Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1I.[Br:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:7]2[N:6]=[C:5]3[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:10]([O:12][C@H:13]4[C@H:17]5[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]5[O:15][CH2:14]4)=[N:11][C:4]3=[CH:3][C:2]=2[Cl:1])=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromophenylboronic acid following a procedure analogous to that described for Intermediate 3. LC (method 2): tR=1.24 min; Mass spectrum (ESI+): m/z=582 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][C:11]2[CH2:13][C@@H:14]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:15]([CH2:16][OH:17])[C:10]=2[CH:9]=1.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CCOCC.N1C=CC=CC=1.C(O)(C)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][C:11]2[CH2:13][C@@H:14]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:15]([CH:16]=[O:17])[C:10]=2[CH:9]=1
Reactant: COC(=O)CCCCc1cc2c(o1)C[C@@H](OC1CCCCO1)[C@@H]2CO
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: COC(=O)CCCCc1cc2c(o1)C[C@@H](OC1CCCCO1)[C@@H]2C=O
Reaction time: 0.83 h
Yield: 55.4 %

Procedure:
A solution of 590 mg of the alcohol prepared in Example 13 in 75 ml of methylene chloride is combined with 271 mg of sodium acetate and 534 mg of pyridinium chlorochromate, and the mixture is stirred under argon for 50 minutes. The mixture is combined with a solution of 0.25 ml of isopropanol and 0.5 ml of pyridine in 50 ml of ether and further stirred for 10 minutes. Subsequently 7.5 g of magnesium sulfate is introduced, the reaction solution is filtered, and the residue is washed with ether. The organic solution is applied directly to a 30 g silica gel column and eluted with a hexane/8% acetone-hexane gradient, thus obtaining 325 mg of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)[CH:7]=1.[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2C(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[F:81][C:82]([F:87])([F:86])[C:83]([OH:85])=[O:84]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:51]3[CH2:52][C@@H:53]4[CH2:56][C@H:50]3[CH2:55][NH:54]4)[CH:9]=2)[CH:7]=1.[C:83]([OH:85])([C:82]([F:87])([F:86])[F:81])=[O:84]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(5-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (40 mg, 0.059 mmol) and 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.68 mg, 0.059 mmol) were dissolved in 1,2-dichloroethane (DCE) (1 mL) in a 1 dram vial and acetic acid (3.71 μL, 0.065 mmol) was added. The mixture was stirred for 30 min and then MP-Triacetoxyborohydride (126 mg, 0.294 mmol) was added. The mixture was stirred overnight. The mixture was filtered through glass fibre filter paper and washed 2× with 0.3 mL of DCE. Trifluoroacetic acid (0.18 mL, 2.336 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and taken up in 1.1 mL of DMSO and purified on a Gilson HPLC eluting at 20 mL/min with a linear gradient running from 10% CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA). The desired fractions were concentrated to give the desired product as a TFA salt. This was converted to the free base by taking up the residue in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The organic phase was washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and dried under 50° C. to give N-({5-chloro-3′-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-3-biphenylyl}methyl)-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (25.8 mg, 57.5%) as a white solid. LC-MS m/z 762 (M+H)+; mp 130-133° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](OCC)=[O:25])=[CH:22][CH:21]=1.Cl.[OH-].[Na+]>>[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](=[O:25])[CH2:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([F:11])[CH:17]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ccnc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Product: O=C(Cc1ccnc(F)c1)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (0.465 L, 1M) in TBF (765 mL) under nitrogen, cooled to 2° C., was added 2-fluoro-4-methylpyridine (25 g, 0.225 mol) and the solution stirred for 45 minutes in an ice bath. Ethyl 4-fluoro-benzoate (35 mL, 0.239 mol) was added and the reaction was stirred for 1.5 hours at RT. The reaction mixture was poured into excess aqueous 2N HCl, and the aqueous layer was made basic with 5 N NaOH and extracted with EtOAc. The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and filtered through a cotton plug. Hexanes were added and the CH2Cl2 was removed under reduced pressure until precipitation of the title compound occurred as a pale yellow solid (43.2 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)N[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[S].[CH:28](Cl)(Cl)Cl>>[CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)N=C(c2ccccc2)NC1c1cccc([N+](=O)[O-])c1
Reactant: ClC(Cl)Cl
Agent: [S]
Product: COC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Temperature: 150 °C

Procedure:
A mixture of methyl 1,6-dihydro-4-methyl-6-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.5 g) and sulfur powder (0.046 g) was heated at 150° C. for 1 hour. After cooling, the mixture was dissolved in chloroform and filtered. The filtrate was evaporated under reduced pressure to give a crystal of methyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyridinecarboxylate (0.2 g).
Reaction SMILES: C(OC([NH:7][C@H:8]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([C@@H:25]([CH3:34])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24])=[O:16])[C@H:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=O)C=C.CC1(C)CC(=O)CC(=O)C1>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.C1COCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:20]([C@@H:25]([CH3:34])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C@@H:8]([C@H:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])[NH2:7]
Reactant: C=CCOC(=O)N[C@H](C(=O)Nc1cc([C@@H](C)CC(=O)OC(C)(C)C)ccc1Cl)[C@@H](C)C(F)(F)F
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
Solvent: C1CCOC1
Product: C[C@H]([C@@H](N)C(=O)Nc1cc([C@@H](C)CC(=O)OC(C)(C)C)ccc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.30 g (2.56 mmol) of tert-butyl (3S)-3-[3-({(3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-chlorophenyl]butanoate (Example 42A, diastereomer mixture) and 2.88 g (20.5 mmol) of dimedone were initially charged in 8.7 ml of abs. THF. At RT, the solution was deoxygenated by passing through argon for 30 min. Subsequently 59.3 mg (0.051 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at RT overnight. After dilution with ethyl acetate, the mixture was washed twice with sat. sodium bicarbonate solution and once with sat. sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1) and separated. This gave 591 mg of the target compound (54.5% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>O1CCCC1>[C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Yield: 53 %

Procedure:
To a solution of 2.16 g of 12-hydroxydodecanoic acid in 30 ml of tetrahydrofuran (THF) is added 1.09 g of pyridine. The mixture is cooled to 0° C. and a solution of 1.04 g of methacryloyl chloride in 15 ml of THF is added dropwise. The mixture is allowed to warm to room temperature while stirring an is then stirred at ambient temperature for 12 hours. The solvent is then removed under reduced pressure and the residual solid is dissolved in 25 ml of diethylether. The solution is washed with distilled water, dried over magnesium sulfate and then evaporated to dryness. The product is purified by chromatography, using a 1:2 mixture of ethylacetate and hexane to give 1.5 g (53% yield) of 12-methacryloyloxydodecanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=O)[C:10](OC)=[O:11])=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.CS(O)(=O)=O>O(C1C=CC=CC=1)C1C=CC=CC=1>[OH:11][C:10]1[C:35]2[C:25](=[CH:26][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:34]=2)[N:24]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COC(=O)C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: CS(=O)(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)c(O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Methyl 2,3-bis(4-methoxyphenyl)-3-oxopropanoate (1.3 g, 4.14 mmol, 1.00 equiv), ethyl 4-aminobenzoate (680 mg, 4.12 mmol, 1.00 equiv), CH3SO3H (118 mg, 1.23 mmol, 0.30 equiv), and Ph2O (20 mL) were placed in a 100-mL round-bottom flask stirred for 1 h at 90° C., then at 180° C. for 3 h, in an oil bath. Upon cooling, 100 ml of petroleum ether was added. The resulting solid was collected by filtration and dried in a vacuum oven, affording 1.1 g (crude) of ethyl 4-hydroxy-2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate as a brown solid.
Reaction SMILES: Br[C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C@@H:18]([O:23][C:24](=[O:31])[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:17][C@@:16]2([CH3:32])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:33].O1C=CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CO>[CH2:27]([N:26]([CH2:25][C:24]([O:23][C@H:18]1[CH2:17][C@@:16]2([CH3:32])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[C@H:8]2[C@H:19]1[C@:20]1([CH3:22])[C@@H:5]([CH2:6][CH2:7]2)[CH2:4][C@H:3]([OH:33])[CH:2]=[CH:21]1)=[O:31])[CH2:29][CH3:30])[CH3:28]
Reactant: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](Br)C[C@]3(C)[C@H]21
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)C=C[C@]3(C)[C@H]21
Reaction time: 0.33 h

Procedure:
2β-Bromo-11β-diethylaminoacetoxy-3α-hydroxy-5α-pregnan-20-one (1 g) was stirred and warmed with dihydropyran (2 ml) in benzene (40 ml) containing p-toluene sulphonic acid monohydrate (406 mg) until a clear solution was achieved. After 20 mins, the mixture was washed with excess sodium bicarbonate solution and brine (2x) and dried with magnesium sulphate. Evaporation of the benzene left a gum which was dissolved in N,N-dimethylformamide (25 ml) and stirred at 120° with calcium carbonate (2.5 g) and lithium bromide (3.3 g) for 5.5 hours. When reaction was complete, the mixture was diluted with methanol and filtered. The methanolic filtrate was made acidic by addition of 2N hydrochloric acid (4 ml). After 4 hours at 20°, excess sodium bicarbonate solution was added and the mixture evaporated to a small volume, extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine (twice) and dried with magnesium sulphate. Evaporation of the solvent left a gum which was filtered through silica gel (30 g) in ethyl acetate and the eluate concentrated. Further purification was achieved by preparative TLC and recrystallisation from aqueous methanol to give title compound m.p. 134°-138°, [α]D +51.6° (270 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: ClCCCN1CCCC1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
4-Iodophenol (2.2 g, 10 mmol) was dissolved in N,N-dimethylformamide (30 mL) under N2, and sodium hydride (0.48 g, 60% dispersion in mineral oil, 12 mmol) was added in portions. 1-(3-Chloropropyl)pyrrolidine (1.77 g, 12 mmol) and sodium iodide (1.8 g, 12 mmol) were added, and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate solution was washed with 1 N HCl (2×). The acidic extracts were made basic with 2 N NaOH, then were extracted with ethyl acetate (2×). All ethyl acetate extracts were combined, dried over MgSO4 and concentrated to give a yellow oil, 2.98 g (90% crude yield). LC-MS (C13H18INO calc'd 331) m/z 332 (M+H).
Reaction SMILES: Cl[C:2]1[C:19](Cl)=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[C:7]([OH:25])[C:8]4[C:13]([C:14]=3[OH:22])=[CH:12][C:11](Cl)=[C:10](Cl)[CH:9]=4)[C:5](=[O:26])[C:4]=2[CH:3]=1.[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:27]1([S:33][C:2]2[C:19]([S:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:18][C:17]3[C:16](=[O:21])[C:15]4[C:6](=[C:7]([OH:25])[C:8]5[C:13]([C:14]=4[OH:22])=[CH:12][C:11]([S:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:10]([S:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:9]=5)[C:5](=[O:26])[C:4]=3[CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1c2cc(Cl)c(Cl)cc2C(=O)c2c1c(O)c1cc(Cl)c(Cl)cc1c2O
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2cc(Sc3ccccc3)c(Sc3ccccc3)cc2C(=O)c2c1c(O)c1cc(Sc3ccccc3)c(Sc3ccccc3)cc1c2O

Procedure:
50 g (116.8 mmol) of 2,3,8,9-tetrachloro-6,11-dihydroxynaphthacene-5,12-dione, 77.22 g (700.8 mmol) of thiophenol, 129.15 g (934 mmol) of potassium carbonate and 400 ml of dimethyl sulfoxide (DMSO) are stirred for 1 day at 100° C. The mixture is poured into a dilute aqueous solution of HCl and stirred. The red crude product is isolated by filtration, washed with water, dried at 140° C. under vacuum. then extracted three times by boiling with cyclohexanone and dried once more. Yield: 80.11 g (95%); melting point >260° C. MS: 722 (M+ ; base peak).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[N:17]2[CH:12]([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[CH:11]1[CH3:20].[CH2:21]=[O:22].[Cl-].[Na+]>O1CCCC1.O>[O:22]=[C:21]1[N:17]2[CH:12]([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[C:11]1([CH3:20])[CH2:10][OH:9]
Reactant: CC1C(=O)N2C1CCOC2(C)C
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(CO)C(=O)N2C1CCOC2(C)C
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1.1 equivalents of freshly prepared lithium diisopropylamide in anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° is added a solution of 8-oxo-2,2,7-trimethyl-3-oxa-1-azabicyclo-[4.2.0]octane in anhydrous tetrahydrofuran which has been cooled to -78° C. After two minutes, the resulting lithium enolate is treated with excess formaldehyde, introduced as a gas just above the surface of the stirred solution. The solution is stirred for 30 minutes at -78° and then poured into water. The aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The combined ethyl acetate solutions are dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give the crude product. Purification by chromatography on silica gel using ethyl acetate/benzene gives 8-oxo-2,2,7-trimethyl-7-(hydroxymethyl)-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26]C1C=CC(F)=CC=1CBr>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as the preparation of compound 10, except that 2-chloro-5-fluoro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.34-7.40 (dd, J=8.5, 5.1 Hz, 1H), 6.97 (td, J=8.3, 2.9 Hz, 1H), 6.72 (dd, J=9.0, 2.9 Hz, 1H), 5.41 (s, 1H), 5.11-5.19 (ABq, J=41.7, 16.7 Hz, 2H), 3.37 (s, 1H), 3.32 (s, 3H), 3.23-3.30 (m, 1H), 2.96 (d, J=12.1 Hz, 1H), 2.81 (t, J=10.2 Hz, 1H), 2.59 (t, J=11.1 Hz, 1H), 2.13 (d, J=10.4 Hz, 1H), 1.76-1.86 (m, 1H), 1.52-1.63 (m, 2H). MS (ES) [m+H] calc'd for C17H21ClFN4O2, 367.1; found 367.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5]1)(=[O:22])=[O:21]
Reactant: CCOC(=O)CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
253 mg of compound 14b and 225 μl triethylamine were dissolved in 10 ml dichloromethane and cooled to −50° C. 140 μl methanesulfonylchloride was added and the mixture was stirred for one hour allowing the temperature to increase to 0° C. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with dichloromethane. The organic extracts were combined and dried with sodium sulfate. Evaporation of the solvent gave 308 mg of the title compound as an almost colorless liquid.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:23])([F:22])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])=[CH:12][CH:11]=1)=[O:8].[CH3:24][N:25](C=O)[CH3:26]>>[CH3:24][N:25]([CH3:26])[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]([F:23])([F:22])[F:5])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CCCc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)CCCc1ccc(NC(=O)C(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (71 mg, 0.60 mmol) was added slowly to a solution of 4-[4-(2,2,2-Trifluoroacetylamino)phenyl]butanoic acid (Formula 45) (0.15 g, 0.55 mmol) in DMF (5 mL) cooled at −5° C. The mixture was stirred for an additional 1 hour at −5° C. Excess dimethylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 hour. Ethyl acetate (50 mL) was added to the mixture, which was washed with brine (2×50 ml). The organic layer was dried over MgSO4, and concentrated to yield N,N-Dimethyl 4-[4-(2,2,2-Trifluoroacetylamino)phenyl]butanamide (Formula 46) (0.17 g, quant.) as a yellowish solid. 1H NMR δ 9.70 (br s, 1H), 7.55 (d, 2H, J=8.6 Hz), 7.11 (d, 2H, J=8.6 Hz), 2.91 (s, 3H), 2.89 (s, 3H), 2.60 (t, 2H, J=7.7 Hz), 2.27 (t, 2H, J=7.7 Hz), 1.89 p, 2H, J=7.7 Hz).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCN(C3CCOCC3)CC2)cc1
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
A solution of Compound 143 (0.166 g, 0.44 mmol) in dichloroethane was added with acetic acid (0.176 mL, 3.08 mmol) and tetrahydro-4-pyranone (0.224 mL, 2.42 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.345 g, 1.63 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=7:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 154 (44.2 mg, 0.093 mmol, 44%).