Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[CH2:21](I)[CH3:22].[H-].[Na+].O>C1COCC1.CN(C=O)C>[N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:21][CH3:22])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 54 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (1.0 g, 3.53 mmol) in THF/DMF (6 ml/1.5 ml), ethyl iodide (2.24 ml, 20.8 mmol) and 60% sodium hydride (422 mg, 10.6 mmol) were added under cooling with ice and stirred at room temperature for 19 hours. The reaction mixture was mixed with water slowly and then with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate:methylene chloride=1:1:15), giving Boc-N-Et-Phe(4-F)-OH (P10) (593 mg, 54%).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH2:9][C@@H:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11]([OH:13])=O)[N:6]=[CH:5]1)[CH:2]=[CH2:3].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:50]([O:53][CH2:54][C@@H:55]([NH2:59])[CH:56]([CH3:58])[CH3:57])[CH:51]=[CH2:52]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@@H:10]([C:11](=[O:13])[NH:59][C@H:55]([CH2:54][O:53][CH2:50][CH:51]=[CH2:52])[CH:56]([CH3:58])[CH3:57])[CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CCOC[C@@H](N)C(C)C
Reactant: C=CCn1cnc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=CCOC[C@@H](NC(=O)[C@@H](Cc1cn(CC=C)cn1)NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the material from step A in 180 ml of DMF was mixed with 4.18 g (27.32 mmol) of N-hydroxybenzotriazole and 5.64 g (27.32 mmol) of N,N′-dicyclohexylcarbodiimide and stirred at RT for 2 h. Addition of 3.56 g (24.84 mmol) of (S)-1-allyloxymethyl-2-methylpropylamine (1-1B) was followed by stirring at RT for a further 24 h and then concentration, and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC. After washing with saturated NaHCO3 solution, 5.02 g of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([C:22](OC)=[O:23])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH2:22][OH:23])[CH:21]=1)[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: COC(=O)c1cc(Br)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(CO)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[3-bromo-5-(methoxycarbonyl)phenoxy]piperidine-1-carboxylate (520 mg, 1.2 mmol) in THF (10 mL) was added lithium tetrahydroborate (27.3 mg, 1.26 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with 1N HCl. The organic solution was washed with brine, dried over Na2SC4, filtered and concentrated. The crude was purified by flash chromatography on a silica gel column to give the desired product. LCMS (M+Na)+: 408.1, 410.1.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:12]1([N:18]2[NH:19][C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]n(-c2ccccc2)c(=O)c2ccccc12
Yield: 58 %

Procedure:
A mixture of phthalic anhydride (0.02 mol) and phenyl hydrazine (0.04 mol) in 95 percent acetic acid (70 ml.) was heated to reflux for 24 hours in the presence of a catalytic amount of sodium acetate (0.4 g). Water was added to the mixture and the precipitate collected. The precipitate was washed with water, agitated with 2 percent aqueous solution of sodium hydroxide and filtered. The filtrate was acidified with concentrated hydrogen chloride. The precipitate was collected and recrystallized from ethyl acetate to produce the product, 2-phenyl-2,3-dihydrophthalazine-1,4-dione.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C1COCC1.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>[CH3:24][O:23][C:21]([C:18]1[CH:17]=[N:16][C:15]([N:13]2[CH2:12][CH2:11][C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:2]([C:36]5[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH2:14]2)=[N:20][CH:19]=1)=[O:22]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(Br)cc4c3C2)nc1
Reactant: O=Cc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)cc5)cc4c3C2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a 0° C. solution of Example 33 (1.5 g, 3.37 mmol) in THF:H20 (4:1) were added Cs2CO3 (10.07 g, 30.99 mmol) and 4-formylphenylboronic acid (1.158 g, 7.75 mmol). The reaction mixture was thoroughly degassed and freshly prepared tetrakis(triphenylphosphine)palladium(0) (1.119 g, 0.96 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture temperature was raised to 80° C. and continued stirring for 12 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the THF was removed under reduced pressure. The mixture was partitioned between ethyl acetate (100 mL) and water (15 mL). The organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide Example 102 (1.0, 62.6%). 1HNMR (CDCl3, 200 MHz) δ: 10.11 (s, 1H), 8.90 (s, 2H), 8.17 (s, 1H), 8.00-7.92 (m, 2H), 7.85-7.80 (m, 2H), 7.64-7.38 (m, 4H), 5.15 (s, 2H), 4.39 (t, 2H, J=5.4 Hz), 3.88 (s, 3H), 2.98 (t, 2H, J=5.4 Hz); m/e=413(M+1).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[NH:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][N:14]1[CH:18]=[C:17]([C:4]2[CH:5]=[C:6]3[NH:12][CH:11]=[CH:10][C:7]3=[N:8][CH:9]=2)[CH:16]=[N:15]1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(-c2cnc3cc[nH]c3c2)cn1
Yield: 61.1 %

Procedure:
To an N2 charged microwave vial, 6-bromo-1H-pyrrolo[3,2-b]pyridine (327 mg, 1.65 mmol) was added and dissolved in DMA (2 mL). The solution was bubbled with N2 for 5 minutes. Next, 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (516 mg, 2.48 mmol) was added to the solution, which was bubbled with N2 for an additional 5 minutes. K2CO3 (320 mg, 2.31 mmol) was dissolved in water (2 ml) and the solution was bubbled with N2 for 5 minutes. The aqueous solution was added to the reaction vessel and the solution was bubbled with N2 again. Finally, the Pd(dppf)2Cl2 (81 mg, 0.10 mmol) was added to the solution, bubbled with N2, sealed and microwaved for 15 minutes at 130° C. The reaction was then transferred to a separatory funnel with dichloromethane (75 mL) and washed with water (2×75 mL). The aqueous layer was back extracted with dichloromethane (75 mL). The organic layers were combined, dried over Na2SO4 and vacuumed down. The crude material was purified by flash chromatography (0-80% acetonitrile/dichloromethane gradient) to afford the title compound (200 mg, 61% yield). MS m/z=199 [M+H+]+.
Reaction SMILES: N1CCCCC1.C1C2C(CO[C:22]([N:24](C)[C@@H:25]([CH2:29][S:30][S:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([OH:28])=[O:27])=O)C3C(=CC=CC=3)C=2C=CC=1>O1CCCC1>[C:32]([S:31][S:30][CH2:29][C@H:25]([NH:24][CH3:22])[C:26]([OH:28])=[O:27])([CH3:35])([CH3:34])[CH3:33]
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CSSC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CN[C@@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
Piperidine (1.8 ml, 18.2 mmol) was added to a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2c-B) (2.70 g, 6.06 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→60/40) to afford (R)-3-(tert-butyldisulfanyl)-2-(methylamino)propanoic acid (Compound 2f-G) (610 mg, 45%).
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]=O)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][NH:25][CH2:26]2)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][N:25]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]3[C:4](=[O:11])[C:3]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]4[C:1]3=[O:16])[CH2:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a stirred solution of 4-phthalimidobutyraldehyde (15.96 g, 0.074 mol) and 7-methoxy-1,2,3,4-tetrahydroisoquinoline (10 g, 0.061 mol) in 1,2-dichloroethane (100 ml) was added sodium triacetoxyborohydride (19.3 g, 0.091 mol) in three equal portions over 10 mins, followed by glacial acetic acid (3.72 ml, 0.061 mol). The resultant mixture was stirred at room temperature for 3 h, then at 45° C. for 1 h, and poured into saturated aqueous potassium carbonate (600 ml). The mixture was extracted into dichloromethane (2×400 ml) and the combined extracts dried (Na2SO4) and evaporated in vacuo. Trituration of the residue with hexane afforded the title compound as a pale brown gum (13.5 g, 60%).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh].CO>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([OH:10])[CH2:3]2
Reactant: O=C1CN2CCC1CC2
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: Cl
Solvent: CO
Solvent: C1=CCCC=CCC1
Product: O[C@@H]1CN2CCC1CC2
Reaction time: 19 h

Procedure:
30.0 g (186 mmol) of 3-quinuclidinone hydrochloride, 18.3 mg (0.0371 mmol) of bis(1,5-cyclooctadiene)dirhodium(I) dichloride, 40.3 mg (0.0743 mmol) of (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine(IIIa, corresponding to an educt/catalyst molar ratio of 2500) and 300 ml of degassed methanol were introduced into an autoclave (450 ml) under argon. The reaction mixture was hydrogenated for 19 hours at 70° C.and 50 bar of H2. It was evaporated and the residue was dissolved in 250 ml of 2N hydrochloric acid. After extraction twice with 40 ml of dichloromethane, the pH was adjusted to 14 with sodium hydroxide solution (30 percent) and the mixture was evaporated. The residue was refluxed with350 ml of ethyl acetate and filtered off hot. The aqueous phase was separated off and the organic phase was evaporated. Recrystallization fromethyl acetate (150 ml) gave 22.3 (94 percent) of (S)-3-quinuclidinol with 24 percent ee. Other data concerning the product was:
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=3)[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4Cc4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4Cc4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of methyl 4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoate (200 mg, 0.338 mmol), prepared in the previous step, and 1 N NaOH (507 μL, 0.507 mmol) in 20 mL of THF plus 20 mL of methanol plus 5 mL water was refluxed under nitrogen for 9 h. The reaction was filtered and then allowed to cool to room temperature. The reaction was acidified by the addition of 2.5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The residue was diluted with water. The solid formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (186 mg, 95%) as an off-white solid, mp 228–229° C. Elemental Analysis for C36H26F3NO3.0.15 H2O.0.04 C4H8O Calc'd: C, 74.47; H, 4.60; N, 2.40. Found: C, 74.52; H, 4.49; N, 2.68.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:37]=[C:38]2[O:44][CH:43]=[CH:42][C:39]2=[N:40][CH:41]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:44]1[C:38]2[C:39](=[N:40][CH:41]=[C:36]([C:17]3[CH:16]=[C:15]4[C:11]([CH:12]=[N:13][NH:14]4)=[C:10]([NH:9][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[O:8])[CH:18]=3)[CH:37]=2)[CH:42]=[CH:43]1
Reactant: Brc1cnc2ccoc2c1
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3cnc4ccoc4c3)cc3[nH]ncc23)cs1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg), 6-bromofuro[3,2-b]pyridine (21 mg) and Pd(dppf)Cl2 (8 mg) were combined in a microwave vial. 1,4-Dioxane (0.5 ml) was added followed by sodium carbonate (44 mg) dissolved in water (0.5 ml). The reaction was heated in the microwave at 140° C. for 20 min. The reaction was filtered through a silica cartridge (1 g) washing with DCM:methanol (3:1). The solvent was then removed under a stream of nitrogen. The residue was dissolved in DMSO (1200 μl) and methanol (400 μl) and MDAP (method M). The product-containing fractions were left overnight, then concentrated and the residue dissolved in 1,4-dioxane:water (2 ml, 1:1, v/v) and freeze-dried. The residue was dissolved in DCM, a few drops of TFA were added and the reaction left overnight. The residue was further purified by MDAP (method K) then dried under nitrogen blowdown to give title compound, 13 mg.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:12]([CH2:20][C:21](=O)[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.C(OCC)C>[NH2:4][C:3]1[C:20]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:21]([CH3:22])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#CC(N)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCO
Product: Cc1[nH]c(-c2ccc(F)cc2)c(N)c1C(=O)c1ccccc1

Procedure:
Starting from 2-amino-2-(p-fluorophenyl)acetonitrile and benzoyl acetone, the open-chain intermediate compound is obtained, b.p. 120° C./0.2 mm Hg. The title compound is obtained in a 66% overall yield, m.p. 209°-10° C. (from ethanol/diethyl ether).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CO.C1C=CC=CC=1>ClC(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:24])[CH2:19][CH2:20][N:21]([CH2:9][CH2:10][NH:8][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1cccs1)N1CC1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1cccs1

Procedure:
A mixture of 7.7 parts of 1-(2-thienylcarbonyl)aziridine, 10.8 parts of 4-(4- chlorophenyl)-4-piperidinol, 8 parts of methanol and 54 parts of benzene is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and dissolved in trichloromethane. The solution is washed twice with water, dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 4.3 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-2-thiophenecarboxamide; mp. 153° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]([CH:45]([OH:51])[C:46]([O:48]CC)=[O:47])=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[OH-].[Li+]>C1COCC1.O.CO>[F:1][C:2]1[C:3]2[C:4]([CH:45]([OH:51])[C:46]([OH:48])=[O:47])=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(O)c1c2n(c3cccc(F)c13)COc1ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3c(C(O)C(=O)O)c5c(F)cccc5n3CO4)cc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-12-yl)-2-hydroxyacetate (233 mg, 0.325 mmol) and lithium hydroxide (54.5 mg, 2.276 mmol) in THF (1 ml), water (0.5 ml) and MeOH (0.5 ml) was stirred at room temperature over night, then concentrated under vacuum. The resulting residue was purified using EP column (30 mm×250 mm), 60% IPA/CO2. This resulted in 128 mg (57.2%) of 2-(11-fluoro-2-(2-(4-fluorophenyl) -3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-12-yl)-2-hydroxyacetic acid (Compound 207) as a white solid. LC-MS (ES, m/z) C34H26F2N4O8S: 688. Found: 689 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Br[C:24]1[C:25]2[N:26]([CH:31]=[CH:32][N:33]=2)[N:27]=[C:28]([Cl:30])[CH:29]=1>C1COCC1>[Cl:30][C:28]1[CH:29]=[C:24]([N:14]([CH2:13][C:12]2[CH:21]=[CH:22][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:25]2[N:26]([CH:31]=[CH:32][N:33]=2)[N:27]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: COc1ccc(CNc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of potassium t-butoxide in THF (4.73 mL, 4.73 mmol) was added dropwise to a solution of N-(4-methoxybenzyl)aniline (0.92 g, 4.3 mmol) in THF (10 mL) at 0° C. The solution was warmed to RT for 15 minutes, recooled to 0° C. and a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 4.30 mmol) from Example 1, step 1b, in THF (10 mL) was added in rapidly. The solution was stirred at 0° C. for 30 minutes and then at RT for 30 minutes. The reaction solution was concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate/heptane to provide 0.75 g (48%) of 6-chloro-N-(4-methoxybenzyl)-N-phenyl imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:7])=[O:6].FC1C=CC(C=O)=CC=1>>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([Cl:7])=[O:6])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Agent: O=Cc1ccc(F)cc1
Product: O=C(Cl)c1ccc(F)cc1

Procedure:
This object is achieved by a process for the preparation of 3-chloro-4-fluorobenzoyl chloride. It comprises reacting 4-fluorobenzaldehyde with a chlorinating agent in the presence of a free-radical initiator in the presence or absence of a solvent at from −20 to 200° C. to give 4-fluorobenzoyl chloride, and reacting the 4-fluorobenzoyl chloride with a chlorinating agent in the presence of a chlorination catalyst in the presence or absence of a solvent at from −20 to 200° C. to give 3-chloro-4-fluorobenzoyl chloride.