Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1>C1COCC1>[Br:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:3])[CH:9]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CCBr)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with NaH (900 mg, 37.52 mmol), MeI (3.14 mL, 50.00 mmol) and THF (7.5 mL). The resulting grey suspension was stirred at rt for 5 min, then a solution of 3-(2-bromethyl)-indol (1.12 g, 5.00 mmol) in THF (25 mL) was added dropwise. After stirring for 18 h at rt, the reaction mixture was concentrated, redissolved in DCM and washed with H2O (3×). The org. layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield the title compound as an yellow oil which was used as such in the next step. LC-MS conditions A: tR=0.95 min, [M+H]+=no ionization.
Reaction SMILES: [H-].[Na+].[C:3]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#N)=[CH:12][CH:11]=2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1.[CH3:19]I.C[N:22]([CH3:31])P(N(C)C)(N(C)C)=O>>[CH3:19][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[C:3]2[S:7][CH:6]=[CH:5][CH:4]=2)=[CH:11][CH:12]=1)([CH3:17])[C:31]#[N:22]
Reactant: N#CCc1ccc(C(=O)c2cccs2)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 3 h

Procedure:
To a stirred mixture of 5.5 parts of sodium hydride dispersion 78% in 150 parts of hexamethylphosphoramide are added dropwise 14 parts of 2-[p-(2-thenoyl)phenyl]acetonitrile over a period of 30 minutes at a temperature of 15° C. Upon completion, stirring is continued for 3hours at room temperature. Then there are added dropwise 34 parts of methyl iodide (strong exothermic reaction) and upon completion, the whole is stirred overnight. The reaction mixture is poured onto water and the product is extracted three times with 200 parts of benzene. The combined extracts are washed five times with water, dried, filtered and evaporated, yielding α-methyl-p-(2-thenoyl)hydratroponitrile as a residue.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13]3[O:20][NH:27][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](C2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1C1CCCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
Trans-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (349 mg, 1.03 mmol) (from example 79, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (41.1 mg, 1.03 mmol) dissolved in water (0.500 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.063 mL, 1.03 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h 20 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5 mL, 30.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase was dried over Na2SO4 and evaporated to yield a yellow oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (170 mg, 53%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.82-1.08 (m, 2H), 1.08-1.32 (m, 3H), 1.45-1.83 (m, 8H), 1.89-2.02 (m, 1H), 2.12-2.23 (m, 1H), 2.79-3.04 (m, 2H), 3.70 (s, 3H), 3.87-4.83 (m, 2H), 5.64 (s, 1H). MS m/z 309 (M+H)+
Reaction SMILES: S(=O)(=O)(O)O.Cl[C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17].CC([O:22]C)(C)C.[OH2:24]>>[F:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[CH2:8][C:7]([OH:22])=[O:24]
Reactant: O
Reactant: COC(C)(C)C
Reactant: Fc1cc(F)c(C#CCl)cc1F
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc(F)c(F)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
50 ml of concentrated sulphuric acid was added to 1-chloroethynyl-2,4,5-trifluorobenzene of formula IV, X═Cl and the mixture heated to 100° C. and left to stir for 1 hour. 50 ml of MTBE and 100 ml of water were then added. The phases were separated and the aqueous phase was re-extracted with 2×50 ml of MTBE. The combined organic phases were counter extracted with 3×50 ml of aqueous NaHCO3 and put to one side. The three aqueous phases of NaHCO3 were recombined and the resulting phase was acidified with hydrochloric acid and then extracted with 3×50 ml of MTBE. The organic phases were concentrated to a residue obtaining 0.25 g of 2,4,5-trifluorophenylacetic acid of formula (I) with a molar yield of 25%.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C@H:7]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:5].[CH3:27][Mg]Br.C[O-].[Na+]>CO>[CH2:12]([N:9]1[CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[CH3:27])[C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H]1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@@H]1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone (example 5 (c)) the title compound was prepared from (3R,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide and methylmagnesium bromide with subsequent epimerisation with NaOMe in methanol. The title compound was obtained as off-white solid. MS (m/e): 327.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([C:31]([F:30])([F:39])[F:40])=[CH:33][CH:34]=3)=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(C(F)(F)F)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 12.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-(trifluoro methyl) aniline (0.133 g, 0.828 mmol), THF (5.0 mL) and 60% NaH (0.033 g, 0.825 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.018 g of the desired product. 1HNMR (DMSO-d6): δ 2.72 (s, 3H), 7.41 (s, 2H), 7.63 (s, 2H), 7.73 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 2H), 9.47 (s, 1H), 11.39 (s, 1H), 11.60 (s, 1H); MS [M+H]+: 520.39.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=2)[N:11]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: Nc1ccc(OCc2ccncc2)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccncc3)c3ccccc23)cn1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-(2-methylpyridin-5-yl)pyrazole (26 mmol), 1-amino-4-(pyridin-4-ylmethoxy)naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+].CO[CH2:43][CH2:44]OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:26][C:27]1[N:32]=[CH:31][C:30]([C:44]2[CH:43]=[CH:3][C:4]([C:2]3[N:6]([S:7]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=3)=[CH:5][N:6]=2)=[CH:29][CH:28]=1
Reactant: COCCOC
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(Cc1cc(-c2ccc(-c3ccc(Cl)nc3)nc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (6-chloropyridin-3-yl)boronic acid (237 mg), sodium hydrogencarbonate (252 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 90° C. for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→3:7), and fractions showing Rf value of 0.6 (eluent: hexane-ethyl acetate=1:1) were collected to give the title compound of Reference Example 172 as a colorless oil (yield 100 mg, 22%). Then, fractions showing Rf value of 0.4 (eluent: hexane-ethyl acetate=1:1) were collected to give the title compound of Reference Example 173 as a pale-yellow powder (yield 100 mg, 19%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:22]([O-])=O.[Na+].O>CC(O)=O.OS(O)(=O)=O>[CH2:14]([C:13]1[N:22]=[N:1][C:2]2[C:3]([C:12]=1[OH:21])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:9])([F:10])[F:11])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1c(C(=O)CCc2ccccc2)cccc1C(F)(F)F
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1c(Cc2ccccc2)nnc2c(C(F)(F)F)cccc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-amino-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one (4.2 g, 13.8 mmol) in AcOH (70 ml) and H2SO4 (10 ml) was added a solution of NaNO2 (1.8 g in 10 ml H2O). The reaction was then heated to 70° C. After 1.5 hr, the reaction was cooled, poured into water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to give 3-benzyl-8-trifluoromethyl-cinnolin-4-ol
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Li+].C1COCC1.Cl>C(OCC)(=O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (0.466 g, 1 mmol), lithium hydroxide (0.237 g, 10 mmol), THF (30 mL), and water (10 mL) were combined and stirred under argon at room temperature overnight. Solvents were pumped off, and the residue taken up in ethyl acetate and water. The mixture adjusted to pH 2.5 with HCl, and extracted with a large volume of ethyl acetate. Organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LC-MS m/z 451.8 (M+H)+, 1.37 min (ret time).
Reaction SMILES: Cl[C:2]1[N:19]=[N:18][C:5]2[CH2:6][CH2:7][N:8]3[C:16]4[CH:15]=[CH:14][CH:13]=[C:12]([F:17])[C:11]=4[CH:10]=[C:9]3[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B(O)O)=[CH:36][C:30]=3[C:31]=2[C:32](=[O:35])[NH:33][CH3:34])=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[F:17][C:12]1[C:11]2[CH:10]=[C:9]3[C:4]4[CH:3]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:33][CH3:34])=[O:35])[C:30]=6[CH:36]=5)[N:19]=[N:18][C:5]=4[CH2:6][CH2:7][N:8]3[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cccc2c1cc1n2CCc2nnc(Cl)cc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc4c(nn3)CCn3c-4cc4c(F)cccc43)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
To a degassed solution of 2-chloro-11-fluoro-5,6-dihydropyridazino[4′,3′:3,4]pyrido[1,2-a]indole (100 mg, 0.37 mmol), (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)boronic acid (169 mg, 0.4 mmol) and K3PO4 (155 mg, 0.73 mmol) in DMF (3 mL) was added Pd(dtbpf)Cl2 (5 mg) under N2. Then the mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After being concentrated, the residue was purified by prep-HPLC to give the product of 5-(11-fluoro-5,6-dihydropyridazino[4′,3′:3,4]pyrido[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 13%). 1H-NMR (CDCl3, 400 MHz) δ 8.11 (d, J=9.0 Hz, 2H), 8.00 (dd, J=5.6, 8.8 Hz, 2H), 7.66 (s, 1H), 7.25 (s, 1H), 7.15˜7.23 (m, 4H), 6.81 (dd, J=7.6, 9.6 Hz, 1H), 6.17 (d, J=4.0 Hz, 1H), 4.47 (t, J=6.4 Hz, 2H), 3.67 (t, J=6.4 Hz, 2H), 3.21 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.97 (s, 3H). MS (M+H)+: 614.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:13]([Cl:18])[CH:12]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)COc1ccc(Br)cc1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
14.5 mL (83.242 mmol) Hünig base was added to a solution of 7.800 g (37.222 mmol) 4-bromo-2-chlorophenol and 4.70 mL (41.537 mmol) ethyl bromoacetate in 100 mL DMF and the mixture was stirred for 4 h at 100° C. The reaction mixture was combined with water and exhaustively extracted with EtOAc. The combined org. phases were washed with saturated aqueous sodium bicarbonate, water and saturated aqueous NaCl, dried over sodium sulphate and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C1N=CN([C:17]([N:19]2C=N[CH:21]=[CH:20]2)=[O:18])C=1.NC1C2[O:32][C:31](=[O:34])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>C1COCC1.CN(C=O)C>[O:32]=[C:31]1[NH:30][C:29]2[CH:28]=[CH:27][CH:26]=[C:20]([NH:19][C:17]([NH:1][CH2:2][C:3]3[O:4][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:7]=3)=[O:18])[C:21]=2[O:34]1
Reactant: Nc1cccc2[nH]c(=O)oc12
Reactant: NCc1ccc(C(F)(F)F)o1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(F)(F)F)o1)Nc1cccc2[nH]c(=O)oc12
Temperature: 70 °C
Yield: 13 %

Procedure:
To a solution of 2-aminomethyl-5-trifluoromethylfurane (1 g, 6.1 mmol) in THF (30 mL) was added CDI (2.1 mol eq) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×20 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (1.6 g, 5.9 mmol). The oil obtained (0.31 g, 1.19 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1c (Scheme 3) was added (0.8 mol eq, 0.15 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (100% EtOAc) to obtain the product as white solid (0.05 g, 13% Yield). 1HNMR (DMSO, 200 MHz) δ 4.37 (d, 2H, J=6), 6.48 (d, 1H, J=2), 6.70 (dd, 1H), 7.01 (m, 2H), 7.16 (m, 1H), 7.70 (dd, 1H, J=2), 8.69 (s, 1H), 11.62 (bs, 1H). [M+1] 341.61 (C14H10F3N3O4 requires 341.24).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:6]=1[NH:29][S:30]([C:33]1[CH:38]=[C:37]([N+:39]([O-])=O)[CH:36]=[CH:35][C:34]=1[N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)(=[O:32])=[O:31])(=[O:3])[CH3:2].[Cl-].[NH4+].O.C(O)(=O)C>C(O)(C)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:6]=1[NH:29][S:30]([C:33]1[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:34]=1[N:42]1[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1)(=[O:31])=[O:32])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)c(OC(C)=O)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2N2CCOCC2)c(OC(C)=O)cc1C

Procedure:
19.5 g (0.029 mol) of the compound obtained in Step (c) above, reduced iron (5.3 g), triirontetraoxide (2.7 g) and ammonium chloride (0.4 g) were suspended in isopropanol (300 ml). To the mixture, a mixed solution of water (40 ml) and acetic acid (2 ml) was added dropwise while refluxing with heating. After the completion of the addition, the mixture was refluxed wih heating for 2 hours and the insoluble materials were removed by filtration while hot. The filtrate was added to water (300 ml) and the crystals thus-precipitated were collected by filtration. Yield: 16.4 g (86%). Melting Point: 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>C1COCC1>[CH:23]([NH:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59.9 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) in 1.6 mL THF was added isopropyl isocyanate (0.0074 mL, 0.076 mmol) and the reaction stirred at rt. After 45 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. After 2.5 hours, an additional 0.0074 mL (0.076 mmol) isopropyl isocyanate was added, the THF evaporated to 1 mL using a stream of nitrogen, the reaction briefly warmed to approximately 50° C. several times, and then stirred at rt overnight. At 21 hours, the reaction was quenched with MeOH, evaporated, then triturated with hot EtOAc to give the title compound as an off-white solid (15.6 mg, 60%). 1H NMR (DMSO-d6) δ: 10.67 (br. s, 1H), 8.25 (s, 1H), 7.97 (dd, J=8.1, 1.3 Hz, 1H), 7.40-7.46 (m, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 6.98-7.09 (m, 2H), 5.96 (d, J=7.3 Hz, 1H), 4.15-4.24 (m, 1H), 3.65-3.80 (m, 2H), 3.44-3.59 (m, 2H), 2.86-2.98 (m, 1H), 1.10 (s, 3H), 1.08 (s, 3H).
Reaction SMILES: C(OC([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](/[C:15]1[CH2:21][C@H:20]2[N:17]([C:18](=[O:25])[C@@H:19]2[C@H:22]([OH:24])[CH3:23])[C:16]=1[C:26]([O:28]CC=C)=[O:27])\[CH3:14])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:24][C@@H:22]([C@H:19]1[C:18](=[O:25])[N:17]2[C@@H:20]1[CH2:21][C:15](/[C:13](/[CH3:14])=[CH:12]/[C@@H:8]1[CH2:9][CH2:10][CH2:11][NH:7]1)=[C:16]2[C:26]([OH:28])=[O:27])[CH3:23]
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.82 g) in a mixture of tetrahydrofuran (28 ml) and ethanol (14 ml) were added successively triphenylphosphine (0.51 g), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (1.79 g), and tetrakis(triphenylphosphine)palladium (0) (220 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration, washed with tetrahydrofuran (40 ml) and dissolved in water (150 ml). The solution was washed with ethyl acetate (50 ml×2), concentrated in vacuo and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3- [(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.52 g).