 (s, 3H), 3.58–3.68 (m, 1H), 3.18–3.42 (m, 4H), 2.76–3.16 (m, 3H), 2.17 (s, 3H), 1.70–1.84 (m, 2H), 1.40 (s, 9H) ppm. MS-ApCI: 421 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([C:39]([OH:41])=O)=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCOCC.CO>[C:14]1([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:28])=[O:2])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:39]([C:32]4[C:33]5[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:29]=[CH:30][CH:31]=4)=[O:41])=[CH:25][CH:26]=3)=[O:7])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1)c1ccnc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 4-amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (29.5 mg, 0.078 mmol), quinoline-4-carboxylic acid (17 mg, 0.10 mmol), and HBTU (38 mg, 0.10 mmol) in 1 mL of DMF was treated with diisopropylethylamine (30 μL, 0.17 mmol). The mixture was stirred over night and was diluted with 15 mL of ethyl acetate and 10 mL of ether and was washed with portions of water (2×10 mL), saturated NaHCO3 (10 mL) and was dried (MgSO4). Concentration gave 48 mg which was dissolved in 3 mL of methanol. Sodium hydroxide solution (0.10 mL, 4 N, 0.4 mmol) was added and the mixture was stirred for 2 hr. The excess base was quenched by addition of 0.1 mL of acetic acid, the solution was filtered through a 0.2μ nylon filter and the filtrate was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 30 min. The peak eluting at 74.5% acetonitrile was the acid N-[[1-(phenylmethyl)cyclopentyl]carbonyl-4-[(4-quinolinylcarbonyl)amino)-L-phenylalanine (15 mg), HR-FAB-MS: obs. mass 522.2393. Calcd. mass 522.2393 (M+H), the peak eluting at 83% acetonitrile was recovered N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine methyl ester (15 mg), HR-FAB-MS: obs. mass 536.2556. Calcd. mass 536.2549 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[CH2:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:19](=[O:21])[CH3:20].[CH3:22]OC(OC)N(C)C.C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CCOCC.C(O)C.CO>[C:13]1([CH2:12][O:11][C:6]2[CH:5]=[CH:4][C:3]3[C:19](=[O:21])[CH:20]=[CH:22][O:1][C:2]=3[C:7]=2[CH2:8][CH:9]=[CH2:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCc1c(OCc2ccccc2)ccc(C(C)=O)c1O
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: C=CCc1c(OCc2ccccc2)ccc2c(=O)ccoc12
Reaction time: 2.5 h
Yield: 67.5 %

Procedure:
A mixture of 5.0 g (17.73 mmol) of 1-[2-hydroxy-4-(phenylmethoxy)-3-(2-propenyl)phenyl]ethanone, 2.3 g (19.48 mmol) of dimethylformamide dimethyl acetal, and 5.0 mL of xylene was stirred and heated in a 120°-130° C. oil-bath as methanol was distilled out using a 3 in. Vigreux column, over a 2.5 hr period. The bath temperature was then raised to 150°-160° C. and the reaction mixture was stirred at this temperature for an additional 30 min. The mixture was cooled and concentrated at 60° C./high vacuum. To the viscous, red-brown, oily residue was added 3.7 g (19.48 mmol) of p-toluenesulfonic acid monohydrate and 50 mL of ethanol. The resulting solution was stirred and refluxed for 24 hr, then cooled and diluted with water. Work-up with ether in the usual manner gave a crude product which was recrystallized from hexane-ethyl acetate. There was obtained 3.5 g (67.6%) of 7-(phenylmethoxy)-8-(2-propenyl)-4H-1-benzopyran-4-one as a yellow solid, mp 90°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O.O>CN1CCCC1=O>[C:12]1([N:18]2[C:6](=[O:8])[C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:11][C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
42.5 g of 4-chloroanthranilic acid were dissolved in 250 ml of N-methylpyrrolidone and 29.5 g of phenyl isocyanate were added dropwise at room temperature in 30 minutes. The mixture was further stirred for 5 hours at 80° C. and then 24.5 g of concentrated sulphuric acid were added dropwise in the course of 1 hour. The mixture was then further stirred at 80° C. for 3 hours, then cooled to room temperature, 500 ml of water were added, the product precipitated out was filtered off by suction, washed with water and dried in a vacuum drying cabinet. In this manner 57.4 g (85% of theory) of pure 3-phenyl-7-chloro-quinazoline-2,4-dione were obtained having a melting point of above 300° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1.CO.C(O)=O>C1COCC1.[Pd]>[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17]2
Reactant: c1ccc(COc2ccc3cc(-c4nc5ccccc5[nH]4)ccc3c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CO
Product: Oc1ccc2cc(-c3nc4ccccc4[nH]3)ccc2c1
Temperature: 100 °C
Yield: 109.8 %

Procedure:
T470 To a solution of 2-(6-(benzyloxy)naphthalen-2-yl)-1H-benzo[d]imidazole (73 mg, 0.21 mmol) in THF (2 mL) was added MeOH (2 mL), Pd—C (10%, 30 mg), and formic acid (0.30 mL). The mixture was flushed with argon and sealed in a microwave vial. The mixture was heated at 100° C. for 5 minutes in a microwave synthesizer. The mixture was filtered off Pd—C and the filtrate was concentrated to give T470 as a white solid (60 mg, 94%). 1H NMR (400 MHz, CD3OD): δ 8.46 (t, J=1.0 Hz, 1H), 8.12 (s, 1H), 8.05 (dd, J=8.8, 2.0 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.62 (m, 2H), 7.29 (m, 2H), 7.16 (m, 2H); MS (ESI): 261 (M+H+).
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12]C)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Cl.[OH-:15].[Na+]>>[OH:15][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: COC(=O)C12CCC(Br)(CC1)CC2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C12CCC(O)(CC1)CC2
Yield: 89 %

Procedure:
Methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate (17.0 g, 69.0 mol) was refluxed in aqueous sodium hydroxide solution (1500 mL, 1%) for 24 h. After cooling, the reaction solution was acidified with hydrochloric acid (6 N, 100 mL) and extracted with diethyl ether (6×500 mL). The combined ether layers were dried over magnesium sulfate and concentrated to afford the title compound (10.4 g, 61.1 mmol, 89% yield), which was used in the next step without further purification. MS (ESI) m/z 169.2 [M+H]−.