Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14](Br)=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Zn](C)[CH3:19]>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14]([CH3:19])=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2scc(Br)c2C(C)C1
Reactant: C[Zn]C
Solvent: C1COCCO1
Product: CCOC(=O)N1CCc2scc(C)c2C(C)C1
Temperature: 100 °C

Procedure:
The product of step (a) (150 mg, 0.47 mmol) was dissolved in 3 mL dioxane and treated with Me2Zn (0.47 mL of 2M in toluene) and Pd(ddf)2Cl2 (11 mg, 0.014 mmol). After heating to 100° C. for 3 hours, the reaction was quenched with water and filtered. The filtrate was partitioned between EtOAc and water (7 mL each). The organic layer was dried over MgSO4 and concentrated to give 92 mg of the sub-title compound, which was used without further purification.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=O>>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(Br)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (60 mg, 0.185 mmol; Example 1, Step 2) and 3-bromo-4-chlorobenzaldehyde (48.6 mg, 0.222 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (91 mg) that was used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:13]O.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([NH2:12])=[O:13])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(Br)c2cc[nH]c2c1
Yield: 97.6 %

Procedure:
A solution of 4-bromo-1H-indole-6-carbonitrile (1 g, 4.50 mmol) in methanol (10 mL) was treated with 30% aqueous hydrogen peroxide (2.7 mL, 4.95 mmol) and a 1 M aqueous sodium hydroxide solution (5 mL) then heated at 40° C. for 1 h. The reaction mixture was cooled, treated with water and cooled in an ice-bath. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to obtain 4-bromo-1H-indole-6-carboxylic acid amide (1.05 g, 97%), which was transformed into the title boronic ester by the general method (Scheme 1) (0.80 g, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[S:5][C:6]=1[Cl:7].[CH3:33]B(O)O.O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:7][C:6]1[S:5][C:4]([C:8]2[C:17]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:3][C:2]=1[CH3:33]
Reactant: CB(O)O
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(Br)c(Cl)s3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(C)c(Cl)s3)c2cc1OC
Temperature: 100 °C
Reaction time: 96 h
Yield: 76 %

Procedure:
4-[2-(4-Bromo-5-chloro-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline (20 mg) was dissolved in dioxane (3 ml) to prepare a solution. Tetrakistriphenylphosphine palladium (25 mg), methylboronic acid (0.1 ml), water (0.3 ml), and cesium carbonate (182 mg) were added to the solution, and the mixture was stirred at 100° C. for 4 days. The reaction solution was filtered, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (13 mg, yield 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:17][CH:18]=1)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[S:17][CH:18]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1csc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)n1
Reactant: Clc1ccc(I)cc1
Product: CCOC(=O)c1csc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)n1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 2-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-thiazole-4-carboxylic acid ethyl ester. 1H NMR (300 Hz, CDCl3): δppm 1.39 (t, 3H), 4.44 (q, 2H), 5.27 (s, 2H), 6.58 (d, 1H), 6.78 (t, 1H), 6.88 (d, 1H), 7.13 (t, 1H), 7.31-7.43 (m, 9H), 8.10 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].Br[CH2:26][CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, lmmol), (prepared as described in Example 49), 1-bromo-3-chloropropane (120 μl, 1.2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in DMF (5 ml) was stirred at ambient temperature overnight. After addition of water, the precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide at 60° C. to give 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 70%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([O:26][C:27]([F:30])([F:29])[F:28])[CH:12]=[C:13]2[C:18]=1[O:17][CH:16]([C:19]([F:22])([F:21])[F:20])[C:15]([C:23]([OH:25])=[O:24])=[CH:14]2>CC(O)=O.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([O:26][C:27]([F:30])([F:28])[F:29])[CH:12]=[C:13]2[C:18]=1[O:17][CH:16]([C:19]([F:22])([F:21])[F:20])[C:15]([C:23]([OH:25])=[O:24])=[CH:14]2
Reactant: O=C(O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccccn3)c2OC1C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)cc(CCc3ccccn3)c2OC1C(F)(F)F
Reaction time: 2.5 h
Yield: 53 %

Procedure:
A mixture of 8-(pyridin-2-ylethynyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid prepared as in Example 621j, Step 2 (684 mg, 1.59 mmole) and 10% Pd/C (100 mg) in glacial HOAc (20 mL) was hydrogenated at 20 psi for 2.5 h. The catalyst was filtrated, the solvent was removed in vacuo and the remaining HOAc was removed by azeotroping with hexanes to give the crude product as a tan solid. The solid was triturated with acetonitrile to give 362 mg (53% yield) of the product as an off-white solid: ESHRMS m/z 434.0834 (M+H, C19H14F6NO4, Calc'd 434.0822); 1H NMR (dmso-d6/300 MHz) 13.43 (brs, 1H), 8.50 (d, 1H, J=4.8 Hz), 7.90 (s, 1H), 7.67 (t, 1H, J=7.7 Hz), 7.46 (s, 1H), 7.26-7.17 (m, 3H), 6.06 (q, 1H, J=7.3 Hz), 3.32-3.01 (m, 4H).
Reaction SMILES: [C:1]([N:8]([CH3:15])[CH:9](C)[CH2:10][CH2:11][CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]1([CH3:26])[C:17]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:16]1([CH3:26])[C:17]([S:22]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:15])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(CCCO)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1S(=O)(=O)OCCCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a 500 mL round bottom flask, charged with 4.75 g (23.4 mmol) of N-BOC-N-methyl-4-aminopentanol (32) in 150 mL of methylene chloride, was added 5.25 g (27.5 mmol) of toluenesulfonyl chloride and 7.0 mL (49.6 mmol) of triethylamine. The mixture was stirred at room temperature for 24 h and then washed with 3×75 mL aliquots of 1 N aqueous HCl. The organic phase was dried over anhydrous magnesium sulfate, vacuum filtered, and concentrated via rotary evaporation. The residue was chromatographed on silica gel, eluting first with 20% ethyl acetate/hexane and then with 30% ethyl acetate/hexane. The fractions containing product (33) were combined and concentrated via rotary evaporation to afford 6.95 g of the product as a very pale yellow oil (83%): 1H-NMR (CDCl3) d 7.78 (2H, d), 7.31 (2H, d), 4.03 (2H, t), 3.15 (2H, t), 2.86 (3H, s), 2.42 (3H, s), 1.73-1.47 (4H, m), and 1.41 (9H, s) ppm.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(N)cc1F
Temperature: 124.5 °C
Reaction time: 26 h
Yield: 36 %

Procedure:
4-Bromo-3-fluoroaniline (20.0 g) was dissolved in a mixed solvent of DMF (64 ml) and N,N-diisopropylethylamine (64 ml). Methyl acrylate (28.3 ml), palladium acetate (1.18 g), and tris(2-methylphenyl)phosphine (11.2 g) were added thereto in a nitrogen atmosphere. The obtained mixture was stirred at a bath temperature of 120 to 129° C. for 26 hours. Toluene was added to the reaction mixture, and the mixture was filtered through Cerite. The Cerite was washed with a mixed solvent of DMF and toluene (1:1, 80 ml). The filtrates were combined and concentrated under reduced pressure. The obtained residue was separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and toluene (70 ml) and n-heptane (10 ml) were added to the obtained residue. The precipitated solid was filtered off, and as a result, Compound 15a (3.74 g, 36%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCCC>C(OC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10][Br:15])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 80.4 %

Procedure:
A mixture of 5-methyl-2-nitro-benzoic acid methyl ester (93.95 g, 481.35 mmol), 1,3-dibromo-5,5-dimethylhydantoin (75.70 g, 264.74 mmol), in methyl acetate (550 mL) was heated at 78° C. for 40 minutes while stirred with a mechanical stirrer. Then a solution of 2,2′-azobisisobutyro-nitrile (3.95 g, 24.07 mmol) in methyl acetate (80 mL) was added, and the mixture was heated at about 75° C. for 13 hours. The mixture was allowed to cooled to 15° C. and stirred for 2 hours to age the precipitate. The suspension was filtered, washed with 10° C. methyl acetate (2×50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL). The organic layer was washed with 2% brine (2×500 mL) and water (2×500 mL), and concentrated to about 2 volumes. To the mixture, was added t-butyl methyl ether (or MTBE, 300 mL). The mixture was heated at about 70° C. for 15 minutes, cooled to about 53° C. over one hour, seeded with the product (about 250 mg, or simply re-crystallized) at 45° C., then at 20˜25° C., while blowing nitrogen with a glass pipette overnight. The resulting solid was filtered via a medium pore-sized funnel, washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 5-bromomethyl-2-nitro-benzoic acid methyl ester as an off-white solid (58.3 g, 44.0% yield). The solid was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[C:34]([F:41])=[C:33]([F:42])[C:32]=1[CH2:43]I>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:43][C:32]1[C:31]([Cl:30])=[CH:36][C:35]([C:37]([F:40])([F:38])[F:39])=[C:34]([F:41])[C:33]=1[F:42])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1c(C(F)(F)F)cc(Cl)c(CI)c1F
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
Cool a solution of (R)-4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (0.94 g, 3.6 mmol) in THF (10 mL) to −78° C. Treat this solution dropwise with 10M LiHMDS in THF (4 mL, 4.0 mmol) and stir at −78° C. for 30 minutes. Treat the solution with 1-Chloro-3,4-difluoro-2-iodomethyl-5-trifluoromethyl-benzene (1.35 g, 3.8 mmol) and allowed to slowly warm to room temperature. The reaction stirs 4 hr at room temperature. Quench the reaction with 1N HCl (aqueous) and extracted with Et2O. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.725 g (41%) of desired product. MS (m/e): 488 (M+1).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:49]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:51]=1)[CH2:12][N:13]([CH:46]1[CH2:48][CH2:47]1)[C:14](=[O:45])[CH:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]2[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=2[Cl:44])=[CH:28][CH:27]=1)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(C(C)(C)C)(C)C.[F-].C([N+](C[CH2:72][CH2:73][CH3:74])(CCCC)CCCC)CCC>C1COCC1>[CH:72]1([C:46]2([N:13]([CH2:12][C:11]3[CH:49]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:51]=[C:9]([OH:8])[CH:10]=3)[C:14](=[O:45])[CH:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][C:36]4[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=4[Cl:44])=[CH:28][CH:27]=3)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:47][CH2:48]2)[CH2:73][CH2:74]1
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3-[[3-{[tert-butyl(dimethyl)silyl]oxy}-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) in THF (0.05 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.5 eq.). The resulting golden yellow solution was stirred at RT for 8 h. The reaction mixture was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 2:1 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound as a white semisolid.
Reaction SMILES: O[C:2]1[C:7]2[C@@:8]3(O)[C@@:21]([O:25][CH3:26])([C@H:22](O)[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49]C)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14](NC4C(OC)C(O)C(OC)C(C)O4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1O)[C:9]3=[O:44].[Cl-].[Li+]>CS(C)=O>[CH3:26][O:25][C:21]12[C:20](=[O:27])[C:19]3[C:10](=[CH:11][C:12]4[C:13](=[O:43])[CH:14]=[CH:15][C:16](=[O:29])[C:17]=4[CH:18]=3)[C:9](=[O:44])[CH:8]1[C:7]1[CH:2]=[C:3]([C:47]([OH:49])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=1[CH2:23][CH2:22]2
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(NC1OC(C)C(OC)C(O)C1OC)C4=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COC12CCc3cc(C)c(C(=O)O)cc3C1C(=O)c1cc3c(cc1C2=O)C(=O)C=CC3=O
Yield: 19.9 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in DMSO (1 mL) was added lithium chloride (121 mg, 2.87 mmol). The reaction mixture was irradiated with microwaves at 120° C. for 21 min. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 100% acetonitrile with 0.05% TFA over 50 min) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-(2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (12.0 mg, 12.5%) as a dark orange-red solid: 1H NMR (500 MHz, acetone-d6) δ 14.27 (s, 1H), 8.06 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.62 (s, 1H), 6.00 (s, 2H), 5.09-5.05 (m, 1H), 4.90-4.83 (m, 1H), 4.78-4.71 (m, 1H), 4.55-4.43 (m, 1H), 3.86-3.82 (m, 1H), 3.74 (s, 3H), 3.73-3.70 (m, 1H), 3.54 (s, 3H), 3.53-3.45 (m, 2H), 3.32 (s, 3H), 3.30-3.20 (m, 2H), 3.06 (t, J=9.1 Hz, 2H), 2.43 (s, 3H), 1.19 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 684 (M+H); HPLC 93.4% (AUC), tR 11.84 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)C(Cl)Cl>[CH3:12][C:11]1([CH3:13])[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9](=[O:14])[CH2:10]1
Reactant: COc1cccc(N(C(=O)C=C(C)C)c2ccc(C)cc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCC(Cl)Cl
Product: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(O)cc32)cc1
Yield: 7.5 %

Procedure:
To a solution of 55 mg (0.19 mmol) of N-(4-methylphenyl)-N-(3-methoxyphenyl)-3,3-dimethylacrylamide (Compound 16) in 2.0 mL of trichloroethane stirring under argon, was added 0.11 g (0.84 mmol) of aluminum chloride and the mixture was heated at 90°-100° C. for 18 hours. The reaction was cooled, poured onto ice, the mixture extracted with diethyl ether (2x) dried (MgSO4), filtered and concentrated in vacuo to give an oil. The mixture was purified by flash chromatography (30% ethyl acetate in hexanes) to give the title compound as a white solid (4.0 mg). PNMR (300 MHz, CDCl3) d 1.37 (6 H, s), 2.41 (3 H, s), 2.65 (2 H, s), 4.76 (1 H, s), 5.92 (1 H, d, J=2.6 Hz), 6.49 (1 H, rid, J=8.3, 2.6 Hz), 7.09 (2 H, d, J=8.1 Hz), 7.17 (1 H, d, J=8.3 Hz), 7.30 (2 H, d, J=8.1 Hz).
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[N:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29]C(C)(C)[O:27]3)[N:21]=[C:20]([C:33]([NH:35][O:36][CH3:37])=[O:34])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].C(O)(C(F)(F)F)=O.[OH-].[NH4+]>C1COCC1.O>[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[N:23]=[C:22]([O:24][CH2:25][CH:26]([OH:27])[CH2:30][OH:29])[N:21]=[C:20]([C:33]([NH:35][O:36][CH3:37])=[O:34])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCC2COC(C)(C)O2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCC(O)CO)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-N-methoxypyrimidine-4-carboxamide (Example 313; 0.60 g, 1.08 mmol) was dissolved in THF/water (4:1; 2.5 ml) and cooled to 0° C. TFA (0.1 ml) was added to the solution which was then slowly warmed to room temperature and stirred overnight. The mixture was neutralized with concentrated ammonium hydroxide and the THF was removed in vacuo. The mixture was diluted with water (4 ml), extracted with DCM, and the organic layers dried over magnesium sulfate. The mixture was concentrated in vacuo and crude product was purified by reverse phase chromatography eluting with acetonitrile/water (0.1% TFA) (33 mg).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[CH3:28][O:29][CH2:30][CH2:31][C:32]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH:6]=[CH:5][S:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:33]
Reactant: COCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (100 mg, 0.22 mmol) and 3-methoxypropionic acid (24 mg, 0.23 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (61 mg, 64%), MS (ISP) m/z=431.3 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([NH:20]C(=O)C)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.O>[C:1]1([C:7]2[C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([NH2:20])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1[nH]nc(-c2ccccc2)c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1[nH]nc(-c2ccccc2)c1C#Cc1ccccc1
Temperature: 90 °C
Yield: 49.6 %

Procedure:
A mixture of N-[3-phenyl-4-(2-phenylethynyl)-1H-pyrazol-5-yl]acetamide (12.5 g, 42 mmol), ethanol (100 mL) and 25% aq. NaOH solution (100 mL) was stirred and heated to 90° C. for 1 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. Diethyl ether was added to the residue and the solid was collected by filtration, washed with diethyl ether and dried in vacuo to provide the title compound as a solid (5.4 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1([C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[NH:9]1)(=[O:8])=[O:7]>C1COCC1>[CH2:1]([C:10]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[S:6](=[O:7])(=[O:8])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC1=NS(=O)(=O)c2ccccc21

Procedure:
This material was prepared by adding 2 equivalents of butyllithium to saccharin in THF at -78° C., followed by aqueous workup at pH 9 as described in the literature by Abramovitch et al., J. Chem. Soc. Perkin I, 1974, 2589.