Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.C([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:21]([CH2:35][C:36]1[CH:41]=[C:40]([Br:42])[C:39]([O:43][CH3:44])=[C:38]([Br:45])[CH:37]=1)[NH:20][CH2:19][CH2:18]2)C1C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:49].Cl>CO>[ClH:49].[Br:45][C:38]1[CH:37]=[C:36]([CH:41]=[C:40]([Br:42])[C:39]=1[O:43][CH3:44])[CH2:35][CH:21]1[C:22]2[C:17](=[CH:16][C:15]([OH:14])=[C:24]([NH:25][S:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: COc1c(Br)cc(CC2NCCc3cc(OCc4ccccc4)c(NS(=O)(=O)c4ccccc4)cc32)cc1Br
Reactant: ClCCl
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)cc(CC2NCCc3cc(O)c(NS(=O)(=O)c4ccccc4)cc32)cc1Br

Procedure:
N-[6-benzyloxy-1-(3,5-dibromo-4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-benzenesulfonamide oxalate (0.389 g, 0.00051 mol) was neutralized in a mixture 1N NaOH-methylene chloride. A free base was dissolved in a methanol—conc. HCl mixture (35 mL of each). The reaction mixture was refluxed for 1h and evaporated. HCl salt was neutralized with conc. NaHCO3 solution. The product was purified by column chromatography (silica gel, chloroform-methanol—aq. ammonia/100:10:1) and dissolved in methanol, a solution of fumaric acid in methanol was added. A fumaric salt was crystallized from methanol—ethyl ether mixture.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:23](=[O:26])(=[O:25])[NH2:24])=[C:9]([O:12][C@@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)C)[CH2:15][CH2:14]3)[CH:10]=2)[C:5](=[O:27])[N:4]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:3]=1.Cl>C(O)C>[NH2:19][C@@H:16]1[CH2:15][CH2:14][C@H:13]([O:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][C:8]=2[S:23]([NH2:24])(=[O:26])=[O:25])[C:5](=[O:27])[N:4]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:3]=[C:2]3[Cl:1])[CH2:18][CH2:17]1
Reactant: COc1ccc(Cn2cc(Cl)c3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(S(N)(=O)=O)cc3c2=O)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Cn2cc(Cl)c3cc(O[C@H]4CC[C@@H](N)CC4)c(S(N)(=O)=O)cc3c2=O)cc1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
32 mg of N-{4-[4-chloro-2-(4-methoxy-benzyl)-1-oxo-7-sulfamoyl-1,2-dihydro-isoquinolin-6-yloxy]-cis-cyclohexyl}-acetamide (130, crude product) were dissolved in 5 ml of ethanol and 15 ml of 2 N HCl and heated for 2 h at 90° C. The solvent was removed under reduced pressure and the residue was dissolved in 6 N HCl and heating at 90° C. was continued for 20 h. After cooling down to room temperature, the aqueous solution was evaporated and the title compound was isolated as HCl-salt (crude product). Rt=1.00 min (Method C). Detected mass: 492.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]#[CH:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:13][Si:14]([CH2:17][N:18]=[N+:19]=[N-:20])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:20]=[N:19][N:18]([CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1cc2ncnc(Cl)c2s1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)Cn1cc(-c2cc3ncnc(Cl)c3s2)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of compound 48.2 (1.0 mmol), trimethylsilylmethyl azide (5.0 mmol), CuI (0.2 mmol), and DIEA (1.0 mmol) in DMF (10 mL) was stirred at room temperature for 24 hours. The solvent was removed and the residue was diluted with water and extracted with EtOAc. The organic layer was washed with dilute aqueous ammonium hydroxide, brine, dried, concentrated and purified by flash column chromatography to provide 4-chloro-6-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidine (compound 48.3) in 80% yield. EIMS (m/z): calcd. for C12H14ClN5SSi (M+)+H 324.04. found 324.00.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:21]([O:25]CC)(=O)[CH:22]=[O:23]>C1COCC1>[CH2:2]([C:22]([OH:23])([CH:21]([OH:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Reactant: CCOC(=O)C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A 100 mL round bottom flask was charged with magnesium turnings (360 mg, 14.6 mmol) and a stir bar. The flask was dried with a heat gun for 5 minutes then cooled under nitrogen. The flask was charged with THF (5 mL) and a small grain of iodine. A solution of linoleyl bromide (4 g, 12.1 mmol) in THF (5 mL) was added slowly and after 5 minutes the reaction initiated vigorously. The solution was stirred at room temperature for 2 hours, and then ethyl glyoxalate (0.5 mL, 2.42 mmol, 50% solution in toluene) was added. The exothermic reaction was finished immediately and quenched with saturated ammonium chloride solution (5 mL). The solution diluted with water and extracted with diethyl ether (3×50 mL). The combined diethyl ether extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The oil was purified by column chromatography on silica gel 60 (eluted with 100% Hexanes to 15% Et2O in hexanes) to afford (6Z,9Z,29Z,32Z)-19-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraene-19,20-diol as a colorless oil (945 mg, 48%).
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.[C:10]1([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]([O:28]CC)(=[O:27])C>O>[C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:10]2[CH:11]=[CH:12][C:13]([C:25]([OH:28])=[O:27])=[CH:14][CH:15]=2)[CH2:21][CH2:20]1)(=[O:24])[CH3:23]
Reactant: CCOC(C)=O
Reactant: CC(=O)N1CCC(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of aluminum chloride(III) (26 g, 195 mmol) and dichloromethane (200 mL) was stirred at 0° C., and oxalyl chloride (20 mL, 228 mmol) was dripped over 10 minutes. Then a mixture of 1-(4-phenylpiperidin-1-yl)ethanone described in Production Example 1-9 (12.3 g, 60.5 mmol) and dichloromethane (50 mL) was dripped over 30 minutes. The mixture was stirred under nitrogen atmosphere at 25° C. for 14 hours. The reaction liquid was poured onto ice and ethyl acetate (1 L) and water (1 L) were added for separation. The aqueous layer was extracted with ethyl acetate (1 L) twice, then the organic layer was washed with water (1 L) twice and then with a saturated saline solution (500 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. Ethyl acetate was added to the concentrated residue and the product was collected by filteration and washed with ethyl acetate to obtain the title compound (9.09 g, 61%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([CH:17]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH3:19])[CH3:16].[CH3:34][CH:35]([CH3:39])[CH2:36]C=O.C(O)(=O)C>ClCCl>[CH2:15]([CH:17]([N:20]([CH2:34][CH:35]([CH3:39])[CH3:36])[CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)NCCNC(=O)OCc1ccccc1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)N(CCNC(=O)OCc1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
Sodium triacetoxyborohydride (1.87 g, 8.84 mmol) was added to a solution of benzyl 2-[(1-ethylpropyl)amino]ethylcarbamate (1.8 g, 6.8 mmol) (Preparation 50), 3-methylbutanal (0.8 ml, 7.5 mmol) and acetic acid (1 ml, 8.85 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with dichloromethane (50 ml) and then washed with saturated aqueous sodium hydrogen carbonate solution (100 ml). The organic phase was dried over anhydrous magnesium sulphate and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane methanol (95:5 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume). This gave the title compound as an oil (1.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH:27]=[CH:28][P:29](=[O:34])([O:32][CH3:33])[O:30][CH3:31])=[C:18]([Cl:52])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])([CH2:35][OH:36])[CH2:27][CH2:28][P:29](=[O:34])([O:32][CH3:33])[O:30][CH3:31])=[C:18]([Cl:52])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(C=CC(CCCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COP(=O)(CCC(CO)(CCCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 287 was reduced in the same manner as in Reference Example 123 and the resulting compound (107 mg) was dissolved in tetrahydrofuran (5.0 mL). A 1 mol/L TBAF-tetrahydrofuran solution (160 μL) was added dropwise and the mixture was stirred for 3 hours at room temperature. Subsequently, water was added and the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified on a silica gel column chromatography (ethyl acetate only) to obtain the desired product as a colorless oil (47 mg).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[OH:20][C@@H:17]1[CH2:18][CH2:19][N:15]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@@H](O)C2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of t-butyl 4-fluorobenzoate (2.17 g, 11.0 mmol) and (R)-(+)-3-pyrrolidinol (1.00 g, 11.5 mmol) in DMSO (8 mL) was added potassium carbonate (1.53 g, 11.0 mmol). The mixture was stirred at 130° C. for 18 h and poured into stirring water (100 mL) while still hot. The resulting beige precipitate was collected by filtration and dried at 120° C. for 1.5 h to afford the title compound (2.64 g, 91% yield). 1H NMR (Acetone-d6) δ (ppm): 7.78 (d, J=9.0 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 4.58 (bs, 1H), 4.15 (bs, 1H), 3.55 (dd, J=10.36, 4.7 Hz, 1H), 3.49 (t, J=6.8 Hz, 1H), 3.42 (td, J=9.2, 2.3 Hz, 1H), 3.28 (d, J=10.8 Hz, 1H), 2.21-2.10 (m, 1H), 2.09-2.03 (m, 1H), 1.56 (s, 9H). m/z: 520.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]=[CH:14][CH2:13][C:12]2=[O:17])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H][H]>[Pd].C(O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C2CC=CCC2=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OC)cc(C2CCCCC2=O)c1

Procedure:
A mixture of 23.6 g. 2-(3,5-dimethoxyphenyl)-4-cyclohexen-1-one, 300 ml. ethanol and 3 g. 10% Pd/C catalyst was hydrogenated at 40 psi (2.8 kg./cm.2). After hydrogen uptake ceased, the mixture was filtered, the filtrate evaporated in vacuo and the residue recrystallized from isopropyl ether to obtain 17 g. of product, M.P. 61°-62° C., lit. [J. Org. Chem., 27, 376 (1962)], M.P. 62.5°-63° C.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.[CH2:18]([S:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](Cl)=[N:31][CH:30]=[CH:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C1COCC1>[CH2:18]([S:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:31][CH:30]=[CH:29]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1nccc2cc(SCc3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1nccc2cc(SCc3ccccc3)ccc12
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
A 100-mL round-bottom flask was charged with tert-butyl 1-pyrrolidinecarboxylate (1.625 ml, 9.27 mmol) and THF (23.33 ml) to give a clear solution. The flask was flushed with Ar (g), then cooled in a −30° C. dry ice-acetone bath for 10 min. Sec-butyllithium (1.4 M in cyclohexane) (8.75 ml, 12.25 mmol) was added drop wise over 5 min. The resulting mixture was stirred for 10 minutes at −30° C., then zinc chloride (1.0 M in diethyl ether) (7.00 ml, 7.00 mmol) was added drop wise. The reaction was stirred for 5 minutes, then the cooling bath was removed. After 25 min, a solid mixture of 6-(benzylthio)-1-chloroisoquinoline (from Intermediate LLL, step 1; 1.0 g, 3.50 mmol), Pd(Ph3P)4 (0.809 g, 0.700 mmol), and copper(i) iodide (0.333 g, 1.750 mmol) was added in one portion. The reaction was capped and stirred at 60° C. for one hour. The reaction was filtered through a pad of diatomaceous earth, washing thoroughly with ethyl acetate. The filtrate was concentrated and purified via column chromatography (80 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane followed by a 20% MeOH/EtOAc flush) to afford tert-butyl 2-(6-(benzylthio)isoquinolin-1-yl)pyrrolidine-1-carboxylate as a yellow solid. (ESI) 421.3 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:43]=[C:42]2[C:38]([C:39]([C:45]3[N:46]=[C:47]4[C:53]([C:54]([OH:56])=O)=[CH:52][N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:48]4=[N:49][CH:50]=3)=[N:40][N:41]2[CH3:44])=[CH:37][CH:36]=1.[O:65]([CH2:72][CH:73]([NH2:75])[CH3:74])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[CH3:74][CH:73]([NH:75][C:54]([C:53]1[C:47]2[C:48](=[N:49][CH:50]=[C:45]([C:39]3[C:38]4[C:42](=[CH:43][C:35]([F:34])=[CH:36][CH:37]=4)[N:41]([CH3:44])[N:40]=3)[N:46]=2)[N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:62])[CH3:63])[CH:52]=1)=[O:56])[CH2:72][O:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)COc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(COc1ccccc1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
In a 100 mL round-bottomed flask, HBTU (78 mg, 0.21 mmol), Hunig's base (0.14 ml, 0.79 mmol) and 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.16 mmol) were combined with DMF (3 ml) to give a light yellow solution. 1-Phenoxypropan-2-amine (48 mg, 0.32 mmol) was added and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc. The reaction mixture was poured into 50 mL sat NaHCO3 and extracted with EtOAc (2×50 mL). The organic layers were combined and washed with water (2×50 mL) then dried over MgSO4 and concentrated in vacuo to provide 81 mg (89%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-phenoxy-ethyl)-amide as a white solid. MS: (M+H)+=575.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[C:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH3:27].Cl>O.O1CCOCC1>[C:26]([NH:29][C:30]1[CH:35]=[C:34]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)c1

Procedure:
A first stock solution was prepared consisting of 2-(4-iodo-phenoxymethyl) -thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 1.56 g, 4 mmol), bis(tri -cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 140 mg, 0.21 mmol), and dioxane (approximately 82 mL). A second stock solution was prepared consisting of potassium carbonate (1.66 g, 12 mmol) and water (approximately 8.2 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction vial containing 3-acetamidobenzeneboronic acid (ASDI Incorporated, Newark, Del.; 107 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min. 1 M HCl (0.1 mL) was added to each vial, and the solution were passed through silica gel columns (1 g of silica), and washed with dimethylacetamide (2×1 mL). The solution was evaporated to dryness to give 2-(3′-acetylamino-biphenyl-4-yloxymethyl) -thiazole-4-carboxylic acid. Mass spectrum MH+=369.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[C:16]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=[C:14]([C:5]2[CH:4]=[C:3]([OH:2])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:6]=2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccccc3)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2cccc(-c3ccccc3)c2)nn1-c1ccccn1
Yield: 90 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 34 of Example C-8 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.[CH:39]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]([CH3:50])[CH3:49])[C:43]=1[N:51]=[C:52]=[O:53])([CH3:41])[CH3:40].C(N(CC)C(C)C)(C)C.Cl>O1CCCC1.C(OCC)(=O)C.C(OCC)C.CN(C)C=O>[ClH:1].[CH:39]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]([CH3:49])[CH3:50])[C:43]=1[NH:51][C:52]([NH:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:37][CH:38]=1)=[O:53])([CH3:40])[CH3:41]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCCc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.2 %

Procedure:
1-(2,6-Diisopropylphenyl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea was obtained by a similar procedure to that described in Example 31 using 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.4 g), 2,6-diisopropylphenyl isocyanate (0.14 g), N,N-diisopropylethylamine (0.18 g) and anhydrous N,N-dimethylformamide (15 ml). To a solution of the product in tetrahydrofuran (10 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added diethyl ether (15 ml) and this mixture was stirred for 1 hour. The precipitate was isolated by filtration and washed with ethyl acetate and n-hexane to afford the title compound (0.4 g, mp 153-155° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:22]1[CH:23]=[C:15]2[C:16]([C:17](=[O:19])[N:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[C:12](=[O:13])[NH:14]2)=[CH:20][CH:21]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccccc1Cl
Yield: 51.6 %

Procedure:
1.14 g (5.22 mmol) of 2-chlorobenzenesulfonylisocyanate and 896 mg (5.22 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 1.00 g of the above-identified compound (yield 51.6%). Properties: colorless crystal, Melting point: 275°-276° C., PMR (δppm, DMSO-d6):7.16 (1H,s), 7.23 (1H,d), 7.63-7.76 (4H,m), 7.86 (1H,d), 8.20 (1H,d), 11.79 (1H,br).
Reaction SMILES: C([N:8]1[CH2:20][C@@H:19]2[C@H:10]([C:11](=[O:25])[NH:12][C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)C1C=CC=CC=1.[ClH:26].[H][H]>CO.CCOCC.[Pd]>[ClH:26].[F:24][C:21]([F:22])([F:23])[C:14]1[C:13]2[NH:12][C:11](=[O:25])[C@@H:10]3[CH2:9][NH:8][CH2:20][C@H:19]3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Nc2c(cccc2C(F)(F)F)[C@@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C1Nc2c(cccc2C(F)(F)F)[C@@H]2CNC[C@@H]12
Yield: 60 %

Procedure:
To a solution of (±)-trans-2-benzyl-6-(trifluoromethyl)-1,2,3,3a-tetrahydro-5H-pyrrolo[3,4-c]quinolin-4(9bH)-one from Example 5, Part B (30 mg, 0.087 mmol) in 10 mL of methanol was added HCl (0.25 mL of a 2M solution in ether, 0.5 mmol) and 10% Pd/C catalyst (10 mg). The resulting mixture was shaken in a Parr apparatus under 65 psi of hydrogen for 3 h. The reaction was filtered through a pad of Celite and concentrated in vacuo. The resulting solid was triturated several times with ether and dried in vacuo to afford 15 mg (60%) of the title compound of Example 6 as an off-white solid. 1H NMR (DMSO-D6): δ 10.09 (broad s, 1H), 9.90 (broad s, 1H), 9.69 (s, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.24 (t, 1H), 3.95-3.88 (m, 1H), 3.52-3.38 (overlapping m, 2H), 3.32-3.20 (overlapping m, 2H), 3.08-2.98 (m, 1H). LRMS (ESI): 257.10 (M+H)+.