Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N#N>C1COCC1>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromophenol (173 g, 1 mol) was dissolved in about 500 ml of freshly distilled THF under protective gas and, after passing argon through the solution, NaH (33 g, (80% in oil), 1.1 mol) was added a little at a time. During this addition the clear solution became turbid and gray and the temperature rose by 20°. The suspension was stirred for about 1 hour at room temperature under a blanket of protective gas. Hexyl bromide (181 g; 149 ml; 1.1 mol) was placed in a dropping funnel and N2 was briefly passed through it; the hexyl bromide was then added to the reaction mixture over a period of 25 minutes while stirring. The mixture, which was still gray, was refluxed at 75° C. After 3 days, (the suspension had now become paler), the salt formed was filtered off with suction and the filtrate was admixed with 20 ml of EtOH to destroy any remaining NaH (no gas evolution). The yellowish solution was evaporated and the product was isolated from the (turbid) solution by means of fractional vacuum distillation: product: 95° C./1 mbar; 172.5 g (67%); (d˜1.17).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][SH:46])=[CH:41][CH:40]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]([S:46][CH2:45][C:42]2[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)C(=CCc1ccccc1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSC(Cc2ccccc2)C(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)OC(C)(C)C)cc1
Temperature: 75 °C
Yield: 50 %

Procedure:
4-(2-tert-Butoxycarbonyl4-phenyl-but-2-enyl)-piperidine-1-carboxylic acid tert-butyl ester (0.8 g, 1.93 mmol) in DMF (10 mL) was added to a suspension of potassium carbonate (0.20 g, 1.44 mmol) ) and 4-methoxy-α-toluenethiol (0.54 mL, 3.85 mmol) in DMF (10 mL) under nitrogen. The mixture was heated to 75° C. for 24 h and allowed to cool to room temperature. The reaction mixture was then poured into H2O and extracted with ethyl acetate. The organic layers were combined and washed with water. The organic layer was dried, filtered, and concentrated under reduced pressure to give 1.8 g crude material. The crude product was purified by column chromatography (ethyl acetate/hexane, 1:10) to give 4-[2-tert-butoxycarbonyl-3-(4-methoxy-benzylsulfanyl)4-phenyl-butyl]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 50%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.[NH:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:3]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a vial containing 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (714.2 mg, 2.115 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 645.9 mg, 3.225 mmol), 1-butanol (8.00 mL) was added followed by DIPEA (582.8 mg, 4.509 mmol). The reaction mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a yellow solid (719.5 mg, 68%). LCMS calc. for C23H28N5O6S (M+H)+: m/z=502.2. found 502.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccccc1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol) and aniline (26 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL) is stirred 25 min, before the addition of NaBH(OAc)3 (60 mg, 0.28 mmol) follows. The solution is stirred overnight at RT, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The combined organic extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 97:3) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.25. MS (LC-MS): 570.0 [M+H]+; tR (HPLC, nucleosil C18 column, 10-100% CH3CN/H2O/ 5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.31 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[H-].[Na+].[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCOC(C)=O>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2]([NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:29])=[N:3][C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Reactant: S=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1nc(NC(=S)Nc2ccccc2)c(F)cn1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 8.4 %

Procedure:
To a suspension of 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (0.20 g, 0.74 mmol) in anhydrous tetrahydrofuran (THF; 3 mL) was added sodium hydride (NaH; 0.044 g of 60 wt % suspension in mineral oil, 1.11 mmol) at 0° C. After gas evolution had subsided, the mixture was transferred via cannula to an ice-cold mixture of phenyl isothiocyanate (1.0 g, 7.4 mmol) in anhydrous THF (5 mL) and stirred for 6 h. The reaction mixture was diluted with EtOAc (25 mL), and the resulting solution was washed with satd aq ammonium chloride (NH4Cl; 15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, filtered, and the solvent evaporated. The residue was purified by precipitation from methanol (MeOH) and Et2O to give (1-benzenesulfonyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-3-phenylthiourea as a light yellow solid (0.025 g, 8%): mp 205-208° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.26 (dd, J=3.7, 1.1 Hz, 1H), 10.87 (m, 1H), 8.65 (m, 1H), 8.10 (d, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 7.71 (m, 2H), 7.45 (m, 2H), 7.34 (m, 2H), 7.10 (m, 1H); ESIMS m/z 405 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(C#N)c(Oc2cccc(Cl)c2)c1
Temperature: 80 °C

Procedure:
To a solution of 2-fluoro-4-methylbenzonitrile (356mg, 3.96 mmol) and 3-chlorophenol (439 μL, 4.16 mmol) in 10 mL of DMSO was added Cs2CO3 (2.58 g, 7.92 mmol). The solution was heated at 80° C. for 4 h. The solution was diluted with EtOAc and was washed with Sat. NaHCO3 solution, water, and brine. The organics were dried (MgSO4), filtered, and concentrated in vacuo to give the title compound without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]=[O:19].[OH-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Product: OCn1ccc2c(OCc3ccccc3)cccc21

Procedure:
Compounds of Formula I also can be prepared as illustrated by exemplary reaction in Scheme 2. Reaction of 4-benzyloxy-indole with formaldehyde in the presence of a base such as NaOH produced 4-benzyloxy-1-hydroxymethyl-indole. The benzyl protecting group was removed by hydrogenation to give the 4-hydroxy-1-hydroxymethyl-indole. Reaction of 4-hydroxy-1-hydroxymethyl-indole with an aryl-aldehyde, such as 5-bromoveratraldehyde and malononitrile in the presence of a base, such as piperidine produced the substituted 7-hydroxymethyl-pyrrolo[2,3-h]chromene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)cc(F)c2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1cc(Br)cc2c1NC(=S)CC2

Procedure:
To a suspension of 6-bromo-8-fluoro-3,4-dihydroquinolin-2(1H)-one (157-3, 2.00 g, 8.19 mmol) in toluene (50 mL) was added Lawesson's reagent (1.66 g, 4.10 mmol). After reflux for 2 h, toluene was distilled off to yield the crude product, which was then purified by flash chromatography on silica gel to obtain title compound (yellow solid). 1H NMR (DMSO-D6, 500 MHz) 6=12.14 (s, 1H), 7.46 (dd, J=2.0 Hz, JHF=10.0 Hz, 1H), 7.34 (s, 1H), 2.94 (d, J=8.0 Hz, 2H), 2.84 (d, J=8.0 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:23](=[O:24])[CH2:22][C:21]([CH3:20])=[O:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: C=C1CC(=O)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)NCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 7 was dissolved in N,N-dimethylformamide (50 mL), and diketene (0.88 g) was added dropwise under ice-cooling. After raising to room temperature, the mixture was stirred for one hour. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-({4-[2-(acetoacetylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.4 g) as a colorless oil. This compound was used in the next step without particular purification. [4-(Trifluoromethoxy)phenyl]hydrazine hydrochloride (390 mg) was dissolved in ethanol (8 mL), pulverized sodium hydroxide (65 mg) was added at room temperature. The insoluble material was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was dissolved again in ethanol (8 mL), 2-({4-[2-(acetoacetylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (600 mg) obtained earlier was added at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (8 mL), diphosphorus pentasulfide (345 mg) and sodium carbonate (329 mg) were added, and the mixture was heated under reflux for 2 hr. The solvent was evaporated, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (690 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[H-].[Na+].[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16](Cl)=[N:15][CH:14]=1>O1CCOCC1>[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[N:15][CH:14]=1
Reactant: CCOC(=O)C=O
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A solution of ethyl glyoxalate (2.80 g) in dry dioxan (100 mL), cooled in ice, was treated with sodium hydride (60% dispersion in oil; 1.30 g) and the mixture was heated at 50° C. for 30 minutes and cooled in ice. A solution of 6-chloro-5-nitro-nicotinic acid methyl ester (5.25 g) [prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590-2594 (1951)] in dioxan (40 mL) was added and the solution was stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was evaporated to dryness, sodium bicarbonate solution was added to pH 7, and the mixture extracted with chloroform, dried (anhydrous sodium sulfate) and evaporated to afford a semi-solid that was chromatographed on silica gel [dichloromethane-hexane (1:1) then dichloromethane] to afford the product (4.70 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:16]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[N:15]=[CH:14][NH:13][CH:12]=2)=[O:18])[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCl (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]1.[C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=1)#[CH:27]>>[C:37]([O:36][C:35]([NH:34][C:30]1[CH:29]=[C:28]([C:26]#[C:27][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]2)[CH:33]=[CH:32][CH:31]=1)=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: C[Si](C)(C)CCOC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2Br)C1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2N2CCC(NC(=O)OCC[Si](C)(C)C)C2)c1
Yield: 91 %

Procedure:
The desired compound was prepared according to the procedure of Example A11, step C, using 2-(trimethylsilyl)ethyl [1-(2-bromo-4-nitrophenyl)pyrrolidin-3-yl]carbamate and tert-butyl (3-ethynylphenyl)carbamate as the starting materials in 91% yield. LCMS for C29H39N4O6Si (M+H)+: m/z=567.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(OCC)C>[CH3:20][S:21]([O:12][CH2:11][CH2:10][S:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: OCCSCC#Cc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCCSCC#Cc1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 1.28 g of 9c and 1.5 ml of triethyl amine in 10 ml of diethyl ether was treated at 0° C. with 0.78 g of methanesulphonyl chloride in 5 ml of diethyl ether. The reaction mixture was stirred for ½ h and then quenched by addition of 20 ml of water. The product was extracted into ethyl acetate and the combined extracts were washed once with 1M K2CO3 and once with water, dried and concentrated, to provide 1.7 g as essentially pure 9d and was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:17][N:18]([CH3:36])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)=[O:27])=[CH:21][CH:20]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:32]([C:31]5[CH:34]=[CH:35][C:28]([C:26]([NH:25][C:22]6[CH:23]=[CH:24][C:19]([N:18]([CH3:36])[CH3:17])=[CH:20][CH:21]=6)=[O:27])=[CH:29][CH:30]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:32]1[C:31]1[CH:30]=[CH:29][C:28]([C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([N:18]([CH3:17])[CH3:36])=[CH:20][CH:21]=2)=[O:27])=[CH:35][CH:34]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: CN(C)c1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Product: CN(C)c1ccc(NC(=O)c2ccc(-c3nc4cc(-c5ccc6nc(-c7ccc(C(=O)Nc8ccc(N(C)C)cc8)cc7)[nH]c6c5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 267 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-(4-dimethylaminophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C44H38N8O2: 711.31; found: 711.38.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([S:12]([F:14])([F:15])([F:16])([F:17])[F:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([N:20]([O:21][CH3:22])[CH3:19])=[O:9]
Reactant: Cc1cc(S(F)(F)(F)(F)F)c(N)cc1C(=O)O
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(N)c(S(F)(F)(F)(F)F)cc1C
Reaction time: 4 h

Procedure:
5-Amino-2-methyl-4-(pentafluorosulfanyl)benzoic acid (500 mg, WO 2005/47239) was dissolved in methylene chloride (30 ml) and admixed while stirring with N,O-dimethylhydroxylamine hydrochloride (176 mg), 1-propanephosphonic anhydride (1.1 ml) and triethylamine (0.25 ml). After stirring for 4 h and leaving to stand overnight, the reaction mixture was concentrated, the residue was taken up with ethyl acetate and the solution was washed twice with potassium hydrogen sulfate solution and twice with sodium hydrogencarbonate solution. After drying over magnesium sulfate, the organic phase was filtered and concentrated. The resulting crude product (500 mg) was converted further directly.
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:36]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[N:37]1>>[Cl:20][C:17]([F:19])([F:18])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[C:2]([C:38]3[NH:37][N:36]=[CH:40][CH:39]=3)[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1)([F:22])[F:21]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 31.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a white powder. HPLC (Condition 4) tR=4.89 min, UPLC-MS (Condition 3) tR=0.98 min, m/z=484.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.89 (m, 2H) 2.83-2.98 (m, 1H) 3.18-3.33 (m, 2H) 3.36-3.49 (m, 1H) 4.13-4.24 (m, 1H) 4.77-4.93 (m, 1H) 6.31-6.43 (m, 1H) 7.62 (d, J=8.59 Hz, 2H) 7.77-7.84 (m, 1H) 7.91-8.09 (m, 3H) 8.64-8.81 (m, 1H) 10.31 (s, 1H) 12.83-12.96 (m, 1H).