Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17](=[O:30])[CH2:18][CH2:19][C:20]([O:22]CC2C=CC=CC=2)=[O:21])[CH:9]=1)([O-])=O>O1CCOCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17](=[O:30])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:9]=1
Reactant: O=C(CCC(=O)n1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21)OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc(Cc2cn(C(=O)CCC(=O)O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
To a solution of benzyl 4-[3-(3-nitrobenzyl)indol-1-yl]-4-oxobutyrate (320 mg) in a mixture of 1,4-dioxane (6 ml) and methanol (3 ml) was added 10% palladium on activated carbon (60 mg), and the mixture was shaken under hydrogen atmosphere (3 atm) at 25° C. for 1.5 hours. The catalyst was filtered off and the filtrate was evaporated. The crude crystals were washed with hot chloroform and hot ethyl acetate to give 4-[3-(3-aminobenzyl)indol-1-yl]-4-oxobutyric acid (157 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][O:12][C:13]([C:15]1[C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[C:16]2[C:17]([CH:9]=[O:10])=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)c(C=O)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.42 g, 2.71 mmol) was added to DMF (0.99 g, 13.57 mmol) at 0° C. The resulting colorless solution was added dropwise to a solution of 2-(4-chloro-phenyl)-1H-indole4-carboxylic acid methyl ester (0.52 g, 1.81 mmol) in 10 mL dry CH2Cl2 at 0° C. The reaction was stirred at 0° C. for 10 min then quenched by addition of 5 mL 2 M NaOAc(aq). The layers were separated and the aqueous layer extracted once with CH2C12. The combined organic layers were dried (MgSO4) then concentrated in vacuo leaving an orange oil which crystallized on standing. The crystals were rinsed with CH2Cl2 then dried in vacuo to yield 2-(4-chloro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl ester, 231 mg (41%) as an off-white solid: m.p. 221-222° C.; 1H NMR (300 MHz, d6-DMSO) 3.93 (s, 3H), 7.49 (app t, J=7.5 Hz, 1H), 7.71 (m, 4H), 7.94 (d, J=7.8 Hz, 2H), 9.71 (s, 1H), 13.67 (br s, 1H). MS (electrospray, [M-H]) 312.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]2)[S:5][C:6]=1[CH3:7].[Li]CCCC.[F:30][C:31]1[C:36]([C:37](N(OC)C)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[F:30][C:31]1[C:36]([C:37]([C:2]2[N:3]=[C:4]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]3)[S:5][C:6]=2[CH3:7])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1C(=O)c1cccnc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
tert-butyl (25)-4-(4-bromo-5-methyl-thiazol-2-yl)-2-isobutyl-piperazine-1-carboxylate (921 mg, 1.737 mmol) in THF (10 mL) was cooled to −78° C. before BuLi (729.6 μL, 2.5 M in hexanes, 1.824 mmol) was added dropwise over approx. 10 mins (temperature kept below −70° C. during addition). Once added, mixture stirred at −78° C. for 30 mins before a solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (319.9 mg, 1.737 mmol) in THF (3 mL) was added dropwise at −78° C. at such a rate that temperature did not exceed −70° C. (−5 mins). Mixture then stirred at −78° C. for 2 h allowed to warm to room temperature over the weekend (3.5 days). Reaction quenched with water, diluted with EtOAc and organic layer separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (80 g SiO2, 0 to 15% EtOAc/petrol) to leave product as a yellow solid (208 mg, 26%); 1H NMR DMSO-d6 δ 0.85 (d, 6H), 1.40-1.35 (m, 12H), 2.63 (s, 3H), 2.97-2.94 (m, 2H), 3.10 (dd, 1H), 3.58 (d, 2H), 3.87-3.80 (m, 1H), 4.20-4.13 (m, 1H), 7.49-7.46 (m, 1H), 8.17-8.12 (m, 1H), 8.39 (dd, 1H); ES+ 463.22.
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11](=[O:38])[N:12]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[N:18]=[C:17]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:40]1[C:41]2[CH2:48][C:47](=[O:49])[NH:46][C:42]=2[N:43]=[CH:44][N:45]=1>CN(C=O)C>[CH2:3]([O:10][C:11](=[O:38])[N:12]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[N:18]=[C:17]1[CH:32]1[CH2:33][CH2:34][N:35]([C:40]2[C:41]3[CH2:48][C:47](=[O:49])[NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:37]1)[CH3:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2CC(=O)N3)CC1)C(=O)OCc1ccccc1
Yield: 79.4 %

Procedure:
Combine {2-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-methyl-carbamic acid benzyl ester dihydrochloride (277 μmol; 160 mg); 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1.30 equiv; 360 μmol; 61.1 mg); DMF (3 mL); TEA (7 equiv; 1.94 mmol; 270 μL) and heat to 160° C. in microwave for 45 min. Evaporate, dissolve the residue in DCM, wash with saturated sodium bicarbonate and evaporate the organic layer. Purify the residue on 40 g silica gel with 3% MeOH/DCM to provide the title compound (138.2 mg; 0.22 mmol; 78%). MS (ES+): m/z=638 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C([O-])=S)=C(CC4CCCCO4)CS[C@H]23)cs1
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(CC2CCCCO2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 62.5 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate (65 mg) was reacted with iodomethyl pivalate (46 mg) in accordance with the procedure of Example 4. The crude reaction product was purified by a column chromatography on a silica gel column (12 g) with elution using chloroform-methanol (10:1 by volume) as eluent to collect fractions containing the titled compound. The fractions so collected were concentrated to a small volume, to which was added diisopropylether dropwise and slowly, resulting in the deposition of crystals. The crystals were taken up by filtration, followed by washing with diisopropylether and drying, affording the titled compound (48 mg; 62%).
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(O)CCCCC.[C:12]1([OH:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N#N>>[C:2]([O:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: Oc1cccc2ccccc12
Agent: N#N
Solvent: CCCCCCO
Product: CC(C)(C)Oc1cccc2ccccc12

Procedure:
In a 200 ml autoclave, 300 mmol of isobutene, 50 mmol of 1-hexanol, 50 mmol of 1-naphthol and 300 mg of tin oxide/silicon dioxide/methylsilicon sesquioxide glass of composition 3 SnO2 : 97 SiO2 : 0 MeSiO1.5 were stirred at a pressure of 40 bar N2 and at a temperature of 140° C. for 16 h. Analysis of the product mixture by gas chromatography gave a yield of 1-naphthyl tert-butyl ether of 39.5% (based on 1-naphthol) as compared to a yield of 1-hexyl tert-butyl ether of 63.6% (based on 1-hexanol). In an analogous way, when the catalyst 1.5 Al2O3 : 97 SiO2 : 0 MeSiO1.5 was used, a yield of 1-naphthyl tert-butyl ether of 67.6% and a yield of 1-hexyl tert-butyl ether of 37.4% were achieved.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH:15]([O-])([O-])OCC>>[CH:1]([N:4]1[CH:15]=[N:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[S:5]1(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1cnccc1N
Reactant: CCOC([O-])[O-]
Product: CC(C)N1C=Nc2ccncc2S1(=O)=O
Temperature: 120 °C

Procedure:
A mixture of 0.5 g of N-isopropyl-4- aminopyridine-3-sulfonamide (Preparation 7) and 5 cm3 of ethyl orthoformate is maintained in an open vessel at 120° C. for 4 hours. After concentrating the solution under partial vacuum, the oily residue obtained is triturated with 10 cm3 of ice-cold water. The crystalline precipitate which appears is collected on a filter and washed with water. It is recrystallized from a methanol/water (1/2) mixture.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([CH3:24])[CH:18]2[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>COCCOC>[Cl:1][C:2]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][CH3:13])=[CH:23][CH:22]=3)[CH:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]2[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCOC(=O)CC1c2cc(OC)ccc2NC1C
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCOC(=O)CC1c2cc(OC)ccc2N(c2nc(Cl)nc3ccccc23)C1C

Procedure:
A mixture of 2,4-dichloroquinazoline (3.2g.), ethyl 5-methoxy-2-methylindolin-3-ylacetate (4.0g.) and triethylamine (2.23ml; dried over potassium hydroxide pellets) in dry 1,2-dimethoxyethane (50ml.) was heated under reflux for 30 mins. The mixture was evaporated in vacuo, and to the residue was added water (100ml.) and ethyl acetate (50ml.). The aqueous layer was separated and extracted with ethyl acetate (2 × 30ml.), and the extracts were washed with water (30ml.), dried(MgSQ 4) and evaporated. The residual syrup slowly crystallised to give ethyl 1-(2-chloroquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetate, m.p. 111°-112° C. This indoline ester (3.6g.) was added to a solution of sodium (0.5g.) in methanol (50ml.; dried over magnesium methoxide), and the resulting solution was heated under reflux for 18 hrs. After removal of methanol in vacuo, the mixture was added to water (50ml.) and acidified with acetic acid to give 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetic acid hemihydrate, m.p. 115°-120° C. This acid (3.0g.) was dissolved in dry methanol (40ml.) containing concentrated sulphuric acid (0.1ml.), and the mixture was heated under reflux for 5 hrs. Saturated sodium acetate solution (2ml.) was added, and the mixture was evaporated in vacuo. The residue was partitioned between water (50ml.) and ether (40ml.). After separation, the aqueous layer was extracted with ether (2 × 20ml.). The ether extracts were washed successively with saturated sodium hydrogen carbonate solution (20ml.) and water (20ml.), dried (Na2SO4), and evaporated to give methyl 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methhylindolin-3-ylacetate as a dark yellow syrup [pure by TLC (system A); NMR: 5--OCH3 at 6.3τ; 2-- OCH3 at 6.15τ ].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]([N:20]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:21][C:22]([C:24]2[C:34]3=[C:35]4[C:30](=[CH:31][CH:32]=[CH:33]3)[CH2:29][CH2:28][CH2:27][N:26]4[CH:25]=2)=O)=[O:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:19])[N:20]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:21][C:22]=2[C:24]2[C:34]3=[C:35]4[C:30](=[CH:31][CH:32]=[CH:33]3)[CH2:29][CH2:28][CH2:27][N:26]4[CH:25]=2)=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(=O)c1cn2c3c(cccc13)CCC2)C(=O)Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2cn3c4c(cccc24)CCC3)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A mixture of 3-(2-{tert-butoxycarbonyl-[2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-ethyl]-amino}-2-oxo-ethyl)-indole-1-carboxylic acid tert-butyl ester (1.04 g, 1.82 mmol) and DBU (0.27 mL, 1.91 mmol) in anhydrous DMF (20 mL) was stirred at 110° C. for 2 h. The mixture was cooled and evaporated. The residue was purified by silica gel column chromatography (eluent: 4/1 then 3/1 hexane/EtOAc) to give 3-[1-tert-butoxycarbonyl-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-indole-1-carboxylic acid tert-butyl ester as a yellow foamy solid (0.64 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ: 8.13 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.30 (m, 1H), 7.05 (m, 3H), 6.89 (m, 2H), 5.00 (s, 2H), 4.03 (t, J=5.6 Hz, 2H), 2.88 (t, J=5.6 Hz, 2H), 2.03 (m, 2H), 1.65 (s, 9H), 1.54 (s, 9H). LCMS: m/e 554.21 [M+H].
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3]I.[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH3:8][O:7][C:5](=[O:6])[C@@H:2]([NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][P:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:23]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)OCC
Temperature: 130 °C

Procedure:
Boc-3-iodo-L-Ala-OMe (9.4 g) was dissolved in triethyl phosphite (100 mL). The mixture was heated at 130° C. overnight and evaporated to dryness to give a yellow oil (8.37 g). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.[CH2:22]([Li])CCC.CI>CCOCC>[CH3:17][Si:16]([CH3:19])([CH3:18])[C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:5](=[CH:4][C:3]([Si:2]([CH3:21])([CH3:20])[CH3:1])=[CH:15][CH:14]=3)[CH:6]([CH3:22])[C:7]=2[CH:8]=1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)c1ccc2c(c1)Cc1cc([Si](C)(C)C)ccc1-2
Solvent: CCOCC
Solvent: CI
Product: CC1c2cc([Si](C)(C)C)ccc2-c2ccc([Si](C)(C)C)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of 1.0 g of 2,7-bis(trimethylsilyl)fluorene in 15 mL of dry ether was added dropwise 2.8 mL of 1.3 M n-butyllithium at 0° C. The mixture was stirred at room temperature for 3 hours, cooled to 0° C., and treated with a solution of 0.25 mL of methyl iodide in 5 mL of dry ether over a period of 5 minutes. The mixture was stirred at room temperature for 8 hours and washed with 2% Na2S2O3 (10 mL) and water (2×10 mL). The pooled aqueous layer was extracted with ether (2×15 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated under reduced pressure to give 1.03 g (98.7%) of the crude 2,7-bis(trimethylsilyl)-9-methylfluorene as a yellow oil which was chromatographed on silica gel (230-400 mesh, 2×40-cm packed column) with an eluant consisting of Skelly B--dichloromethane (6:1) to give 0.78 g (74.7%) of the crude hydrocarbon as a colorless oil. Crystallization from 95% ethanol gave 0.69 g (66.1%) of the pure 2,7-bis(trimethyl-silyl)-9-methylfluorene as white needles, m.p. 107°-108.5° C.; 1H NMR (CDC13): δ 0.34 (s, 18H, SiMe3), 1.58 (d, 3H, CH3), 3.96 (q, 1H, CH), 7.40-7.90 (m, 6H, aryl).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@@H:52]1[CH2:56][CH2:55][N:54]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added (3R)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followed by stirring for 4 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (21.8 mg, 51%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH2:28])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH:28][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:32][CH:33]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCc1cccc(COc2ccc(Cl)cc2)c1
Product: O=c1c(NCc2cccc(COc3ccc(Cl)cc3)c2)c(Nc2ccncc2)c1=O
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 3-(4-chlorophenoxy-methyl)-benzylamine.
Reaction SMILES: F[C:2]1[C:9]([I:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[SH:15][CH2:16][C:17]([NH2:19])=[O:18].C[O-].[Na+]>CO>[NH2:5][C:4]1[C:3]2[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:8]=[C:9]([I:10])[C:2]=2[S:15][C:16]=1[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)CS
Reactant: N#Cc1c(C(F)(F)F)ccc(I)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1sc2c(I)ccc(C(F)(F)F)c2c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To the above benzonitrile intermediate (140 mg, 0.444 mmol) in 4 mL of MeOH was added 2-mercaptoacetamide (100 mg/mL in MeOH-ammonia solution) (0.49 mL, 0.533 mmol) and 0.5M sodium methoxide in MeOH (1.78 mL, 0.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated and purified by silica gel chromatography eluting with 2-5% MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 79 mg (46%) of 3-amino-7-iodo-4-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid amide as a yellow crystalline solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:24]([NH2:26])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)=O.C(Cl)Cl.[OH-].[Na+]>O>[NH2:1][C@H:2]([C:24]([NH2:26])=[O:25])[CH2:3][S:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=CO
Product: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To the Boc-Cys(Trt)-NH2 (100 gm), added formic acid (600 ml) at temperature of about 10° C. to about 20° C. Heated the solution to about 20° C. to about 35° C. and stirred for 30 minutes at the same temperature. Added an additional quantity of formic acid (200 ml) and stirred for two hours. Cooled the reaction mass to about 0° C. to about −10° C. and charged methylene chloride (1000 ml), DM water (100 ml) and adjusted pH to 7.5-9.0 with 8N aqueous Sodium hydroxide solution. Heated the solution to about 25° C. to about 35° C. and separated the organic layer and extracted the aqueous layer with methylene chloride (250 ml) and separated the aqueous and organic layer. Combined the organic layer and washed with DM water and concentrated the organic layer under reduced pressure to obtain the residue. The residue was crystallized from hexane (100 ml) to obtain the H-Cys(Trt)-NH2 as white solid material.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Product: Brc1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 155 °C
Yield: 42.2 %

Procedure:
A mixture of carbazole (300 mg, 1.81 mmol), 4,4′-dibromobiphenyl (846 mg, 2.71 mmol), copper (344 mg, 5.43 mmol), 18-crown-6 (187 mg, 0.71 mmol), potassium carbonate (750 mg, 5.43 mmol), and anhydrous N, N-dimethylformnamide (10 ml) was degassed for 30 minutes. The mixture was heated at about 155° C. for 66 hours under argon. After being cooled to RT, the mixture was poured into methylene chloride (400 ml) and the subsequent mixture was filtered. The filtrate was loaded on silica gel. A flash column (silica, 10% methylene chloride in hexane) and reprecipitation in methylene chloride/hexanes yielded 304 mg (42% yield) of pure product 10; confirmed by HNMR
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[OH:22].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:16]([OH:22])=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)c(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2O)cc1
Yield: 35.8 %

Procedure:
4′-(Methylsulfonyl)-2,4-biphenyldiol (500 mg, 36%) was prepared as a clear oil from [4-(methylsulfonyl)phenyl]boronic acid (1.06 g, 5.29 mmol), 4-bromo-1,3-benzenediol (1 g, 5.29 mmol), Pd(PPh3)2Cl2 (100 mg, 0.14 mmol), 2M Na2CO3 (5 mL) and DME (5 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.52 (s, 1H), 7.88-7.80 (m, 2H), 7.75-7.69 (m, 2H), 7.13 (d, 1H, J=8.4 Hz), 6.41 (d, 1H, J=2.2 Hz), 6.32 (dd, 1H, Ja=8.4 Hz, Jb=2.4 Hz), 3.31 (s, 3H); LRMS (ESI), m/z 263 (M−H).