Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[N:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)([O-:3])=[O:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[OH:50][CH:46]1[C:16]2[C:9](=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[CH:15]=2)[NH:8][CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:47]1([CH3:49])[CH3:48]
Reactant: CC(C)C=O
Reactant: N#Cc1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(O)c2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a mixture of 4-[(3-nitro-benzylidene)-amino]-benzonitrile (21 g, 84 mmol) and ytterbium(III) triflate hydrate (5.21 g, 8.4 mmol) in dry tetrahydrofuran (150 mL) at 25° C. was added isobutyraldehyde (8.4 mL, 92 mmol) and water (1.5 mL, 84 mmol) dropwise. The reaction mixture was stirred at 25° C. for 15 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (25 g, 92%) as a light yellow oil: LC/MS m/e calcd for C18H17N3O3 (M+H)+: 324.35, observed: 324.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:18]([CH3:19])[C:17](=[O:20])[C:16](C(O)=O)=[CH:15][C:11]=2[CH:12]=[N:13][N:14]=1.C1COCC1.O.O.C([O-])(=O)C.[Li+].C1C(=O)N([Br:43])C(=O)C1>O>[Br:43][C:16]1[C:17](=[O:20])[N:18]([CH3:19])[C:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:14][N:13]=[CH:12][C:11]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(=O)c(C(=O)O)cc2cnnc(-c3ccc(F)cc3F)c21
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c(Br)cc2cnnc(-c3ccc(F)cc3F)c21
Temperature: 55 °C

Procedure:
To a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (1.00 g, 3.15 mmol) in 10:1 THF:H2O (11 mL), stirred at 55° C., was added lithium acetate dihydrate (67 mg, 0.66 mmol). The mixture was stirred at 55° C. and treated with NBS (1.51 g, 8.48 mmol) in three equal portions at 30 min intervals. After addition of NBS was complete, the reaction mixture was stirred an additional 1 h at 55° C. In a separate flask, a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (0.92 g, 2.89 mmol) in 10:1 THF:H2O (10 mL) stirred at 55° C. was treated with lithium acetate dihydrate (62 mg, 0.61 mmol) followed by NBS (1.39 g, 7.80 mmol) under the same conditions. Upon complete reaction, the two reaction mixtures were combined, diluted with water, and extracted with CH2Cl2. The combined organic layers were washed with 20% THF in water, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography [eluting with a gradient of 10-40% B in A where the eluents were: A=CH2Cl2; B=1:49.5:49.5 MeOH:EtOAc:CH2Cl2] to give 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one as a yellow solid. MS (ESI, pos. ion) m/z: 350, 352 (M+1, M+3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH:9]([CH3:19])[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH:9]([CH3:19])/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C(C)[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(=N/O)C(C)[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 132, step 6, from (3R)-3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)-2-methyl-1-(2-methylpyridin-4-yl)propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=457.0 ([M+H]+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH2:24]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)[CH3:23]
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCOc1ccccc1N1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1
Yield: 53.6 %

Procedure:
2.9 grams of 5-(piperazinylpropoxy)-3,4-dihydrocarbostyril, 2.5 g of o-bromoethoxybenzene and 1.5 g of sodium carbonate are mixed with 80 ml of n-butanol and refluxed for 20 hours. After cooling, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. Then chloroform is removed by distillation and the residue thus obtained is recrystallized from ethanol to obtain 2.2 g of 5-{3-[4-(2-ethoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals having a melting point of 155°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[C:23]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[C:23]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC(C)c1ccc(NCc2cccnc2N(C)C)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cccnc1N(C)C)c1ccc(C(C)C)cc1)CCC2
Yield: 85.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(2-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.40 g) as starting materials, N-[(2-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:34])([F:33])[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1>C(Cl)Cl>[F:33][C:9]([F:8])([F:34])[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ncc(C(F)(F)F)cn3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cnc(N2CCC3(CCNC3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1.5 ml) was added to a solution of tert-butyl 8-(5-(trifluoromethyl)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (300 mg, 0.78 mmol, 1.0 eq.) in methylene chloride (6 ml) at 0° C. and the reaction mixture was stirred at 25° C. for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure to give the desired product as a yellow sticky solid which was directly used in the next step.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:14]([O:16][C:17](=[O:35])[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[N:28][C:27]([NH2:30])=[C:26]3[O:31][C:32](Cl)=[CH:33][C:25]=23)[CH:21]=[N:20]1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:35])[CH:23]=2)=[C:25]2[CH:33]=[C:32]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[O:31][C:26]=12
Reactant: OB(O)c1cccc2cnccc12
Reactant: CCOC(=O)Cn1cc(-c2cnc(N)c3oc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cn1cc(-c2cnc(N)c3oc(-c4cccc5cnccc45)cc23)cn1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A solution of isoquinoline-5-boronic acid (53.9 mg, 0.312 mmol) and ethyl[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]acetate (50.0 mg, 0.156 mol) in 1,4-dioxane (0.85 mL) and H2O (0.3 mL) was charged with potassium carbonate (32 mg, 0.23 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (1 mg, 0.002 mmol) under an atmosphere of nitrogen. The mixture was heated in a microwave reactor at 100° C. for 40 min. Purification of the residue by flash chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 27 mg (41%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 9.36 (s, 1H), 8.57-8.63 (m, 1H), 8.52 (d, J=6.06 Hz, 1H), 8.37 (d, J=7.33 Hz, 1H), 8.27 (d, J=8.08 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J=7.58 Hz, 2H), 7.85 (t, J=7.83 Hz, 1H), 7.55-7.62 (m, 1H), 7.53 (s, 1H), 4.28 (q, J=7.16 Hz, 2 H), 1.95 (s, 2H), 1.32 (t, 3H); MS (ESI): 415.16 [M+H]+; HPLC tR=0.94 min (TOF: polar—3 min).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[S:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:30])(=O)=O>O>[CH2:1]([N:8]1[C:16]2[C:15]([S:17][CH3:30])=[N:14][C:13](=[O:18])[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCn1c(=O)[nH]c(=S)c2c1ncn2Cc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(=O)nc(SC)c2c1ncn2Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a mixture of 7-benzyl-3-pentyl-6-thioxo-1,3,6,7-tetrahydro-2H-purin-2-one (5.3 g, 16 mmol) in a solution of sodium hydroxide in water (2 M, 50.0 mL) was added dimethyl sulfate (2.3 mL, 24 mmol). The reaction mixture was stirred at 80° C. overnight, quenched with acetic acid and extracted with dichloromethane (DCM). The organic layer was dried and concentrated to provide the desired product (5.2 g, 98% yield). LCMS calculated for C18H23N4OS (M+H): 343.2. found: 343.1.
Reaction SMILES: NC1N=C(NC2O[C@H](CO)[C@@H](O)[C@H]2[OH:11])N=C(P(O)(OO)=O)C=1N.N[C:25]1[N:30]=[C:29]([NH:31][CH:32]2[O:38][C@H:37]([CH2:39][O:40][P:41]([OH:44])([OH:43])=[O:42])[C@@H:35]([OH:36])[C@H:33]2[OH:34])[C:28]([NH2:45])=[C:27]([OH:46])[N:26]=1>>[NH2:45][C:28]1[C:27](=[O:46])[NH:26][C:25](=[O:11])[NH:30][C:29]=1[NH:31][CH:32]1[O:38][C@H:37]([CH2:39][O:40][P:41]([OH:44])([OH:43])=[O:42])[C@@H:35]([OH:36])[C@H:33]1[OH:34]
Reactant: Nc1nc(O)c(N)c(NC2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)n1
Reactant: Nc1nc(NC2O[C@H](CO)[C@@H](O)[C@H]2O)nc(P(=O)(O)OO)c1N
Product: Nc1c(NC2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)[nH]c(=O)[nH]c1=O

Procedure:
As noted above, in bacteria and fungi, GTP cyclohydrolase II (EC 3.5.4.25) catalyzes the reaction of GTP with a purine to produce 2,5-Diamino-6-hydroxy-4-(5′phosphoribosylamino)-pyrimidine; diaminohydroxyphosphoribosylaminopyrimidine deaminase (EC 3.5.4.26) catalyzes the reaction of 2,5-Diamino-6-hydroxy-4-(5′phosphoribosylamino)-pyrimidine to produce 5-amino-6-(5-phosphoribosylamino)uracil; 5-amino-6-(5-phosphoribosylamino)uracil reductase (EC 1.1.1.193) catalyzes the reaction of 5-amino-6-(5-phosphoribosylamino)uracil to produce 5-Amino-6-(5′phosphoribitylamino)uracil; lumazine synthase catalyzes the reaction of 5-Amino-6-(5′phosphoribitylamino)uracil to produce 6,7-Dimethyl-8-ribityl lumazine; and riboflavin synthase (EC 2.5.1.9) catalyzes the reaction of 6,7-Dimethyl-8-ribityl lumazine to produce riboflavin
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[O:5][CH:6]=1.O=S(Cl)[Cl:12]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[O:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)co1
Product: O=C(Cl)c1cc(Br)co1
Temperature: 25 °C

Procedure:
The crude 4-bromo-furan-2-carboxylic acid (30 g, 157 mmol) was placed in a 500 mL round bottom flask equipped with a magnetic stirring bar and a reflux condenser, and the flask was alternately evacuated and filled with nitrogen several times. The solids were suspended in benzene (400 mL), treated with SOCl2 (60 mL, 823 mmol) and the mixture was heated to reflux in a heating mantle. Dark tarry materials form on the walls of the reaction flask during the course of the reaction. After ˜135 minutes at reflux a sample of the reaction was concentrated under reduced pressure and analyzed by 13C NMR. The NMR was quite clean and showed the reaction to be complete. [13C-NMR (400 MHz, CDCl3): δ 154.9, 147.6, 146.3, 126.0, 102.5] After ˜3 hours at reflux the reaction mixture was allowed to cool to ambient temperature. The pale brown supernatant solution of the acid chloride was decanted from the dark solids, and the solids were rinsed with additional benzene. The benzene solutions were combined and concentrated under reduced pressure to afford 4-bromofuran-2-carbonyl chloride as a pale brown oil. This crude material was carried on to the amide formation without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C(P(CCCC)CCCC)CCC.[CH3:34][O:35][C:36](=[O:50])[CH:37]([CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39].CCCCCCC>C1C=CC=CC=1>[CH3:41][O:40][C:38](=[O:39])[CH:37]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:12][CH2:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:47][CH:48]=1)[C:36]([O:35][CH3:34])=[O:50]
Reactant: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Reactant: COc1ccc(C(=CCO)c2ccc(OC)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: COC(=O)C(Cc1ccc(OCC=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
Under a nitrogen atmosphere, 3,3-bis-(4-methoxy-phenyl)-prop-2-en-1-ol (500 mg, 1.95 mmol), tributylphosphine (424 (mg, 2.1 mmol) and 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (464 mg, 1.95 mmol) were successively dissolved in dry benzene (50 mL). Solid azodicarboxylic dipiperidide (ADDP) (530 mg, 2.1 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and di hydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified by chromatography eluting with heptane/ethylacetate (4:1) to give 150 mg (16%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>O1CCCC1>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:23])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester (2.50 g, 7.39 mmol) in tetrahydrofuran (30 mL) was treated with a 0.8M aqueous lithium hydroxide solution (11.1 mL, 8.86 mmol). The reaction mixture was stirred at 25° C. for 23 h. The resulting reaction mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous hydrochloric acid solution (15 mL). The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (2.20 g, 96%) as a white solid which was used without further purification: mp 137-138° C.; FAB-HRMS m/e calcd for C16H22O4S (M+H)+ 311.1317, found 311.1321.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[O:1]([C:8]1[N:13]=[C:12]([C:14]([Cl:20])=[O:16])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccnc(Oc2ccccc2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-phenoxy-pyrimidine-4-carboxylic acid, 17, (0.19 g, 0.89 mmol) in methylene chloride (10 mL) containing a few drops of DMF is added oxalyl chloride (0.1 mL). The solution is stirred for 2 hours at room temperature and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[CH:6]Cl.[C:10]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])#[CH:11]>>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[CH:6][C:11]#[C:10][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[Si](C)(C)C#CC=CCl
Reactant: C#Cc1ccccc1C#N
Product: C[Si](C)(C)C#CC=CC#Cc1ccccc1C#N
Yield: 53 %

Procedure:
The Title compound may be produced in two steps using compound a1 Example 1 and compound a3 from Example 3 as starting materials. Firstly, compound a1 and compound a3 were reacted according to Method A set forth in the above-described General Synthesis Procedures I to form 2-(6-trimethylsilyl-3-hexen-1,5-diynyl)benzonitrile, which was subsequently dissolved into into dry methanol with K2CO3 to give a brown oil in 53% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:21])[C:12]=3[N:22]=[C:9]2[CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl>[NH2:21][C:13]1[C:12]2[N:22]=[C:9]3[CH2:8][O:7][CH2:6][C@H:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[N:10]3[C:11]=2[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 0 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
(11S)-11-(3-Aminopropyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (190 mg, 0.640 mmol) was dissolved in 8 mL of CH2Cl2 and the reaction mixture was cooled to 0° C. under N2. Triethylamine (356 μL, 2.56 mmol) was added followed by iso-butyryl chloride (67 μL, 0.643 mmol). After stirring overnight, the reaction mixture was diluted with 20 mL of CH2Cl2 and was washed successively with saturated NaHCO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% methanol/CHCl3) gave a white solid. Crystallization from ethyl acetate gave N-{3-[(11S)—6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}-2-methylpropanamide (80 mg) as a white solid, mp 207-208° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
6-Bromo-N-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and 4-fluoroaniline (84 mg, 0.76 mmol) in a similar manner as described in Example 13 to give 26 mg (19%) of an off-white solid. 1H-NMR (DMSO-d6): δ 811.07 (s, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.12 (dd, 1H), 6.92 (t, 2H), 6.70-6.68 (m, 2H), 5.89 (d, 1H), 4.73-4.71 (m, 1H), 2.68-2.53 (m, 2H), 1.99-1.73 (m, 4H); MS m/z (M−1) 357, 359.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CC(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:34]1[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc([N+](=O)[O-])cc23)CC1
Temperature: 60 °C
Reaction time: 13 h
Yield: 89 %

Procedure:
To a solution of 4-chloro-6-nitroquinazoline (prepared according to the literature: Alexander J. Bridges et al. J. Med. Chem. 1996, 39, 267-276, and references therein; 12 g, 57.5 mmol) and DIEA (10 mL, 57.5 mmol) in 230 mL IPA was added Boc-piperazine (10.7 g, 57.5 mmol). The reaction mixture was heated to 60° C. and stirred for 13 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified on silica gel (1:1 to 1:4 DCM:EtOAc gradient) to furnish 4-(6-nitro-quinazolin-4-yl)-1-Boc-piperazine as a pale yellow oil (18.3 g, 89%). LCMS (APCI+) m/z 360 [M+H]+. HPLC Rt 3.06 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][S:23][C:21]2[O:22][C:18]([C:15]3[CH:16]=[CH:17][C:12]4[O:11][CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[C:13]=4[CH:14]=3)=[N:19][N:20]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: COc1ccc(CSc2nnc(-c3ccc4occ(-c5ccc(OC)cc5)c4c3)o2)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[CH2:16][CH2:17][CH3:18])=[C:11]([F:20])[CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[C:11]([F:20])[CH:10]=1
Reactant: CCCC(O)c1ccc(Br)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
Trifluoroacetic acid (366 mL, 3.21 mmol) was added dropwise to a 0° C. solution of 1-(4-bromo-2-fluorophenyl)butan-ol (440 mg, 1.8 mmol) in dichloromethane (10 mL). Added Dess-Martin periodinane (1.21 g, 2.85 mmol) and let reaction warm to room temperature and stir for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 1-(4-bromo-2-fluorophenyl)butan-1-one (330 mg, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ): 7.65-7.69 (m, 1H), 7.32-7.45 (m, 2H), 2.83-2.87 (m, 2H), 1.62-1.71 (m, 2H), 0.90 (m, 3H).