Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.79 mmol) in methylene chloride (25 mL) was added dropwise 4-fluorobenzoyl chloride (89 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 130 mg (65%) of the title compound as white crystals: mp 189-190° C.; [α]21D -30° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 367 (11, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[S:34](=[O:35])[CH2:33][CH2:32][C:11]=3[N:12]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[S:34](=[O:35])[CH2:33][CH2:32][C:11]=3[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Yield: 59.8 %

Procedure:
6.90 g ethyl 4-{4-[4-(3-chloro-phenylamino)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-benzoate and 70 ml of 1 molar sodium hydroxide solution are placed in 40 ml of methanol and 40 ml of tetrahydrofuran, then refluxed for 1.5 hours with stirring. The resulting solution is evaporated down, the residue is cooled and acidified slightly with 2 molar hydrochloric acid. The precipitate formed is suction filtered, washed and dried. The substance is stirred with ethyl acetate/methanol 9:1, suction filtered and dried. 3.90 g of the product are obtained as a powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 120 °C
Yield: 90 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol) in 2,2-dimethyl-oxirane (3 mL) was added cesium carbonate (130 mg, 0.40 mmol). The reaction was heated at 120° C. for 30 minutes using microwave irradiation. The reaction was cooled then filtered through a plug of cotton wool, flushing with DCM. The filtrate was concentrated in vacuo giving 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol as a beige solid (620 mg, 90%). 1H NMR δ (ppm) (CDCl3): 7.82 (1H, d, J=0.65 Hz), 7.69 (1H, s), 4.07 (2H, s), 1.32 (12H, s), 1.15 (6H, s). 1 Exchangeable proton not observed
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH:9]=1.[Br:51]N1C(=O)CCC1=O>C(#N)C>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:49])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:29][CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)[C:9]=1[Br:51]
Reactant: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)C1CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4l, 265 mg, 0.37 mmol) and N-bromosuccinimide (80 mg, 0.45 mmol). To this was added acetonitrile (5 mL). The resulting solution was stirred at room temperature for 18 hours. At 18 hours, the reaction was reduced in vacuo and the residue was purified via silica gel chromatography to yield the title compound as yellow oil. Yield=255 mg.
Reaction SMILES: [Na+].[CH2:2]([O:5][C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21]([O-:23])=O)[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH:3]=[CH2:4].[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:42]=1[CH2:43][NH2:44])[CH2:37][CH:38]=[CH2:39].C(OC1C=CC=CC=1CNC(C1N=C2C=C(C)C([C@H](OC(C)(C)C)C(OC)=O)=C(N3CCC(CCC=C)(C)CC3)N2C=1)=O)C=C>>[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:42]=1[CH2:43][NH:44][C:21]([C:19]1[N:20]=[C:16]2[CH:15]=[C:14]([CH3:24])[C:13]([C@H:25]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[C:12]([N:9]3[CH2:10][CH2:11][C:6]([CH3:35])([O:5][CH2:2][CH:3]=[CH2:4])[CH2:7][CH2:8]3)[N:17]2[CH:18]=1)=[O:23])[CH2:37][CH:38]=[CH2:39]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)[O-])cn23)CC1
Reactant: C=CCCOc1ccc(F)cc1CN
Agent: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)NCc4ccccc4OCC=C)cn23)CC1
Agent: [Na+]
Product: C=CCCOc1ccc(F)cc1CNC(=O)c1cn2c(N3CCC(C)(OCC=C)CC3)c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc2n1
Yield: 61 %

Procedure:
Prepared from (S)-5-(4-(allyloxy)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylic acid sodium salt and 2-(but-3-en-1-yloxy)-5-fluorobenzylamine in 61% yield using the same procedure as (S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1):651.35.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:11]=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>O1CCCC1.CCCCCC>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39](=[O:40])[CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:11]=[N:10][N:9]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCCn1nnnc1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCn1nnnc1C(C(=O)Nc1ccc(F)cc1F)c1ccccc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
The compound from (a) above (1.5 g; 4.5 mmoles) was dissolved in tetrahydrofuran (20 mL), cooled to -20° C., and then treated dropwise with n-butyllithium (2.8 mL; 4.5 mmoles) for over 5 minutes. The solution was stirred for 5 minutes before adding 2,4-difluorophenyl isocyanate (0.7 g; 4.5 mmoles). The ice bath was removed and the solution gradually warmed to room temperature over 30 minutes, at which time the reaction was quenched with water (20 mL) and diluted with ethyl acetate. The layers were separated and the organic portion was washed with aqueous HCl (1N), aqueous sodium carbonate (10%), and brine. The solution was dried over magnesium sulfate, filtered, and stripped to dryness leaving a viscous liquid that was dissolved in 75% hexane/25% ethyl acetate and chromatographed using silica gel. Yield: 0.9 g (41%).
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]1[NH:9][C:8]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]/[C:16](=[O:28])[N:17]3[CH2:20][CH:19]([O:21][CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH2:18]3)=[CH:13][C:7]=2[CH2:6][N:5]1[CH2:29][C:30]([O:32]CC)=[O:31].O>CO>[O:3]=[C:4]1[NH:9][C:8]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]/[C:16](=[O:28])[N:17]3[CH2:20][CH:19]([O:21][CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH2:18]3)=[CH:13][C:7]=2[CH2:6][N:5]1[CH2:29][C:30]([O-:32])=[O:31].[Na+:2]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])CN1Cc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2NC1=O

Procedure:
A solution of sodium hydroxide (1N, 438 μL, 0.44 mmol) was added to a suspension of (E)-ethyl 2-(2-oxo-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate (100 mg, 0.22 mmol) in methanol (5 mL) at room temperature. The reaction mixture was refluxed for 15 minutes then poured into cold water. The resulting precipitate was filtered and washed with diethyl ether. The title product was obtained as a white solid (53.5 mg, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23](CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1.CN(C=O)C.[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:21]#[N:23])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCC1
Reactant: CCN(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of Example 39A (1.88 g, 6.6 mmol) and triethylamine (0.92 mL, 6.6 mmol) in THF (20 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (1.51 g, 13.2 mmol). The mixture was allowed to warm up to room temperature and stirred for 12 hours after which it was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to provide a yellow liquid. The yellow liquid was taken up in 100 mL of dry DMF under nitrogen and tetrabutylammonium cyanide (5 g, 20 mmol) was added to the solution. The mixture was heated to 50° C. for 60 hours after which the mixture was poured into cold water and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (MgSO4), filtered, concentrated under reduced pressure and purified by flash silica gel chromatography eluting with 50% ethyl acetate/50% hexane to provide the titled compound. MS (DCI/NH3) m/e 294 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 5H) 1.49 (s, 4H) 1.86 (m, 2H) 1.99 (m, 2H) 2.03 (m, 1H) 2.10 (m, 2H) 3.40 (m, 2H) 3.52 (m, 2H) 3.69 (m, 1H) 4.58 (m, 1H) 4.65 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[CH3:30])=[O:12])[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:44]([NH2:47])([CH3:46])[CH3:45].C(OCC)(=O)C>COC(C)(C)C>[CH3:45][CH:44]([NH:47][C:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:27])[F:26])=[CH:16][C:15]=1[CH3:30])=[O:12])=[O:10])[CH3:46]
Reactant: CC(C)N
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1ccnc(Cl)c1C(=O)O
Solvent: COC(C)(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1ccnc(Cl)c1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
In 10 ml of t-butyl methyl ether was dissolved 500 mg of 2-chloro-4-[4-(heptafluoro-2-propyl)-2-methylphenyl]aminocarbonyl-3-pyridinecarboxylic acid, followed by adding thereto 340 mg of ok trifluoroacetic anhydride, and the resulting mixture was stirred at room temperature for 2 hours. After the disappearance of the starting material was confirmed by TLC, 330 mg of isopropylamine was added to the mixture, followed by stirring at room temperature for another 2 hours. After completion of the reaction, ethyl acetate was added and the reaction solution was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography using ethyl acetate/n-hexane as an eluent, to obtain 460 mg of the desired compound as white crystals.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][CH2:38][CH:39]([N:46]([CH3:48])[CH3:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CS(C)=O.C(N(CC)CC)C>C(#N)C>[CH3:47][N:46]([CH3:48])[CH:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][NH:37][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(CN)c1ccccc1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCC(c4ccccc4)N(C)C)n3Cc3ccccc32)cc1
Temperature: 82 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a suspension of 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (1.21 g, 2.25 mmole) in acetonitrile (25 mL) was added a solution of (2-amino-1-phenylethyl) dimethylamine (0.250 g, 1.52 mmole) in acetonitrile (5 mL), followed by dimethylsulfoxide (5 equivalents) and triethylamine (2.2 equivalents). The mixture was stirred at 82° C. under nitrogen for 18 hours. The solvent was evaporated, and the residue diluted with dichloromethane. The solution was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was flash chromatographed over silica gel Merck-60 using a gradient of 30 to 80% ethyl acetate in dichloromethane to provide the title compound as a light brown amorphous solid (0.777 g). MS [(+)ESI, m/z]: 585.19 [M+H]+ Anal. Calcd for C37H36N4O3.0.2 C4H8O2: C, 75.38; H, 6.29; N, 9.30. Found: C, 75.42; H, 6.38; N, 9.04.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([CH3:37])([CH3:36])[C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]([C:21]1[S:47][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=2)=[CH:24][N:23]=1)([CH3:37])[CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCC(=O)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc([N+](=O)[O-])c2)s1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To a solution of the product of Step 1 (680 mg, 1.31 mmol) in toluene (6.5 mL) was added Lawesson's reagent (530 mg, 1.31 mmol) and the mixture was heated to 100° C. for 20 hours and then cooled to it then the mixture was concentrated in vacuo. Purification by chromatography on silica gel (100:0 to 50:50, hexanes:ethyl acetate) provided 461 mg (0.892 mmol, 68%) of 2-(1-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropan-2-yl)-5-(3-nitrophenyl)-1,3-thiazole as a colorless viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][C:7]2=O)([O-])=O.[ClH:20]>>[ClH:20].[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7]2
Reactant: CCOC(=O)C1CC(=O)c2cc([N+](=O)[O-])ccc2C1
Agent: Cl
Product: CCOC(=O)C1CCc2cc(N)ccc2C1

Procedure:
Ethyl 6-nitro-1,2,3,4-tetrahydro-4-oxo-2-naphthalenecarboxylate was treated according to the procedure described in step (1) of Referential Example 1 but using concentrated hydrochloric acid instead of 48% hydrobromic acid to give ethyl 6-amino-1,2,3,4-tetrahydro-2-naphthalenecarboxylate hydrochloride with m.p. 117°-130° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:52]([O-])(=[S:54])[CH3:53].[K+]>C(Cl)(Cl)(Cl)Cl>[CH3:25][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]=2[CH:5]([C:52](=[S:54])[CH3:53])[CH2:4][CH2:3]1
Reactant: CC([O-])=S
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3C(C)=S)cc1

Procedure:
To a solution of 543 mg (1.64 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (obtainable from Compound M by coupling with ethyl-4-iodobenzoate) in 20 ml of CCl4 was added 320 mg (1.81 mmol) of N-bromosuccinimide and 26 mg (0.11 mmol) of benzoyl peroxide. The mixture was refluxed for 3 hours under argon atmosphere, cooled, filtered through celite and concentrated in vacuo to a dark brown syrup. The syrup was taken up in 20 ml of dry THF and 780 mg (6.9 mmol) of potassium thioacetate was added. The mixture was refluxed for 4 hours under argon atmosphere, concentrated in vacuo and purified by chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a pale yellow solid.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])C1C=CC=CC=1>CO.[Pd]>[C:9]([OH:22])(=[O:8])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCOCCOCCOCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCOCCOCCOCC(=O)O

Procedure:
Benzyl-3,6,9,12-Tetraoxatridecanoate (5 mmol) is dissolved in methanol (50 ml) and 10% palladium on carbon is added (100 mg catalyst/mmol). The suspension is shaken under 30 psi H2 until the starting material is consumed. The suspension is filtered through a short pad of Celite, washed thoroughly with methanol, and the solvent evaporated. The product is used directly without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[CH3:20][CH:19]([CH3:21])[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CC(C)C(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CC(C)C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 78.8 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 8.8 mg (0.10 mMol) isobutyric acid, 11.8 mg (79%) of the title compound were recovered.
Reaction SMILES: C[O-].[Na+].[C:4]1([CH:10]2[CH2:18][C:17]3[C:12](=[C:13]([Cl:22])[C:14]([Cl:21])=[C:15]([O:19][CH3:20])[CH:16]=3)[C:11]2=[O:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:25][CH3:26].C1C=CC=CC=1>O.CN(C)C=O>[CH2:25]([C:10]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:18][C:17]2[C:12](=[C:13]([Cl:22])[C:14]([Cl:21])=[C:15]([O:19][CH3:20])[CH:16]=2)[C:11]1=[O:23])[CH3:26]
Reactant: CCI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCC1(c2ccccc2)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
Sodium methoxide (1.24 g., 0.023 mole) is added portionwise to a stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (4.61 g., 0.015 mole), iodoethane (15.5 ml., 0.15 mole), benzene (60 ml.) and dimethylformamide (60 ml.) under nitrogen in an ice-water bath. The reaction mixture is left to come to ambient temperature over one hour, then poured into water (1 l.), the benzene layer separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3.23 g. of 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at 139°-141° C. on crystallization from benzene:hexane, 1:1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([F:16])[C:12]([OH:15])=[C:13]([F:14])[C:8]=2[O:7][CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[C:9]2[CH:10]=[C:11]([F:16])[C:12]([OH:15])=[C:13]([F:14])[C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)Cc1coc2c(F)c(O)c(F)cc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1COc2c1cc(F)c(O)c2F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
(5,7-Difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (0.16 g, 0.66 mmol) obtained in Step C of Preparation Example 50 was dissolved in MeOH, and 10% Pd/C (30 mg) was added thereto. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours and then filtered. The filtrate was distilled under reduced pressure and then purified using EtOAc/Hex (1:4) solution by column chromatography to obtain the title compound (0.13 g, 81%).
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1.[I-:23].[K+].Cl>CS(C)=O.[Cu]I>[I:23][C:2]1[C:7]2[C:8](=[O:20])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: [I-]
Reactant: COc1ccc(-c2coc3cc(OC)cc(Br)c3c2=O)cc1
Agent: [Cu]I
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2coc3cc(OC)cc(I)c3c2=O)cc1
Temperature: 115 °C
Yield: 88.5 %

Procedure:
A suspension of 5-bromo-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran (95 mg), copper(I) iodide (250 mg) and potassium iodide (462 mg) in DMSO (6 mL) was heated at 115° C. for 2 h. The mixture was cooled, poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and brine and dried over MgSO4. Chromatography on silica gel (eluant: ethyl acetate-dichloromethane-hexane 1:10:20) afforded the title compound (95 mg). 1H NMR (DMSO-d6): 8.40 (s, 1H), 7.63 (d, 1H, J=2.7 Hz), 7.47 (d, 2H, J=8.7 Hz), 7.22 (d, 1H, J=2.7 Hz), 6.99 (d, 2H, J=8.7 Hz), 3.90 (s, 3H), 3.79 (s, 3H); MS: 409 (MH+); HPLC tR: 2.83 min.