Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:38])=[C:12]([CH2:14][O:15][C:16]2[CH:37]=[CH:36][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)\[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:18][CH:17]=2)[N:13]=1.O.Cl>O1CCCC1.CO>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:38])=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)\[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:36][CH:37]=2)[N:13]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
Lithium hydroxide monohydrate (76.0 mg) was added to a solution of methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyric acid (328 mg, yield 79%) as colorless crystals. m.p. 124-125° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[F:38])=[O:29])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:17])[CH:12]=2)[CH:6]=1.C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[F:38])=[O:29])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: COC(=O)CNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCC(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate (110 mg, 0.2 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 1 hour, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetic acid as white solid. Yield: 100 mg, 93%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[NH2:8])(=[O:3])[CH3:2].[C:14]([C:17]1[C:18](=[O:28])[O:19][C:20]([OH:27])=[C:21]([C:24](=O)[CH3:25])[C:22]=1[OH:23])(=[O:16])[CH3:15]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:8][C:24](=[C:21]2[C:22]([OH:23])=[C:17]([C:14](=[O:16])[CH3:15])[C:18](=[O:28])[O:19][C:20]2=[O:27])[CH3:25])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: COc1ccc(N)cc1NC(C)=O
Solvent: CO
Product: COc1ccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1NC(C)=O

Procedure:
The aniline thus prepared (0.8 g., 0.0045 mol) is added to a hot suspension of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 50 ml. of methanol. The mixture is refluxed for one hour and filtered to obtain 3-[1-(3-acetamido-4-methoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 252°-253° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[N:10]O)=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][N:4]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:12]([F:15])([F:13])[F:14])[CH:7]=1)#[N:10]
Reactant: COc1ncc(C(F)(F)F)cc1C=NO
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ncc(C(F)(F)F)cc1C#N
Reaction time: 1 h

Procedure:
2-Methoxy-5-(trifluoromethyl)-3-pyridinecarboxaldehyde oxime (3.9 g, 0.018 mol) was added to a mixture of 1.9 ml (0.020 mol) of phosphorus oxychloride in 20 ml of acetonitrile and the resulting mixture heated at reflux with stirring for 1 hour. It was then allowed to cool and was poured onto ice. The mixture obtained was extracted several times with methylene chloride and the combined extracts were in turn extracted with saturated aqueous sodium chloride. The methylene chloride solution was dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain 3.2 g (89 percent of theory of the title compound as a yellow oil which solidified on standing. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[C:13]([O:17][C@H:18]([CH3:31])[C@H:19]([NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([Cl:30])[N:24]=1)CO)([CH3:16])([CH3:15])[CH3:14].N1C(C)=CC=CC=1C>C(Cl)Cl.[Cl-].[Na+]>[C:13]([O:17][C@@H:18]([C@H:19]1[CH2:7][O:6][C:5](=[O:11])[N:22]1[C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([Cl:30])[N:24]=1)[CH3:31])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)nc(Cl)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 151.4 %

Procedure:
Triphosgene (35 mg, 0.12 mmol, 0.4 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, 0.30 mmol) in DCM (3 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.14 mL, 1.2 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 5 hours. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (0.057 g, white solid) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 4.73 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.65 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41 (m, 1H), 2.52 (s, 3H), 1.26 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 314.1 (M+H)+; Rt-1.02 min.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].S(Cl)(Cl)=O.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[S:19][C:20]([C:23]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:24])=[CH:21][N:22]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: CS(N)(=O)=O
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)O)s3)CC2)c(Cl)c1Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)NS(C)(=O)=O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 227; 0.160 g, 0.397 mmol) was suspended in toluene (3 ml) and thionyl chloride (0.288 ml, 3.97 mmol) was added dropwise at room temperature. The solution was refluxed for 1 h. Excess thionyl chloride and toluene were removed in vacuo. The precipitate formed was dissolved in dioxane and methane sulfonamide (0.075 g, 0.794 mmol) was added. The mixture was stirred at 100° C. for 0.5 h after which DBU (0.119 ml, 0.794 mmol) was added. The mixture was stirred for a further 1 h at room temperature was acidified with 10% HCl solution. The mixture was extracted with EtOAc and washed with water. The organic layer was dried over sodium sulfate and conc in vacuo. The crude mixture dissolved in DMSO, and was purified by reverse phase HPLC eluting with acetonitrile/water (0.1% TFA) to afford the desired product. (15 mg).
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH2:29][C:30]([O:32]C)=[O:31])=[N:21]2)=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][N:2]([C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH2:29][C:30]([OH:32])=[O:31])=[N:21]2)=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)Cc1nn(Cc2ccc(N(C)C(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc2ccccc2c1)c1ccc(Cn2nc(CC(=O)O)c3ccccc32)cc1
Yield: 32.7 %

Procedure:
Methyl 2-[1-[4-(N-methyl-2-naphthamido)benzyl]-1H-indazol-3-yl]acetate (about 1.0 mmol) was dissolved in tetrahydrofuran (30 mL), and in an ice bath, 20 mL aqueous solution dissolving lithium hydroxide monohydrate (210 mg, 5.0 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH=3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered, dried, and purified by preparative liquid phase to obtain a white solid 147 mg, at a total yield over two steps of 32.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1)[NH2:6].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH:13]4[CH2:17][CH2:16][CH2:15][O:14]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1
Reactant: COc1cc(N)ccc1OCCC1CCCO1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC1CCCO1
Yield: 98 %

Procedure:
Acylation of 3-methoxy-4-(2-(tetrahydrofuran-2-yl)ethoxy)aniline from step A with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound in 98% yield was achieved via the procedure described in step C of Example 1. The crude product was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:26]1[CH:27]=[CH:28][C:29]2[S:33][CH:32]=[CH:31][C:30]=2[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[S:33]1[C:29]2[CH:28]=[CH:27][C:26]([NH:1][C:2]3[CH:14]=[C:13]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:34][C:30]=2[CH:31]=[CH:32]1
Reactant: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Reactant: Brc1ccc2sccc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(Nc3ccc4sccc4c3)c2)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-(2-(3-methoxyphenyl)ethyl)benzoate 0.13 g were added 5-bromobenzothiophene 0.21 g, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg at room temperature, and it was stirred at 110° C. for 12 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 6 hours. 5-Bromobenzothiophene 0.21 g, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((benzothiophen-5-yl)amino)-4-(2-(3-methoxyphenyl)ethyl)benzoate.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](NC(=O)C)[CH:5]=[CH:4][C:3]1=2.S(O)(O)(=O)=O.NC1C=C2C(=CC=1)C(=O)CCC2.N([O-])=O.[Na+].[I-:37].[K+]>S(=O)(=O)(O)O.O>[I:37][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]2
Reactant: [I-]
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: Nc1ccc2c(c1)CCCC2=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCc2cc(I)ccc21

Procedure:
A mixture of N-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-acetamide 2.5 grams (12.3 mmole) in 20 mL 20% sulfuric acid was heated at 90° for 45 minutes. The solution was allowed to cool to room temperature whereupon 6-amino-3,4-dihydro-2H-naphthalen-1-one sulfate (not shown) precipitated as a solid mass. To this solid was added 20 mL water and 20 mL glacial acetic acid. The resulting solution was stirred in an ice bath and a solution of 1.72 grams (25 mmoles) sodium nitrite in 15 mL water was added dropwise over 0.5 hour. The reaction mixture was slowly poured into a well stirred solution of 8 grams (48 mmoles) potassium iodide in 80 mL water. The mixture was extracted with 200 mL ethyl ether, and the organic phase was washed with water, then saturated sodium hydrogen sulfite, then with saturated sodium chloride. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230-400 mesh eluting with 5% ethyl acetate in hexane. 6-Iodo-3,4-dihydro-2H-naphthalen-1-one was obtained as a white solid, 3.12 grams (94%), m.p. 77-78°.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)C(C)C)(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as the free base. Treatment with 1 equiv 1M HCl in dioxane and concentration in vacuo afforded 46 mg of the corresponding hydrochloride salt. Yield 77%, ES MS m/z 433
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)[O:31][C:32](Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]3[N:10]([C:9]=2[C:30]([O:31][CH3:32])=[O:29])[CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2ccc(F)cc2)c(-c2ccccc2)c2n1CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 176.2 %

Procedure:
A solution of 6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (prepared according to Laufer et al., 1.11 g, 4 mmol) in CHCl3 (20 ml) is cooled to 0° C. in an ice bath, treated with triethylamine (0.44 g, 4.4 mmol), and diphosgene (0.43 g, 2.2 mmol), dissolved in CHCl3 (5 ml) is added dropwise. After addition is complete, the mixture is stirred at RT for a further 4 h in the cold. After addition of MeOH (4 ml), it is additionally stirred at RT for 16 h. The reaction solution is washed with water, and then with Na2CO3 solution (10%) until acid-free and finally washed again with water. The separated CHCl3 phase is dried using Na2SO4 sicc. and concentrated. As a residue, 1.3 g (100%) of methyl 2-(4-fluorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate are obtained (GC. 93%). The substance is used in the next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:20][OH:21])[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH2:15][CH2:16][C:17](=[O:19])[O:21][N:20]=3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1CCC(c2ccc(-c3ccc(Cl)cc3)cc2)=NO1
Yield: 31.5 %

Procedure:
A stirred suspension of 4-(4′-chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid (2.126 g, 0.00700 mol) and 4-methylphenyl)sulfonic acid monohydrate (0.067 g, 0.00035 mol) in toluene (22 mL) was heated under nitrogen at reflux over a Dean-Stark trap for 7 hours, and allowed to cool. The volatiles were rotary evaporated. The residue was dissolved/suspended in dichloromethane and chromatographed on silica gel (221 g, 230-400 mesh), eluting with dichloromethane (20×200 mL) to give 0.63 g of 3-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-6-oxo-6H-1,2-oxazine as a light purple solid; mp 190-192° C.
Reaction SMILES: C(O[Na])C.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:10]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: CCO[Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Yield: 59 %

Procedure:
In an ethanol solvent, 1 N ethoxy sodium (NaOEt) (1.1 eq.) was added dropwise to 3-hydroxybenzaldehyde (1.0 eq.) and ethyl α-bromoisobutyrate (1.1 eq.), and the reaction mixture was refluxed. After the ethanol was evaporated, the residual was distributed between ethyl acetate and water, and an organic layer was dried by using MgSO4, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (8:1) to obtain Compound 97b.
Reaction SMILES: [F:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:4][C:3]=1[CH:15]=O.[NH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1.[BH3-]C#N.[Na+].C1CCCCC1>CO.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:4][C:3]=1[CH2:15][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: C[Si](C)(C)CCOCn1cnc(C=O)c1F
Reactant: c1ccc2c(c1)CCCN2
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1cnc(CN2CCCc3ccccc32)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a stirred solution of 5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde (202 mg) at room temperature in methanol (10 ml) under an argon atmosphere were added zinc chloride (409 mg) and 1,2,3,4-tetrahydroquinoline (100 mg). The clear light yellow solution was stirred for 4 hours and 30 minutes. Then, NaBH3CN (141 mg) was added in one portion. The mixture was heated to 60° C. and stirring at that temperature was continued for 22 hours. The reaction was directly adsorbed on silica gel. The crude product was isolated by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/ethyl acetate 65:35) to give 1-[5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-ylmethyl]-1,2,3,4-tetrahydroquinoline (238 mg) as colorless viscous oil. MS (ISP): 362.3 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].[C:9]([Mg]Cl)#[CH:10]>C1COCC1>[OH:8][CH:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:9]#[CH:10]
Reactant: Cn1cccc1C=O
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1cccn1C

Procedure:
3-Hydroxy-3-(1-methyl-pyrrol-2-yl)-1-propyne was prepared according to Method A above using 1-methyl-2-pyrrolecarboxaldehyde (0.450 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 422 mg, 76%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][NH:18][C:17](=[O:22])[CH:16]=[C:11]12)=[CH2:5])C.C1C(=O)N([Br:30])C(=O)C1.CCOC(C)=O>C1COCC1.O.[Cl-].[Na+].O>[Br:30][CH2:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][NH:18][C:17](=[O:22])[CH:16]=[C:11]12)=[O:5]
Reactant: C=C(OCC)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C=C2c3cccc(C(=O)CBr)c3CCN2C(=O)CN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
111-2. A solution of 9-(1-ethoxyvinyl)-3,4,7,8-tetrahydro -[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (1.2 g, 4.02 mmol) in a mixture of THF/H2O (3:1, 40 mL) was treated with NBS (716 mg, 4.02 mmol) and the mixture was stirred at 0° C. for 10 min. The mixture was partioned between AcOEt and brine and the org. phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (880 mg) that was used as it is in the next step. UPLC-MS: MS 349.0 (M+H+); UPLC rt 0.69 min.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7](=[O:31])[C:6]=2[C:5]([OH:32])=[CH:4][CH:3]=1>CC(C)=O>[CH3:3][C:2]1([CH3:15])[N:27]([CH2:26][CH2:25][NH:24][C:9]2[C:8]3[C:7](=[O:31])[C:6]4[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=4[OH:32])[C:14](=[O:16])[C:13]=3[C:12]([NH:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][C:5]3([CH3:6])[CH3:4])=[CH:11][CH:10]=2)[CH2:28][CH2:29][O:30]1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Solvent: CC(C)=O
Product: CC1(C)OCCN1CCNc1ccc(NCCN2CCOC2(C)C)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A suspension of 3.11 g. of 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethylamino)ethyl]amino]anthraquinone [prepared as described in Example 1(A)] in 150 ml. of acetone is stirred and heated under rapid reflux. The condensate is returned to the flask by percolation through a dehydration system consisting of 40 g. of 4 A molecular sieves supported by a sintered glass plate. After a 24 hour reaction period the resulting solid is collected by filtration and is washed with hot acetone to give 2.77 g. of the product of the Example as a blue-black solid, m.p. 255°-256° C.