Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH:15]3[C:16]4[C:11](=[CH:10][C:9]([OH:8])=[CH:18][CH:17]=4)[CH2:12][CH2:13][NH:14]3)=[CH:20][CH:21]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc2c(c1)CCNC2c1ccc(OCCN2CCCC2)cc1
Yield: 56.1 %

Procedure:
A mixture of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.300 g, 0.70 mmol), ammonium formate (0.883 g, 14.0 mmol), and 20% Pd(OH)2/C (0.050 g) in MeOH (50 ml) was refluxed under N2 for 1 hr, then filtered through Celite®. The filtrate was evaporated in vacuo to a yellow residue that was suspended in a mixture of H2O (5 ml) and saturated NaHCO3 solution (5 ml), then extracted with CH2Cl2 (4×10 ml). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 0.133 g of yellow oil. The aqueous layer was extracted again with CH2Cl2 (4×50 ml) to give an additional 0.083 g of yellow oil, for a total of 0.216 g (91% yield) of product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:17])SC2C=CC(C)=CC=2)=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O)=[O:41]>S1C=CC=C1C([O-])=O.[Cu+]>[CH3:1][C:2]1[C:7]([C:8]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:40]=[O:41])=[O:17])=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(SC(=O)c2cc(-c3ccccc3)cnc2C)cc1
Reactant: O=Cc1ccccc1B(O)O
Agent: [Cu+]
Agent: O=C([O-])c1cccs1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Product: Cc1ncc(-c2ccccc2)cc1C(=O)c1ccccc1C=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
S-(4-methylphenyl) 2-methyl-5-phenylpyridine-3-carbothioate (100 mg, 0.31 mmol), copper (I) thiophene-2-carboxylate (89.6 mg, 0.47 mmol), Pd2 dba3CHCl3 (26 mg, 0.025 mmol), tri-2-furylphosphine (17.3 mg, 0.074 mmol) and 2-formylphenylboronic acid (51.7 mg, 0.34 mmol) were combined in a dry flask. The flask was purged with argon and 3.0 mL of THF were added. Argon was bubbled through the solution for 5 minutes and the solution was stirred and heated to 50° C. After 18 hours, the reaction mixture was diluted with EtOAc, washed with 1N HCl, brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (100-70% hexanes/EtOAc gradient) to afford the title compound. LRMS (APCI) calculated for C20H16NO2 [M+H]+, 302.1; found 302.1.
Reaction SMILES: [O:1]1[CH2:17][C:2]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C:4]1([CH2:15][CH3:16])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].CN(C)C=O.[BrH:29].N1C=CC=CC=1>C(Cl)(Cl)Cl.O>[Br:29][CH2:17][C:2]([OH:1])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C:4]1([CH2:15][CH3:16])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]
Reactant: CCC1(CC2(c3ccccc3)CO2)C(=O)c2ccccc2C1=O
Reactant: Br
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC1(CC(O)(CBr)c2ccccc2)C(=O)c2ccccc2C1=O
Yield: 23.3 %

Procedure:
To the mixture of 1.53 g of 2-(2,3-epoxy-2-phenylpropyl)-2-ethylindan-1,3-dione, 15 ml of chloroform and 1 ml of dimethylformamide, was added 0.96 g of pyridine hydrobromide. After refluxing under heating for 6 hours, the reaction mixture was poured into water and was added 20 ml of chloroform. The organic layer was washed with water and with a saturated saline solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=4/1) to obtain 0.45 g of the compound No. 36 shown in Table 2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:13]([Cl:12])(=[O:15])=[O:14])[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11]
Reactant: O=S(=O)(O)Cl
Reactant: Fc1cc(F)c(Cl)c(F)c1Cl
Product: O=S(=O)(Cl)c1c(F)c(Cl)c(F)c(Cl)c1F
Temperature: 80 °C
Yield: 65.4 %

Procedure:
1,3-Dichloro-2,4,6-trifluorobenzene (5.0 g, 25 mmol) and chlorosulfonic acid (10.0 mL, 150 mmol) were mixed at ambient temperature under a nitrogen atmosphere and the reaction was heated at 80° C. for 24 h. The mixture was then allowed to cool to ambient temperature and was poured onto 12 g of crushed ice. The product was extracted with diethyl ether, dried over MgSO4, and the solvent was evaporated to produce 4.9 g of the title compound, which was used without further purification.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3][CH2:2]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:12][CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOc2ccccc21
Reaction time: 2 h

Procedure:
To chroman-4-ylmethanol (15.0 g), methylene chloride (80 ml) and triethylamine (12.9 ml) was added dropwise methanesulfonyl chloride (6.85 ml) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with methylene chloride. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give chroman-4-ylmethyl methanesulfonate.
Reaction SMILES: I[C@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=O)[O:7]2)[CH2:4][CH2:3]1.CSC.B.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[Cl-].[NH4+].[O:29]1CCC[CH2:30]1>O.Cl.C(OCC)C>[CH3:30][O:29][CH2:9][C@H:8]1[CH2:2][CH2:3][C@@H:4]2[C@@H:6]([CH2:5]2)[O:7]1
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@H]2I
Reactant: C1CCOC1
Agent: B
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CSC
Solvent: CCOCC
Solvent: CI
Product: COC[C@H]1CC[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (2.8 g) was dissolved in a solvent mixture of tetrahydrofuran (27 mL) and water (3 mL), and concentrated HCl (0.1 mL) was added thereto, followed by heating under reflux for 1 hour. The solvent was distilled away under reduced pressure, to thereby give (1R*,3R*,4R*)-3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g) as a colorless solid. 2) The product obtained from the above-described reaction (3.22 g) was dissolved in tetrahydrofuran (50 mL), and borane-dimethyl sulfide complex (as 2M tetrahydrofuran solution, 47 mL) was added to the solution under ice cooling, followed by stirring at room temperature for 12 hours. The solvent was distilled away under reduced pressure, and the residue was dissolved in isopropanol (10 mL). To the solution was added 1N aqueous sodium hydroxide (12 mL) at room temperature, and the mixture was stirred for 12 hours. After the mixture was concentrated to about one-fifth of its original volume, the resultant mixture was diluted with water and methylene chloride, followed by stirring for 10 minutes. The organic layer was separated, and was sequentially washed with saturated aqueous ammonium chloride and saturated brine, followed by drying over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), to thereby give (1R*,3R*,6S*)-7-oxabicyclo[4.1.0]hept-3-ylmethanol (1.25 g) as a colorless oily matter. 3) The product obtained from the reaction in the above step 2) (4.63 g) was dissolved in tetrahydrofuran (50 mL), and to the solution was added potassium bis(trimethylsilyl)amide (as 0.5N toluene solution, 80 mL) at −78° C., followed by stirring at the same temperature for 10 minutes, and methyl iodide (2.93 mL) was added thereto. The resultant mixture was heated to 0° C., and was stirred for 1 hour. Saturated aqueous ammonium chloride was added to the thus-obtained mixture, and the mixture was diluted with diethyl ether. The organic layer was separated, and was washed with saturated brine, followed by drying over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), to thereby give the title compound (3.7 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:114][C:115]([CH3:135])=[CH:116][CH2:117][CH2:118]/[C:119](/[CH3:134])=[CH:120]/[CH2:121][CH2:122]/[C:123](/[CH3:133])=[CH:124]/[CH2:125][S:126][CH2:127][C@H:128]([NH2:132])[C:129]([OH:131])=[O:130]>C(Cl)Cl>[OH:11][CH2:10][C@@H:9]([C:12](=[O:14])[NH:132][C@H:128]([C:129]([OH:131])=[O:130])[CH2:127][S:126][CH2:125]/[CH:124]=[C:123](\[CH3:133])/[CH2:122][CH2:121]/[CH:120]=[C:119](\[CH3:134])/[CH2:118][CH2:117][CH:116]=[C:115]([CH3:135])[CH3:114])[NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-serine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight and the CH2Cl2 was removed by rotary evaporation. The remaining residue was dissolved in ethyl acetate (50 mL). The resulting organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (51 mg, 10%) to yield Compound N-55. 1H-NMR (500 MHz, CD3OD): δ 1.47 (s, 9H), 1.62 (bs, 6H), 1.69 (s, 3H), 1.71 (s, 3H), 1.99 (t, J=7 Hz, 2H), 2.05-2.22 (m, 6H), 2.81 (dd, J=7.5, 14 Hz, 1H), 3.01 (dd, J=4, 14.5 Hz, 1H), 3.17 (dd, J=7, 13 Hz, 1H), 3.27 (dd, J=8, 12.5 Hz, 1H), 3.33 (bs, 2H), 3.74-3.80 (m, 2H), 4.22 (t, J=5 Hz, 1H), 4.63 (dd, J=5, 7.5 Hz, 1H), 5.11 (m, 2H), 5.23 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.2, 16.3, 17.8, 26.0, 27.4, 27.8, 28.7, 30.4, 33.6, 40.8, 40.9, 53.3, 58.0, 59.6, 63.4, 80.9, 121.6, 125.2, 125.5, 132.1, 136.3, 140.6, 157.8, 173.0, 173.8; ES-MS: mass calcd for Chemical Formula: C26H44N2O6S 512.7. Found (M+Na) m/z 535.4.
Reaction SMILES: [C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[C@@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[N:18][CH:19]=[C:14]2[C@@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Cl)ncc3[C@H]2C)cc1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Nc4ccccc4)ncc3[C@H]2C)cc1

Procedure:
A solution of 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-(R)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.32 g; 0.51 mmol) (from Example 14e supra) and aniline (0.12 mL; 1.32 mmol) (Aldrich) in toluene (0.25 mL, dried over molecular sieves) was heated in an oil bath at 110° C. for 1.75 hours. The reaction was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (Biotage 40L; 40:60 ethyl acetate-hexanes) to give 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-3-(4-methoxy-phenyl)-4-(R)-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.30 g; 81.6%). This material showed an e.e. of ≧95%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[C:7]1([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCCSc1ccccc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(4-chlorobutyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 396.8 (M+H)+.
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=CC=1.[CH3:18]C(=C)C.[Si]([O-])([O-])([O-])[O-].[Al+3].[Si]([O-])([O-])([O-])[O-].[Si]([O-])([O-])([O-])[O-].[Al+3].[Al+3].[Al+3]>>[OH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:8]([CH3:9])([CH3:10])[CH2:5][C:6]2([CH3:7])[CH3:18]
Reactant: C=C(C)C
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Al+3]
Agent: [O-][Si]([O-])([O-])[O-]
Product: CC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
114 g (0.5 mol) of 2,2-bis-(4-hydroxyphenyl)-propane, 90 g (1.6 mol) of isobutylene and 25 g of an aluminum silicate are stirred in an autoclave for 6 hours at around 300° C. under the naturally prevailing pressure. The catalyst is then filtered of while still hot. 41.8 g (44% of the theoretical) of 5-hydroxy-1,1,3,3-tetramethyl indane are isolated by fractional distillation in vacuo from the 170.9 g of reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1[CH:13]=[CH:14][N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[NH:18][CH2:17][C:16]=12.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[CH2:21][N:15]2[CH:14]=[CH:13][CH:12]=[C:16]2[CH2:17]1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reaction time: 18 h
Yield: 75.4 %

Procedure:
The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[N:21]=[C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]3)[N:19]=[C:18]3[C:14]=1[N:15]=[CH:16][N:17]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:8][CH2:7]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[N:21]=[C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:25][CH2:24]3)[N:19]=[C:18]3[C:14]=1[N:15]=[CH:16][N:17]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc([N+](=O)[O-])ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1

Procedure:
12.65 g of product obtained in stage 3 above in 130 ml of methanol are introduced into a round-bottomed hydrogenation flask; 500 mg of Pd/C are added and the mixture is stirred under a pressure of 1400 mbar of hydrogen for 12 hours. The mixture is filtered over clarcel and the solvent is then evaporated off. The residue is chromatographed on 600 g of silica, with 60/40 dichloromethane/ethyl acetate as eluent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CO.C(N(CC)CC)C.[C:52](OC(=O)C)(=[O:54])[CH3:53]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:20]=[CH:21][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][N:29]([C:52](=[O:54])[CH3:53])[CH:28]([CH3:32])[CH2:27]6)=[CH:23][CH:24]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNC(C)C5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-(1H-indol-5-yl)-5-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (50 mg) was suspended in 1 mL dichloromethane and 1 mL of methanol and treated with triethylamine (100 mL) and acetic anhydride (20 μL) and stirred for one hour. The mixture was concentrated in vacuo, taken up in EtOAc and washed with water and brine and dried over MgSO4. The residue was suspended in methanol and treated with 5 N NaOH and heated at 50° C. for one hour. The mixture was diluted with dichloromethane and washed with water and brine, dried over MgSO4 and purified by MPLC silica gel chromatography (0-20% MeOH in DCM) to yield an analytical sample (464 M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7].[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[CH2:4][O:5][CH2:6][CH3:7]
Reactant: CCOCc1ccc(F)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCOCc1cc([N+](=O)[O-])c(F)cc1Br

Procedure:
By the method of Example 2, Step D, 7.18 g (0.0308 mole) of ethyl 2-bromo-4-fluoro benzyl ether, 2 ml of fuming nitric acid, and 18 ml of concentrated sulfuric acid were reacted in 20 ml of 1,2-dichloroethane, yielding 3.1 g of ethyl 2-bromo-4-fluoro-5-nitrobenzyl ether.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.CC(C)([O-])C.[K+].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[S:22][CH:23]=1>O1CCCC1>[F:33][C:30]([F:31])([F:32])[C:26]1[CH:25]=[C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][N:1]3[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]3)[N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)cs2)c1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2csc(-c3cccc(C(F)(F)F)c3)n2)c1
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of ethyl 1H-pyrazole-4-carboxylate (140 mg, 1.0 mmol) in tetrahydrofuran (4 mL) was added potassium tert-butoxide (146 mg, 1.30 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 20 min. The compound (278 mg, 1.00 mmol) obtained in Example 21a was added to the reaction mixture, an ice bath was removed and the mixture was stirred for 13 hr. The reaction mixture was further heated under reflux for 1 hr, N,N-dimethylformamide (1 mL) was added and the mixture was stirred at 75° C. for 1.5 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (273 mg, 71%) as colorless crystals.
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12.[CH3:19][S:20]S(C)(=O)=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:19][S:20][C:11]1[N:12]=[CH:13][N:14]2[CH:18]=[CH:17][S:16][C:15]=12
Reactant: Ic1ncn2ccsc12
Reactant: CSS(C)(=O)=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncn2ccsc12
Reaction time: 1 h

Procedure:
A 1 M ethylmagnesium bromide/THF solution (1.4 ml) was added under ice cooling to a solution of 0.31 g of 7-iodoimidazo[5,1-b]thiazole in 3 ml of dry THF in an argon atmosphere. The mixture was stirred at the same temperature for one hr. Methyl methanethiolsulfonate (0.15 ml) was added thereto. The mixture was stirred at room temperature for 12 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution. Ethyl acetate was added thereto. The mixture was washed with a dilute aqueous sodium thiosulfate solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 0.15 g of 7-methylthioimidazo[5,1-b]thiazole.