Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH2:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH:4][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9]
Reactant: O=S1(=O)CCCO1
Reactant: CCC(C)CN
Solvent: C1CCOC1
Product: CCC(C)CNCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of (+/−)-2-methylbutylamine (10 g, 115 mmol) in tetrahydrofuran (80 mL) was slowly added a solution of 1,3-propane sultone (13.5 g, 109 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×30 mL). The solid was suspended 95% Acetone/EtOH (200 mL). The suspension was stirred at room temperature for 5 minutes. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound DS (17.6 g, 78%). 1H NMR (D2O, 500 MHz) δ ppm 3.07 (t, 2H, J=7.8 Hz), 2.93 (m, 3H), 2.76 (m, 1H), 2.01 (m, 2H), 1.67 (m, 1H), 1.30 (m, 1H), 1.09 (m, 1H), 0.81 (d, 3H, J=6.8 Hz), 0.77 (t, 3H, J=6.8 Hz). 13C NMR (D2O, 125 MHz) δ ppm 53.48, 48.13, 46.92, 31.96, 26.38, 21.29, 16.11, 10.19. ES-MS 210 (M+1).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:19])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][CH2:20][N:18]([CH2:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH2:10])[CH3:19])=[CH:28][CH:27]=1
Reactant: CN(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1N
Reaction time: 16.5 h

Procedure:
A mixture of (1R,2S)-[2-({[3-(4-fluoro-phenyl)-propyl]-methyl-amino}-methyl)-cyclohexyl]-carbamic acid benzyl ester (400 mg, 970 μM) and 20% palladium hydroxide on charcoal (Pearlman's catalyst, 200 mg) in methanol (25 mL) was shaken in a pressure bottle under a hydrogen atmosphere (55 psig) for 16.5 hours. The mixture was filtered and the solid was washed with methanol. The combined filtrates were concentrated under vacuum to provide a tan viscous oil (268 mg, quantitative), used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:25]([OH:27])=O)[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:54][CH2:55][CH2:56][NH2:57]>ClCCl>[F:54][CH2:55][CH2:56][NH:57][C:25]([C:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:10]([CH2:11][C:12]2[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])[CH:15]=[CH:14][N:13]=2)[CH:9]=1)=[O:27]
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc2c(C(=O)NCCF)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.3 %

Procedure:
See FIG. 21(a). 6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (111 mg, 0.29 mmol) was taken dichloromethane (10 mL). Triethyl amine (0.204 mL, 1.46 mmol) was added to get a clear solution. 1-Propanephosphonic acid cyclic anhydride (0.348 mL, 0.59 mmol) was added and stirred at RT for 5 minutes. Added 2-Fluoroethylamine hydrochloride (87 mg, 0.88 mmol) and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with dichloromethane, washed with water, brine solution. The organic layer was separated, dried over sodium sulphate, evaporated to get the crude compound. The compound was purified by silica gel chromatography using methanol and dichloromethane as eluent. Yield-44.3%. ES+MS m/z: 425.2 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3 H ) 2.39 (s, 3 H ) 3.66 (q, J=5.21 Hz, 1 H ) 3.75 (q, J=5.15 Hz, 1 H ) 4.49 (t, J=4.99 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 4.90 (q, J=8.85 Hz, 2 H ) 5.63 (s, 2 H ) 7.07 (d, J=5.65 Hz, 1 H ) 7.76 (s, 1 H ) 8.11 (s, 1 H ) 8.17 (d, J=5.65 Hz, 1 H ) 8.34 (s, 1 H ) 8.88 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:12][CH2:13][C:14](O)=O>Cl>[Cl:12][CH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)CCl
Agent: Cl
Product: O=[N+]([O-])c1ccc2nc(CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,4-diamino-nitrobenzene (15.3 g, 0.10 mole) and chloroacetic acid (14.18 μm, 1.5 eq) in 5.0 N aqueous HCl (80 mL) was heated at reflux for 1 hr. After cooling to RT, the reaction was filtered through celite and the filtrate was stored at 0° C. for 2 days. The crystals that formed, were collected and recrystallized from a mixture of EtOH and water to give 7.2 μm of the hydrogen chloride salt of 2-chloromethyl-5-nitro-benzimidazole. A portion of this salt (528 mg, 2.13 mmole) and morpholine (1.31 mL, 7 eq) in toluene (15 mL) were heated at reflux for 4 hr. After cooling to RT, the reaction was filtered and the filter cake was washed with toluene. The solvent was removed from the filtrate to leave the crude 2-[N-morpholinylmethyl]-5-nitro-benzimidazole as an oil. A portion of this material (657 mg) and 10% palladium on charcoal (650 mg) in EtOH (10 mL) was stirred overnight under a hydrogen atmosphere (balloon). Removal of the catalyst by filtration and the solvent left the crude 5-amino-2-[N-morpholinylmethyl]-benzimidazole as an oil. A portion of this material was coupled with 556 as described for 570 to afford 573 (HPLC retention time (YMC ODS S7 3×50 mm): 0.92 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15](F)=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[C:23]([O-])([O-])=[O:24].[K+].[K+].CO>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([O:24][CH3:23])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(F)cc2F)c(Cl)c1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Yield: 91.9 %

Procedure:
At 35° C., 13.7 g (0.04 mole) 4-chloro-3-(2,4-difluoro-5-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 5.5 g (0.04 mole) K2CO3, and 100 mL methanol were stirred for 1 hour. The reaction was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was purified chromatographically using 25% ethyl acetate in hexane as the eluent to give 13.0 g (90%) of 4-chloro-3-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a white solid, mp 116° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.[NH:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[B:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)=[CH:4][CH:5]=1)([OH:11])[OH:10]
Reactant: O=S1(=O)CCNCC1
Reactant: OB(O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A suspension of (4-bromomethylphenyl)boronic acid (2.00 g, 9.31 mmol), thiomorpholine 1,1-dioxide (1.50 g, 11.1 mmol), and potassium carbonate (2.60 g, 18.8 mmol) in acetone (25 mL) was stirred at 40° C. for 18 hours. The mixture was cooled to room temperature and the volatiles were evaporated. The residue was suspended in saturated aqueous ammonium chloride (100 mL). The aqueous phase was decanted from the waxy solid, rinsed with water (50 mL), and decanted again. The waxy solid was dissolved in methanol (50 mL), filtered to remove insoluble salts and evaporated to obtain 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide as a tan foam (2.48 g). The recovered material was crude by 1HNMR but was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:14][C:10]1([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:13][O:12][CH2:11]1
Reactant: CC1(COCCCCCCBr)COC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(COCCCCCCOc2ccc(C=O)cc2)COC1
Temperature: 150 °C
Yield: 82 %

Procedure:
A mixture of JYC-I-143-A (5 g, 18.9 mmol), 4-hydroxybenzaldehyde (2.53 g, 20.7 mmol), and K2CO3 (5.21 g, 37.7 mmol) in 50 mL of DMF was heated at 150° C. for 5 h. The reaction mixture was allowed to cool down to room temperature and poured into a separatory funnel containing H2O. The mixture was extracted with CH2Cl2 and the organic phase was washed with H2O and a saturated NaCl aqueous solution. The organic phase was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give brown oil. The crude product was purified by column chromatography (silica gel, hexanes:ethyl acetate:=4:1 (v/v)) to give light yellow liquid (4.75 g, 82%). 1H NMR (300 MHz, CDCl3, δ): 9.84 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.47 (d, J=5.5 Hz, 2H), 4.32 (d, J=5.5 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.44 (s, 2H), 1.80 (m, 2H), 1.60 (m 2H), 1.44 (m, 4H), 1.27 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ): 190.66, 164.13, 131.88, 129.72, 114.66, 80.09, 76.00, 71.33, 68.20, 39.85, 29.38, 28.94, 25.85, 25.73, 21.30. HRMS-FAB (m/z): [M+H]+ calcd for C18H27O4, 307.1909; found, 307.1905.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:17][O:18][C:19]1[C:20]([CH3:33])=[C:21]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[CH3:17][O:18][C:19]1[C:20]([CH3:33])=[C:21]([CH:22]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:23])[C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2ccccc2OCc2ccccc2)c(OC)c(OC)c1OC
Reaction time: 2 h
Yield: 100 %

Procedure:
Under ice-cooling, into a Grignard reagent (35 ml, a tetrahydrofuran solution) prepared from 2-(benzyloxy)bromobenzene (11.50 g, 0.044 mol) and magnesium (1.16 g, 0.048 mol) was dropped a solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (5.00 g, 0.021 mol) in anhydrous tetrahydrofuran (30 ml) and the mixture was stirred for 2 hours more. The reaction solution was poured into a saturated aqueous solution of ammonium chloride followed by extracting with ether. The extract was washed with a saturated saline and dried. The reaction solution was filtered and the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (8.80 g, 0.021 mol, 99%).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][CH:12]([CH2:20][CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)[C:24](O)=[O:25]>>[CH3:11][CH:12]([CH2:20][CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:24]=[O:25])=[CH:16][CH:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(C)Cc1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCC(C)Cc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (150 cc) was added to a flask containing 14.0 gm hexamethylenetetramine (HMTA). (+)2-methylbutylbenzene (14.8 gm) was then added and the mixture was refluxed for 21 hours. The deep orange mixture was distilled to remove excess trifluoroacetic acid. When about one third the volume remained, the mixture was poured into 600 ml ice water and stirred for 15 minutes. Sodium carbonate was added with stirring until the mixture was basic and the product was extracted with ether. The ether extract was washed with water and dried over sodium sulfate. The ether was removed leaving 18 gm crude (+)-4(-2-methylbutyl)benzaldehyde. This was vacuum distilled (78° C. at 0.07 mm Hg). The structure of the product was confirmed by NMR. The yield of the product was 78%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30](O)=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[Cl:29][C:24]1[CH:23]=[C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[C:16]([CH2:30][OH:31])=[N:17]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(=O)O)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (from example 15 step A) (5 mg, 0.01 mmol) in THF (1 ml) at room temperature under argon was added 1 M BH3 in THF (31 uL, 0.031 mmol). The reaction mixture was stirred at room temperature for one hour. Methanol (2 mL) was carefully added to the reaction mixture and stirred at room temperature for two hours. Solvents were removed in vacuo. EtOAc (10 mL) and 1 N NaOH (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (10 mL), and brine (10 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(1-(3,4-dichlorophenyl)-3-(hydroxymethyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (2.3 mg, gum, 42.6%). 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.48 (m, 9H) 1.68-1.93 (m, J=3.95 Hz, 2H) 1.88-2.17 (m, 2H) 2.65-2.84 (m, 1H) 3.27-3.46 (m, 2H) 3.55-3.76 (m, 2H) 4.43-4.60 (m, 1H) 4.67 (s, 2H) 6.08-6.35 (m, 1H) 7.40-7.62 (m, 2H) 7.63-7.83 (m, 1H). MS (ESI) 414 (M+H-tBu).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.[CH2:14]([Mg]Br)[CH:15]([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:11])[CH2:14][CH:15]([CH3:17])[CH3:16])=[C:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: Cc1c(C=O)oc2ccc(Cl)cc12
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(O)CC(C)C)oc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution (20 mL) of 5-chloro-3-methyl-1-benzofuran-2-carbaldehyde (1.00 g) synthesized in Example A88(2) in tetrahydrofuran was added a 1.0M solution (10.3 mL) of isobutylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (650 mg, 50%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:5][C:6]2[O:11][C:10](=[O:12])[CH:9]=[CH:8][C:7]=2[CH:13]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(O)C.C(O)(C)C>[OH:17][CH:16]([CH2:18][N:28]1[CH2:29][CH2:30][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)[CH2:15][O:14][C:4]1[C:3]([O:2][CH3:1])=[CH:13][C:7]2[CH:8]=[CH:9][C:10](=[O:12])[O:11][C:6]=2[CH:5]=1
Reactant: COc1cc2ccc(=O)oc2cc1OCC1CO1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2ccc(=O)oc2cc1OCC(O)CN1CCC(c2ccccc2)CC1
Yield: 69 %

Procedure:
Method C (27 h at 45° C.); starting materials; 6-methoxy-7-(oxiranylmethoxy)-2H-1-benzopyran-2-one (example 86) and 4-phenylpiperidine; yield 69%; fusion point 114°-115° C. (from isopropanol and ethanol). Hydrochloride: method G; yield 82%; fusion point 202°-205° C. (from isopropanol and ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([C:21]([O:23][CH3:24])=[O:22])#[C:16][C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([C:16]1[C:12]2([CH3:13])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([CH3:14])([C:15]=1[C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11]2)=[O:18]
Reactant: Cc1ccc(C)n1C(=O)OC(C)(C)C
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)C1=C(C(=O)OC)C2(C)C=CC1(C)N2C(=O)OC(C)(C)C
Yield: 50 %

Procedure:
A mixture of crude 2,5-dimethyl-pyrrole-1-carboxylic acid tert-butyl ester (prepared according to a literature (Haiser, H.-P.; et al. J. Org. Chem. 1984 49(22) 4203-4209); 500 mg) and dimethyl acetylenedicarboxylate (0.5 mL, ca 4 eq) was stirred at 120° C. under argon for 2 h. Purification by silica gel flash chomatography on SiO2 eluting with EtOAc/heptane (gradient from 1:20 to 1:2 ratio) gave compound 780A (166 mg, 50% yield) as a colorless liquid. HPLC: 90% at 3.67 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [F:1][CH:2]([F:25])[CH:3]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][CH2:5][N:6]1C(=O)C2=CC=CC=C2C1=O.[ClH:26]>>[ClH:26].[ClH:26].[F:1][CH:2]([F:25])[CH:3]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][CH2:5][NH2:6]
Reactant: O=C1c2ccccc2C(=O)N1CCC(NCc1ccccc1)C(F)F
Agent: Cl
Product: NCCC(NCc1ccccc1)C(F)F
Temperature: 110 °C

Procedure:
A solution of N-(4,4-difluoro-3-benzylaminobutyl) phthalimide (0.585 g, 1.72 mM) prepared as in Step D in concentrated hydrochloric acid (50 ml) is heated at 110° C. for 15 hours. The solvent is evaporated in vacuo, and the residue is taken up in cold water (50 ml). The aqueous phase is filtered and concentrated in vacuo, washed three times with diethyl ether, and then evaporated to dryness. The oily residue is triturated several times with isopropanol. The solvent is removed in vacuo yielding a white foam: 0.490 g (quantitative yield) of the required compound.
Reaction SMILES: [F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:23])([F:1])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 115 °C
Yield: 98.1 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4(3H)-one (480 mg, 1.5 mmol) were added DIEA (0.55 mL, 3.0 mmol) and phosphorous oxychloride (10 mL, 108 mmol), and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. Toluene was added and evaporated twice to remove residual phosphorous oxychloride. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL), and the separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazoline as a brown viscous oil (500 mg).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([S:15]([Cl:14])(=[O:17])=[O:16])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)c1cc2cccc(C)c2o1
Product: CC(=O)c1cc2c(S(=O)(=O)Cl)ccc(C)c2o1
Yield: 24 %

Procedure:
There was reacted 1.0 g (5.8 mmole) of 2-acetyl-7-methylbenzofuran with chlorosulfonic acid as in Example 1, yielding 0.36 g of 2-acetyl-4-chlorosulfonyl-7-methylbenzofuran (yield: 24%, MS (m/z): 232 (M+), 257, 237 and 173). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hydrochloride as in Example 1 to give an ester compound (yield: 73%, MS (m/z): 339 (M+), 266, 237 and 173), which was then hydrolyzed to give 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-methylbenzofuran (yellow plates, yield: 71%). The physical constants are shown in Table 4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]2)=[O:5])[CH3:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][O:22][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1=C(c2cc(CCCO)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2cc(CCCO[Si](C)(C)C(C)(C)C)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of compound B3 (3.56 g, 8.17 mmol), imidazole (1.39 g, 20.4 mmol), and TBDMS-Cl (1.85 g, 12.2 mmol) in DMF (70 mL) was stirred at 0° C. for 30 min, then at rt for 1 h. The mixture was diluted with EtOAc and washed with aq. 10% Na2CO3 (2×), and brine (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:6→1:3→1:1) yielded the title compound (2.47 g, 55%). LC-MS: tR=0.94 min; ES+: 550.40.