Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.O/N=C(\N)/C>CN(C=O)C.O>[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28]1[O:29][N:15]=[C:10]([CH3:11])[N:9]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(Cl)c5)nn34)ccnc2c1
Agent: C/C(N)=N/O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(-c6nc(C)no6)c(Cl)c5)nn34)ccnc2c1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
HATU (0.370 g, 0.974 mmol) and 2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.300 g, 0.650 mmol) were taken up in DMF (5 mL). Added Hunig's Base (0.339 ml, 1.95 mmol). Stirred for 10 min. Added (Z)—N′-hydroxyacetamidine (0.289 g, 3.90 mmol). Stirred for an additional 30 min. Removed DMF in vacuo. Suspended in water. Isolated product by filtration. The resulting solid was allowed to try under vacuum. Split into 3 portions and separately took up in dioxane (4 mL) in a microwave tube and heated for 12 min at 150° C. Combined all 3 reactions. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=500.0 [M+1]+. Calc'd for C25H18ClN7O3: 499.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10]C)[CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[Li+].[I-]>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([OH:10])[CH:3]=1)[C:7]#[N:8]
Reactant: COc1cc(Cl)cc(C#N)c1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: N#Cc1cc(O)cc(Cl)c1
Temperature: 170 °C
Yield: 93.5 %

Procedure:
step 2—A 250 flask was charged with 5-chloro-3-methoxy-benzonitrile (7.0 g, 41.766 mmol) and 2,4,6-collidine (100 mL). The mixture was heated to 170° C. and LiI (16.76 g, 125.298 mmol) was added and the reaction mixture was heated for 4 h. When the methyl ether was consumed the reaction was cooled to RT and quenched with 10% aqueous HCl. The resulting mixture was extracted with EtOAc and washed with water and brine. The EtOAc extract was dried over (Na2SO4) and filtered. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (10:90) to afford 6.0 g (94%) of 3-chloro-5-hydroxy-benzonitrile.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=1>>[CH2:18]([C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1)[CH3:19]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC3(CC2)OCCO3)nc1

Procedure:
The title compound is prepared from 1,4-dioxa-8-azaspiro[4.5]decane and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described for Intermediate 61.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.[Cl:30][SiH:31]([Cl:33])[Cl:32]>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][Si:31]([Cl:33])([Cl:32])[Cl:30])=[CH:24][CH:23]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: COc1ccc(CCl)cc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Product: COc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 45 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.056 g (0.2 mmol) of tricyclohexylphosphine, 0.271 ml (2.0 mmol) of 4-methoxybenzyl chloride, and 1.00 ml (9.91 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 0.23 g of (4-methoxybenzyl)trichlorosilane (yield; 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl>[OH-].[Na+]>[CH2:15]([O:14][C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
2-Amino-5-hydroxy-benzoic acid (3.0 g) was dissolved in a 1N aqueous solution of sodium hydroxide (50 ml), to which was added dropwise carbobenzyloxy chloride (3.5 g). The mixture was stirred for one hour at room temperature, which was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure to leave 2-benzyloxycarbonylamino-5-hydroxybenzoic acid as blackish brown crystals (2.9 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+].C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1
Reactant: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.5 h

Procedure:
To (S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (174 mg, 0.41 mmol) at room temperature was added 1.4 mL of a 1:1 TFA:CH2Cl2 solution. The reaction mixture was stirred for 30 min and diluted with 10 mL of saturated NaHCO3 and 10 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give (S)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol. LC/MS: m/z 321.2 (M+H)+ at 1.89 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) which was used for the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[NH3:19]>>[NH2:1][C@H:2]([C:15]([NH2:19])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: N
Product: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of Tyr(3-tBu)-OMe (12.4 g, 49 mmol) and concentrated aqueous ammonia (240 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the thus obtained residue was subjected to silica gel column chromatography (CHCl3:MeOH=10:1), giving Tyr(3-tBu)-NH2 (T1) (10 g, 80%).
Reaction SMILES: [Li][CH2:2]CCC.C(N(C(C)C)C(C)C)(C)C.[CH:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.IC>C1COCC1.O>[CH3:2][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1CCCC1
Agent: CC(C)N(C(C)C)C(C)C
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of nBuLi in hexanes (242 mL, 387 mmol) was added to a −78° C. solution of thisopropylamine (39.1 g, 387 mmol) in anhydrous THF (300 mL) and the resultant mixture was stirred for 30 min at −78° C. A solution of ethyl cyclopentanecarboxylate (50 g, 352 mmol) in anhydrous THF (150 mL) was added dropwise into the mixture and the reaction mixture was stirred at −78° C. for 1 h. Iodomethane (79.2 g, 558 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred overnight The mixture was poured into water and extracted with ethyl ether. The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 1-methylcyclopentanecarboxylate (47 g, 85%). 1H NMR (300 MHz, DMSO-d6): δ 4.03 (q, J=7.2 Hz, 2 H), 1.37-2.03 (m, 8 H), 1.15-1.12 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH2:39][C:40]2[NH:49][C:43]3=[N:44][CH:45]=[C:46](I)[CH:47]=[C:42]3[N:41]=2)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:17]([CH:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:46]3[CH:47]=[C:42]4[N:41]=[C:40]([CH2:39][CH2:38][C:34]5[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][N:35]=5)[NH:49][C:43]4=[N:44][CH:45]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: O=C(c1ccccc1)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC(C(=O)c6ccccc6)CC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 37 %

Procedure:
A mixture of 0.612 g of 1-(4-bromo-benzene-sulfonyl)-4-benzoyl-piperidine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 6 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 6 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 19 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-25:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate gives 0.21 g of the title compound as a solid of m.p. 174-175° C. The mass spectrum shows the molecular peak MH+ at 582.3 Da.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)c(Cl)c1
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Yield: 1.91 %

Procedure:
The above compound is prepared by nucleophilic displacement reaction of 4-hydroxy benzaldehyde and 3-chloro-4-fluorobenzonitrile under basic conditions as described in Example 243, step 1.91% yield.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=2[CH:11]=1)[CH:14]=[CH2:13]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2nc(C#N)sc2c1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
2-cyano-6-hydroxybenzothiazole 32 (336.2 mg, 1.91 mmol) and allyl bromide (331 μl, 3.82 mmol) were dissolved in N,N-dimethylformamide (1.5 ml), potassium carbonate (404.6 mg, 1.53 mmol) was added in an argon atmosphere, and the reaction mixture was stirred for an hour at room temperature. Water (20 ml) was added to the reaction mixture, and after extraction with ethyl acetate (3×50 ml) and drying of the organic layer with anhydrous sodium sulfate, the result was concentrated in vacuo. The resulting residue was purified by preparative thin-layer silica gel column chromatography {one 20 cm×20 cm×1.75 mm plate; hexane-ethyl acetate (1:1)}, yielding 6-allyloxy-benzothiazole-2-carbonitrile 33 (418.1 mg, 90%) as a pale yellow solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][N:9]([CH3:30])[C:10]([CH:12]1[CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([F:29])[CH:18]=2)(O)[CH2:13]1)=[O:11]>>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][N:9]([CH3:30])[C:10]([CH:12]1[CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([F:29])[CH:18]=2)=[CH:13]1)=[O:11]
Reactant: CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 75 °C

Procedure:
TFA (9.9 ml, 128 mmol) was added to a DCE solution (64 ml) of example 19, 3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid dimethylamide (2.05 g, 6.4 mmol) and the mixture was heated to 75° C. for 18 hrs and concentrated down to obtain TFA salt of intermediate 3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobut-2-enecarboxylic acid dimethylamide. This was redissolved in absolute EtOH (64 ml), Wilkinson's catalyst (296 mg) was then added and this mixture was subjected to hydrogenation at 60° C. using 45 psi H2. After 1 hr 45 min reaction time, it was concentrated down and the residue was redissolved into 1N HCl (50 ml) and extracted twice with EtOAc (2×120 ml). The aqueous layer was then basified with 15% aq. NaOH (40 ml) and extracted with EtOAc (3×200 ml). The combined organic phases were dried over MgSO4, and concentrated down to obtain crude material. This was purified by flash chromatography using a 120 g ISCO™ column and 4% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were combined and concentrated under reduced pressure to give the title compound (1.0 g, 51% yield). Rf=0.40 (10% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C18H25F N2 O, 304.4, found, 305.4 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.10 (t, J=7.8 Hz, 1H), 6.78 (dd, J=1.2, 6.6 Hz, 1H), 6.72 (dd, J=1.7, 11.2 Hz, 1H), 3.4 (s, 2H), 3.48-3.38 (m, 1H), 3.13-3.04 (m, 1H), 2.79 (s, 3H), 2.70 (s, 3H), 2.58-2.50 (m, 2H), 2.37-2.30 (m, 4H), 2.22-2.12 (m, 2H), 1.60-1.52 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 174.3, 161.2 (d, JC-F=245.7 Hz), 147.0, 131.4, 123.4 (d, JC-F=15.0 Hz), 121.9, 113.0 (d, JC-F=22.5 Hz), 54.0, 52.5, 36.7, 35.8, 35.5, 33.3, 31.6, 23.5.
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH3:28][S:29]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=[O:31])=[O:30]
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Temperature: 10 °C

Procedure:
The oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)propan-2-ol, prepared in Example 15 is dissolved in 200 ml of toluene, cooled to about 10° C., and to that solution is added 10.5 g of triethylamine. Then 8.5 g of methanesulfonyl chloride is added dropwise to the solution and an exothermic reaction is noted along with the precipation of triethylamine hydrochloride crystals. The addition occurs over about a 45 minute period and the solution is allowed to warm to about 20° C. Then the reaction mixture is poured into water and extracted with toluene-ether. The organic extracts are separated, dried over magnesium sulfate and evaporated to yield 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate as an oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].C1(C)C=CC=CC=1.[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1Cl)=[O:16].CN(C)P(N(C)C)N(C)C>O>[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1[O:2][CH3:1])=[O:16]
Reactant: C[O-]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)cncc2C(F)(F)F)c(OC)c1OC
Yield: 63.9 %

Procedure:
16.4 g (304 mmol) of sodium methoxide was added to a toluene 150 ml solution of 18.5 g (47.5 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-trifluoromethylpyridine obtained in Step (c) and 16.6 ml (95.4 mmol) of hexamethylphosphorous triamide, followed by stirring under reflux with heating for 30 minutes. Water was added to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 11.7 g (yield: 64%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine (melting point: 103 to 106° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:37][O:38][CH2:39][Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:37][O:38][CH3:39])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COCc1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 85, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added methoxymethyltributylstannane (220 mg, 0.66 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (35 mg). The mixture was heated to reflux for 16 hours, and then cooled. An additional portion of tetrakis(triphenylphosphine)palladium(0) (30 mg) was added, and reflux was continued for a further 8 hours. The solvent was removed in vacuo, and the residue was flash chromatographed using a gradient elution of a mixture of 1% methanol and 99% dichloromethane, through to 5% methanol and 95% dichloromethane, to give the title compound (33 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]1[CH:22]2[C:23]3[C:32]([CH:11]([C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][C:21]=42)[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:10]1[OH:33])=[CH:31][C:30]1[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:24]=3.C(N(CC)CC)C.Cl>CS(C)=O.C(OCC)(=O)C.C(Cl)Cl>[CH:26]1[C:25]2[C:30](=[CH:31][C:32]3[CH:11]4[C:10](=[O:33])[C:9](=[O:8])[CH:22]([C:23]=3[CH:24]=2)[C:21]2[C:12]4=[CH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:29]=[CH:28][CH:27]=1
Reactant: OC1C2c3cc4ccccc4cc3C(c3cc4ccccc4cc32)C1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1C(=O)C2c3cc4ccccc4cc3C1c1cc3ccccc3cc12
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
Dry DMSO (dimethyl sulfoxide) (132 mmol, 9.4 ml) and 69 ml of dry CH2Cl2 were charged into a three-necked reaction vessel in an inert gas atmosphere, and cooled to −60° C. with an acetone/liquid nitrogen bath. To the mixture, 119 mmol (16.5 ml) of anhydrous trifluoroacetic acid was slowly added dropwise with the liquid temperature being kept at −60° C. and the resultant solution was stirred for 10 minutes. Then, to the resultant mixture, 6,13-dihydro-15,16-dihydroxy-6,13-ethanopentacene (3.81 mmol, 1.29 g) dissolved in a minimum amount of dry DMSO was slowly added dropwise, and the resultant solution was stirred for 15 hours. Triethylamine (275 mmol, 20.7 ml) was added dropwise into the solution while maintaining the liquid temperature at −60° C., which was then stirred for 1.5 hours. The reaction solution was slowly poured into 2M HCl (200 ml) and was extracted with CH2Cl2. The resultant organic layer was washed with ion-exchanged water and saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude product, which was then added with ethyl acetate. Insoluble matter was collected by filtration to give 6,13-dihydro-6,13-ethanopentacene-15,16-dione.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[N:18]1([CH2:24][CH:25]([OH:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>C(OCC)C>[N:18]1([CH2:24][C:25](=[O:37])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccccc1OCC(O)CN1CCOCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(COc1ccccc1[N+](=O)[O-])CN1CCOCC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A five liter round bottom flask was charged with 63.8 ml (0.45 mole) of trifluoroacetic anhydride and 400 ml of MDC under nitrogen. The resulting solution was cooled to -65° C. with a dry ice bath, treated with 42.6 g (0.54 mole) of dimethylsulfoxide over a period of 15 minutes, stirred for 30 minutes, and then treated with a solution of 90 g (0.32 mole) of 2-[3-(4-morpholinyl)-2-hydroxy-1-propyloxy]nitrobenzene in 200 ml of MDC over a 35 minute period. The reaction mixture was stirred for 30 minutes, with 261 ml of diisopropylethylamine, the reaction temperature allowed to rise to -10° C. and the mixture treated with one liter of diethyl ether. The pale yellow solid which separated was collected by filtration, slurried in 1.5 liters of diethyl ether and the product collected and dried to give 73.7 g of 2-[3-(4-morpholinyl)-2-keto-1-propyloxy] nitrobenzene.
Reaction SMILES: [Na].[C:2]1([CH:8]2[O:13][CH2:12][CH:11]([OH:14])[CH2:10][O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O.ClCCl>[C:2]1([CH:8]2[O:13][CH2:12][CH:11]([O:14][CH3:17])[CH2:10][O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1COC(c2ccccc2)OC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
10 g of the sodium salt of 1b, obtained by reaction with sodium hydride in dimethylformamide, was treated with 16 g of methyl iodide. The mixture was stirred at 50° C. for 5 hours, and the dimethylformamide was eliminated in vacuo. The residue was dissolved in dichloromethane, washed and dried. The solvent was evaporated off and the product was chromatographed on silica gel (eluent : dichloromethane) to give 2b.