Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([F:17])=[CH:5][CH:4]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([F:17])=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3cc(F)ccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c2c(nc3cc(F)ccc13)CCCC2O
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a cooled suspension of 5.0 g of 9-amino-3,4-dihydro-6-fluoroacridin-1(2H)-one in 85 ml of tetrahydrofuran was added 22 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour and then quenched with 8 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate, and the combined organics were dried over anhydrous magnesium sulfate. This was filtered and concentrated to obtain 5.0 g of a powder, mp 203°-206° C. d. This was recrystallized from tetrahydrofuran/hexane to obtain 3.95 g of an analytically pure powder, mp 207°-209° C. d.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:32](Cl)(=[O:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:32]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])=[N:7][CH:6]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: CCCCCCS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 60 °C
Yield: 7.6 %

Procedure:
To a solution of [4-(6-aminopyridin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.035 g, 0.10 mmol) in pyridine (3 mL) was added hexanesulfonyl chloride (0.022 mL, 0.12 mmol). After heating at 60° C. for 20 h, the mixture was diluted with ethyl acetate (100 mL), washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by preparative thin layer chromatography afforded the title compound as a white solid (3.8 mg, 8% yield). 1H NMR (300 MHz, CDCl3) δ 7.66, 7.29, 4.08, 3.91, 3.38, 3.27, 3.08, 1.84, 1.35, 1.27, 0.87. MS (ES+) m/z 499.4 (M+1).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23][C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[C:29]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:28][C:27]2=[S:46])=[O:25])[O:14][CH2:13][CH2:12][O:11]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:57][O:58][CH2:59][CH2:60][C:61](=[O:69])[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63].C(O)(=O)C>C1COCC1>[CH2:3]([C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@H:23]([C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[C:29]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[O:28][C:27]2=[S:46])=[O:25])[C@@:61]([OH:69])([CH2:60][CH2:59][O:58][CH3:57])[C:62]([O:64][C:65]([CH3:66])([CH3:67])[CH3:68])=[O:63])[O:11][CH2:12][CH2:13][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCC1(CCCCCC/C=C/CC(=O)N2C(=S)OC(c3ccccc3)(c3ccccc3)[C@@H]2C(C)C)OCCO1
Reactant: COCCC(=O)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N2C(=S)OC(c3ccccc3)(c3ccccc3)[C@@H]2C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Temperature: -78 °C
Yield: 79.5 %

Procedure:
Lithium chloride (5.12 g, 121 mmol) was heat dried with a heat gun under reduced pressure. Under a nitrogen atmosphere, a mixture of No. 5499685 (E)-10-(2-heptyl-[1,3]dioxolan-2-yl)-1-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-dec-3-en-1-one (25.0 g, 40.3 mmol) and THF (80 mL) was added at room temperature. Further THF (145 mL) was then added to the reaction vessel. The mixture was stirred until it became homogeneous and then cooled to −78° C. Lithium hexamethyldisilazide (1 M solution in THF, 7.74 mL, 7.74 mmol) was added, and the mixture was stirred for 2 h. To the reaction mixture was added dropwise a mixture of tert-butyl 4-methoxy-2-oxo-butyrate (10.6 g, 56.5 mmol) and THF (25 mL) and the mixture was stirred for further 1 hour. To the reaction mixture was added acetic acid (4.61 mL, 80.6 mmol) and the cooling bus was removed. Water was added and the mixture was extracted with ethyl acetate. The organic layer was then washed with water, an aqueous solution of 1% NaHCO3, water, and a saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified with SP1 (SiO2 cartridge, 20% ethyl acetate/n-hexane, Rf=0.3) to obtain No. 6801291, tert-butyl (E)-(2S,3S)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-undec-4-enoate (25.9 g, 80% yield).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16](=N)N)[CH:9]=1)[CH3:6].ClC[CH2:21][C:22]#[N:23].[OH-].[Na+]>O.C(O)C>[CH3:6][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][CH2:16][CH2:21][C:22]#[N:23])[CH:9]=1)[CH3:4]
Reactant: CN(C)Cc1ccnc(CSC(=N)N)c1
Reactant: N#CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCC#N)c1
Reaction time: 7 h
Yield: 89.9 %

Procedure:
To a solution of S-(4-dimethylaminomethyl-2pyridylmethyl)isothiourea trihydrochloride (21.54 g) and 3-chloropropionitrile (8.01 g) in water (90 ml) and ethanol (65 ml) at 0° C (ice-salt bath) under nitrogen, was added dropwise over 30 minutes, a solution of sodium hydroxide (11.5 g) in water (120 ml), keeping the temperature below 3° C. After having been stirred for 7 hours and allowed to stand for 20 hours, the solution was extracted with 3:1 chloroform:ethanol (3×160 ml). The combined extracts were washed with water and dried (MgSO4) Solvent was evaporated at reduced pressure and the residue vacuum-distilled to give 3-(4-dimethylaminomethy-2-pyridyl-methylthio)propionitrile (13.66 g) as a pale yellow liquid, b.p.0.005 mm 148°-152° C.
Reaction SMILES: [CH2:1]([C:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:37]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C:4]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:1][CH2:2][OH:37])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (obtained as described in Example 111) in THF-H2O (1:1, 20 mL) were added NaIO4 (1.0148 g, 4.74 mmol, 5 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.1708 g, 0.0167 mmol, 0.018 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and NaBH4 (0.200 g) was added. After the mixture was stirred for 1 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[CH3:19])#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][N:14]3[CH3:19])[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(=O)O
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2cccc3c2ccn3C)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude (R)-2-(5-cyano-6-(1-methyl-1H-indol-4-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (151 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 396.4 (M+H); UV 202.2, 273.1, 324.8 nm; t 0.613 min.
Reaction SMILES: [CH:1]1([CH:5]=[C:6]2[CH2:15][CH2:14][C:13]3[CH:12]=[C:11]([C:16]([O:18]C)=[O:17])[CH:10]=[CH:9][C:8]=3[C:7]2=O)[CH2:4][CH2:3][CH2:2]1.Cl.[Cl:22][C:23]1[CH:30]=[C:29]([NH:31][NH2:32])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[Cl:22][C:23]1[CH:30]=[C:29]([N:31]2[CH:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:6]3[C:7]([C:8]4[CH:9]=[CH:10][C:11]([C:16]([OH:18])=[O:17])=[CH:12][C:13]=4[CH2:14][CH2:15]3)=[N:32]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCC1)C2=O
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCC2)cc1Cl
Yield: 65 %

Procedure:
The title compound was prepared according to Method B and Method C from methyl 6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 19 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1) to give 2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (150 mg, 0.36 mmol, 65% yield) as a yellow solid. The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclobutyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.77 (m, 4H), 1.77-1.98 (m, 3H), 2.07-2.18 (m, 1H), 2.51-2.59 (m, 1H), 2.80-2.93 (m, 1H), 2.97-3.07 (m, 1H), 3.44-3.56 (m, 1H), 4.88 (dd, J=9.40, 6.98 Hz, 1H), 7.22 (dd, J=8.86, 1.88 Hz, 1H), 7.42 (d, J=2.15 Hz, 1H), 7.67 (d, J=8.86 Hz, 1H), 7.75-7.83 (m, 2H), 8.01 (d, J=8.06 Hz, 1H). ES-MS m/z 420 (M+H)
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>ClCCl>[C:19]([C:10]1[C:11]([CH3:13])=[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=1)[S:6][CH2:5][CH2:4][CH:3]2[CH2:1][CH3:2])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CCC1CCSc2c(C)ccc(C)c21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Reaction time: 1.5 h
Yield: 72.2 %

Procedure:
A mixed solution containing 1.91 g (9.26 mmol) of the 4-ethyl-5,8-dimethylthiochroman and dichloromethane was dropwise added to a mixed solution containing 1.49 g (11.1 mmol) of aluminum chloride, 0.82 ml (11.6 mmol) of acetyl chloride and 6 ml of dichloromethane at 0° C., and the mixture was stirred for 1.5 hours. The reaction mixture was poured into ice and a solution containing 5% hydrochloric acid and extracted with dichloromethane. The extract was washed with a saturated sodium hydrogencarbonate, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give 1.66 g (yield 72%) of 6-acetyl-4-ethyl-5,8-dimethylthiochroman.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(OCC)(=O)C>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([NH:19][C:20]([NH:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:12]=1)=[O:21])=[O:18]
Reactant: Nc1cc(-c2ccc(F)cc2)no1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(-c2ccc(F)cc2)no1
Reaction time: 17 h

Procedure:
3-(4-Fluorophenyl)-5-aminoisoxazole (250 g.) was combined with 300 g. of 2-chlorobenzoyl isocyanate in 50 ml. of ethyl acetate. The reaction mixture was stirred overnight (about 17 hours) and the resulting solid was filtered, washed with ethanol, ether, and then dried, m.p., 200°-202° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[S:17]1C=[CH:20][CH:19]=[C:18]1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1cccs1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 12 (2.24 g, 10 mmole) in absolute THF (10 ml) was added dropwise to a 1M solution of thiophen-2-yl-magnesium bromide in THF (20 ml, 20 mmole) under argon and while cooling with ice, and stirred for 20 hours at RT. To work up the reaction mixture saturated ammonium chloride solution (10 ml) and water (10 ml) were added while cooling with ice and the mixture was extracted with diethyl ether (3×10 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated by evaporation.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH:21]([CH3:23])[CH3:22]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH:21]([CH3:23])[CH3:22])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC(=O)N2
Reactant: CC(C)C(=N)N
Agent: Cl
Product: Cc1ccc2c(c1)-c1nc(C(C)C)ncc1CC(=O)N2
Yield: 91 %

Procedure:
Analogous to Scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and isobutyramidine hydrochloride. Yield: 91%.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.C([Li])CCC.Cl[C:16]1([C:28]([F:31])([F:30])[F:29])[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:18](=[O:27])[O:17]1>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]2[NH:19][C:18](=[O:27])[O:17][C:16]([C:2]#[C:3][C:4]3[O:5][CH:6]=[CH:7][CH:8]=3)([C:28]([F:29])([F:30])[F:31])[C:21]=2[CH:22]=1
Reactant: BrC(Br)=Cc1ccco1
Reactant: O=C1Nc2ccc(Cl)cc2C(Cl)(C(F)(F)F)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#Cc2ccco2)(C(F)(F)F)O1
Temperature: 25 °C
Yield: 110.5 %

Procedure:
To a solution of 5.9 g (25 mmoles) of 1,1-dibromo-2-(furan-2-yl)ethylene in 124 mL of anhydrous THF at −20° was added dropwise 31.0 mL of 1.6 M n-butyllithium in hexanes (50 mmoles). This solution was allowed to warm to ambient temperature over a period of 30 min, after which time it was cooled to −50°. 4,6-Dichloro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (2.65 g, 9.27 mmoles) was added in one portion, and the resulting solution was allowed to warm to −35° over 40 min. The reaction was quenched by the addition of aqueous ammonium chloride, and this mixture was poured onto water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (elution with 15% and 30% ethyl acetate in hexanes) affording 3.5 g of a solid which was recrystallized from ethyl acetate/hexanes to afford 3.03 g (95.7%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[NH:15]1[C:19]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)=[N:18][N:17]=[N:16]1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[NH:18]1[C:19]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:23][CH:22]=2)=[N:15][N:16]=[N:17]1
Reactant: O=Cc1ccc(Cc2nnn[nH]2)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Cc4nnn[nH]4)cc3)nc2c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
IBX (0.437 g, 1.562 mmol) was dissolved in anhydrous DMSO (5 mL) and [4-(1H-tetrazol-5-ylmethyl)-phenyl]-methanol (0.270 g, 1.562 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 4 hours. Water (20 mL) was added. The white precipitate was filtered off, washed with water, and dried under vacuum. The crude compound was mixed with methanol (20 mL) and stirred for 30 minutes, before being filtered. The filtrate was concentrated to give 4-(1H-tetrazol-5-ylmethyl)-benzaldehyde as a white solid. Yield: 0.267 g (99%). To a solution of 2-amino-4,6-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethyl acetamide (5 mL) were added 4-(1H-tetrazol-5-ylmethyl)-benzaldehyde (0.260 g, 1.4 mmol), sodium hydrogen sulfite (58.5%, 0.159 g, 0.88 mmol) and p-toluenesulfonic acid (19 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h, then cooled to room temperature. Water (40 mL) was then added. A yellow precipitate was formed and filtered off, washed with water, and small amount of methanol. It was triturated with 10% methanol in ether to give 0.107 g of solid, which was further purified by preparative HPLC, to give the title compound (0.082 g, 28%) as a white solid. MS (ES) m/z: 365.1 (M+1). MP 295-296° C.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C(OCC)C>[O:12]1[CH2:13][CH2:14][N:9]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
A solution of ethyl 2-chloro-2-oxoacetate (1.25 g, 9.18 mmol) in diethyl ether (5 mL) was added dropwise to a solution of morpholine (1.0 g, 11.48 mmol) in diethyl ether (20 mL) and triethylamine (1.16 g, 11.48 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The yellow-colored oil was transferred into 25 mL iced water and extracted with ethyl acetate (3×20 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give 1 g of the crude product, which was used further without any purification. Crude yield 47%. 1H NMR (400 MHz, CDCl3) δ 4.33-4.38 (q, 2H), 3.72-3.76 (m, 4H), 3.65-3.68 (m, 2H), 3.47-3.50 (m, 2H), 1.37-1.40 (t, 3H). LCMS m/z 187.93 [M+H]+, tR=0.525 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
To a solution of 4-bromothiophene-2-carbaldehyde 63 (Avocado, UK) (1.20 g, 6.3 mmol) in THF (50 mL) at rt was added dropwise morpholine (0.96 g, 11 mmol). After the reaction was stirred at rt for 5 minutes, NaBH(OAc)3 (3.18 g, 15 mmol) was added in one portion. The resulting mixture was stirred at rt for 3 h. Ethyl acetate (80 mL) was added and then washed with NaHCO3 (20 mL×2) and brine (20 mL). The organic layer was dried with MgSO4. After the solvent was evaporated, the residue was purified by silica gel column chromatography to give 64 (1.31 g). 1H NMR (400 MHz, CDCl3) 6, 2.50–2.52(m, 4H), 2.67 (s, 2H), 3.72–3.75 (m, 4H), 6.87(s, 1H), 7.15 (d, J=1.4 Hz, 1H). MS (EI) m/z (M+H+) 263.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O)C.BrC[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][CH2:14][CH2:4][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: BrCCCc1ccccc1
Product: c1ccc(CCCN2CCNCC2)cc1

Procedure:
1-Ethoxycarbonylpiperazine and 1-bromo-3-phenylpropane were used as the starting materials and treated in the same manner as in Reference Example 9 to give 1-(3phenylpropyl)piperazine.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>CC1C=CC(S(O)(=O)=O)=CC=1.O.C1COCC1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 96 %

Procedure:
A round-bottom flask was charged with 20 (1.76 g, 10 mmol), p-TsOH.H2O (38 mg, 0.2 mmol), 3,4-dihydro-2H-pyran (1.26 g, 15 mmol) and THF (20 mL). The reaction mixture was degassed with nitrogen and heated at reflux for 18 h, and then the solvent was removed under reduced pressure. The residue was diluted with DCM (250 mL) and water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0.5 to 1.0% MeOH) to afford 2.5 g (90%) of methyl 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxylate (22) as a grey oil: MS (ESI) m/z=261.2 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.[CH3:16][N:17]=[C:18]=[O:19]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH:15][C:18]([NH:17][CH3:16])=[O:19])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: N[C@@H]1CCN(c2cccc3c2CCO3)C1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N[C@@H]1CCN(c2cccc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 497.5 %

Procedure:
(R)-N-(2,3-Dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (0.1 mmol) was dissolved in CH2Cl2 and methyl isocyanate (0.12 mmol) was added. The reaction was stirred at room temperature for 1 hour. The solvents were removed in vacuo, and the compound purified by flash chromatography eluting with 10% methanol in ethyl acetate to give 130 mg (98%) of the desired product as a solid.