Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.CCOCC.O>[CH2:11]([O:18][C@@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCCCCC[C@@H](CO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCC[C@@H](C=O)OCc1ccccc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
CH2Cl2 (10 mL) and oxalyl chloride (1.72 mL, 20.3 mmol) were added to an oven-dried 2-neck round bottom flask containing a magnetic stir bar under Ar. The flask was immersed in a dry ice/acetone bath. A solution of DMSO (2.88 mL, 40.6 mmol) in CH2Cl2 (10 mL) was added to the stirred solution of oxalyl chloride slowly. 403 (5.4 g, 18.5 mmol) was dissolved in CH2Cl2 and added dropwise, over a period of 15 minutes, to the cold, stirred reaction mixture. After stirring for 2 hours, Et3N (12.9 mL, 18.46 mmol) was added to the reaction mixture, which was then allowed to warm to room temperature. The mixture was diluted with Et2O (˜300 mL) and water. The ether layer was washed with sat. aq. NaHCO3, 1M aq. HCl, and brine. The Et2O layer was then dried over MgSO4, filtered through paper, and concentrated by rotary evaporation. The crude product was purified by chromatography on silica (gradient elution from hexanes to 1:1 EtOAc/hexanes); fractions containing the desired product were pooled and concentrated affording 404 (3.58 g, 67%) as a clear, slightly viscous oil. 1H NMR (400 MHz, CDCl3): δ 9.66 (d, J=1.9 Hz, 1 H), 7.37-7.31 (m, 5H), 4.69 (d, J=11.7 Hz, 1H), 4.55 (d, J=11.7 Hz, 1H), 3.78-3.75 (m, 1 H), 1.68 (dd, J=14.3, 7.2 Hz, 2H), 1.49-1.35 (m, 2H), 1.25 (br s, 14H), 0.89 (t, J=6.7, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH:18]=[CH:17]2>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]2[CH2:29][CH2:28][N:27]([S:24]([C:19]3[CH:18]=[CH:17][C:16]4[C:21](=[CH:22][CH:23]=[C:14]([Cl:13])[CH:15]=4)[CH:20]=3)(=[O:26])=[O:25])[CH2:32][CH2:31]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: Cc1cc(Br)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-bromo-2-methylbenzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH3:12][C:13]1([CH3:45])[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]2[C:15](=[CH:16][C:17]([F:44])=[C:18]([C:31]#[C:32][C:33]3[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=3)[CH:19]=2)[S:14]1>C1COCC1.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:21]2[C:20]3[C:15](=[CH:16][C:17]([F:44])=[C:18]([C:31]#[C:32][C:33]4[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=4)[CH:19]=3)[S:14][C:13]([CH3:45])([CH3:12])[CH:22]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(C#Cc2cc3c(cc2F)SC(C)(C)C=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: Cc1cccs1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2F)SC(C)(C)C=C3c2ccc(C)s2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2-methylthiophene (130.0 mg, 1.30 mmol) in 2.0 mL of THF was cooled to -78° C. and n-butyllithium (83.3 mg, 1.30 mmol, 0.84 ml of a 1.6M solution in hexanes) was added and the solution warmed to 0° C. during 1.5 hours. A solution of ZnCl2 (341.0 mg, 2.50 mmol) in 3.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature, stirred for 40 minutes, and transferred via cannula to a solution of ethyl 4-[(2,2-dimethyl-4-trifluoromethanesulfonyloxy-7-fluoro-(2H)-thiochromen-6-yl)ethynyl]-benzoate (Compound 211, 158.0 mg, 0.31 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. Thei solution was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 70.0 mg (50%), was isolated by column chromatography (3% EtOAc/hexanes) as a waxy solid. 1H NMR (300 MHz, CDCl3) δ:8.01 (2H, d, J=8.3 Hz), 7.61 (1H, d, J=7.5 Hz), 7.58 (2H, d, J=8.3 Hz), 7.13 (1H, d, J=7.2 Hz), 6.82 (1H, d, J=4.4 Hz), 6.73 1H, d, J=4.4 Hz), 5.96 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.52 (3H, s), 1.46 (6H, s), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[B-](F)(F)F.[CH3:25][O+](C)C>C(Cl)Cl>[CH3:25][O:1][CH2:2][C:3]1([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C(NC1(CO)CCOCC1)OCc1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(NC(=O)OCc2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To benzyl 4-(hydroxymethyl)tetrahydro-2H-pyran-4-ylcarbamate (0.59 g, 2.23 mmol) in DCM (24 ml) was added protonsponge (0.53 g, 2.5 mmol) followed by trimethyloxoniumtetrafluoroborate (0.36 g, 2.5 mmol) at 0° C. After 20 min at 0° C., reaction mixture was warmed up to room temperature and stirred further for 16 h, at which time LC/MS confirmed full conversion of starting material to product. Reaction mixture was quenched with sat. NH1Cl and with DCM (75 ml). Organics were separated and washed with brine (20 ml) and dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (66%-100%) gave slightly impure desired benzyl 4-(methoxymethyl)tetrahydro-2H-pyran-4-ylcarbamate (0.31 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([Br:22])=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([Br:22])=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Product: O=C(Nc1nc(C(F)(F)F)c(Br)s1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-bromo-4-(trifluoromethyl)thiazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-bromo-4-(trifluoromethyl)thiazole: refer to J. Heterocycl. Chem., 1991, 28, 1017.)
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:35])[CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH:22]([CH3:35])[CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(O)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[N:15]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(CCOc3ccccc3)c2=O)cn1
Yield: 20 %

Procedure:
Prepared as in Example 10-65 from 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) and (2-bromoethoxy)benzene. Yield: 20%. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.40 (s, 3H), 3.15 (s, 3H), 3.99 (t, J=4.4 Hz, 2H), 4.13 (t, J=4.8 Hz, 2H), 5.20 (s, 2H), 6.80 (d, J=8 Hz, 2H), 6.90 (t, J=7.1 Hz, 1H), 7.22 (t, J=8 Hz, 2H), 7.75 (s, 1H), 8.17 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.031 μM.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.[O:23]1CCC[CH2:24]1>>[F:8][C:7]1[C:2]2[NH:1][C:24](=[O:23])[N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:3]=2[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: C1CCOC1
Reactant: Cc1cc(F)c(N)c(NC2CCN(C3CCOCC3)CC2)c1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Reaction time: 0.5 h

Procedure:
A mixture of (2-amino-3-fluoro-5-methylphenyl)[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amine (0.5 g), N,N′-carbonyldiimidazole (0.66 g) and tetrahydrofuran (7 ml) was heated to reflux. After 30 minutes, tetrahydrofuran (3 ml) was added, and the mixture heated at reflux for a further 1½ hours. The reaction mixture was filtered and washed with tetrahydrofuran (10 ml), then the solid was dried at 40-45° C. under high vacuum to give the title compound (0.323 g).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[C:15](#[N:18])CC>CN(C)C1C=CN=CC=1>[C:15]([C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1)#[N:18]
Reactant: CSc1nc(Cl)c(I)c(C(F)(F)F)n1
Reactant: CCC#N
Agent: CN(C)c1ccncc1
Product: CSc1nc(C#N)c(I)c(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
4-Chloro-5-iodo-2-methylthio-6-trifluoromethylpyrimidine (5.00 g) was dissolved in propionitrile (125 ml) and 4-(dimethylamino)-pyridine (1.81 g) was added at room temperature with stirring. After several minutes, precipitates appeared, however, it was stirred over night at room temperature. The slurry was cooled to ice bath temperature, and then added sodium cyanide (1.04 g) water (10 ml) solution. The mixture was warmed to room temperature and stirred 3 hr. The reaction mixture was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica get column chromatography (hexane-ethyl acetate) to give 4-cyano-5-iodo-2-methylthio-6-trifluoromiethylpyrimidine (2.56 g) as yellow solid, mp 68-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]C)=[O:12])[CH2:7][N:6]1[S:15]([CH3:18])(=[O:17])=[O:16])=[O:4].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][N:6]1[S:15]([CH3:18])(=[O:17])=[O:16])=[O:4]
Reactant: COC(=O)C1CCC(C(=O)OC)N(S(C)(=O)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1CCC(C(=O)O)CN1S(C)(=O)=O
Reaction time: 0.75 h
Yield: 38 %

Procedure:
To a solution of (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid dimethyl ester (46.5 g) in methanol (850 ml) and water (85 ml) was added 1 molar sodium hydroxide (166 ml) within 20 minutes at reflux temperature. The reaction mixture was stirred for 45 minutes at reflux, cooled and concentrated. The residue was taken up in water (300 ml) and washed with Et2O. The aqueous phase was acidified with 1 molar HCl (166 ml) and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was crystallized from acetone/Et2O to obtain (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid 2-methyl ester (16.8 g) as a colourless solid, mp 130–133° C., MS: 206 (M+-59).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=O)=O)=CC=1.[CH3:30][O:31][C:32](=[O:46])[CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40](O)[CH:41]=2)[CH:36]=1.[H-].[Na+].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.O>[CH3:30][O:31][C:32](=[O:46])[CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:10][CH2:11][C@H:12]([OH:21])[CH2:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:41]=2)[CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Reactant: COC(=O)COc1ccc2cc(O)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc2cc(OC[C@H](O)CCc3cccnc3)ccc2c1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Prepared according to the method described in example 26e) from (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (1.00 g), 6-Hydroxy-2-naphthyloxyacetic acid methyl ester, sodium hydride (60% dispersion in mineral oil, 0.11 g) in dimethylformamide (15 ml) with heating at 75° C. for 1 hour. The adduct was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride hydrate (1.5 g) was added. After 4 hours, the mixture was diluted with water and extracted with ether. The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:acetone (3:2 then 1:1) to give the sub-title compound as a solid (0.22 g).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[CH:24][N:23]=1.O>N1C=CC=CC=1>[S:1]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[CH:24][N:23]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CN(C)c1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc(/C=C/c3ccc(N(C)C)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
Tosyl chloride (52 mg, 0.27 mmol) was added to a solution of compound 9 (43 mg, 0.116 mmol) in pyridine (5.0 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then warmed up to room temperature and stirred for 3 h. Water was added and reaction mixture was extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over sodium sulfate and evaporated. The residue was purified by PTLC (4% MeOH in DCM as developing solvent) to give product 10 (25 mg, Yield: 41%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.0 Hz), 7.76 (3H, m), 7.39 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.0 Hz), 6.87 (2H, m), 6.75 (3H, m), 4.46 (2H, t, J=4.6 Hz), 4.16 (2H, t, J=4.8 Hz), 3.81 (2H, t, J=4.8 Hz), 3.66 (6H, m), 2.99 (6H, s), 2.43 (3H, s), HRMS (EI) m/z calcd. for [C28H34N2O6S]+ 526.2138.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@H:21]4[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:27][C@H:24]1[CH2:23][CH2:22][C@H:21]([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:28])[CH3:1])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:26][CH2:25]1)(=[O:33])=[O:32]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@H](O)CC4)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c3)ncnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TEA (73 μL, 0.52 mmol). The resulting solution was then cooled to 0° C. and methanesulfonyl chloride (34 μL, 0.45 mmol) was added. The reaction was held for 2 hours, at which point tlc and LCMS indicated complete reaction. The reaction was partitioned between water and DCM, the phases were separated and the aqueous phase was extracted with additional solvent. The combined organic phase was washed with water, then saturated NaCl, then was dried over MgSO4 and reduced in vacuo to give the crude product which was used without further purification (173 mg, 95%). NMR (400 MHz, CDCl3): δ 8.83 (s, 1H), 8.24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m, 1H), 3.54 (m, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=492.1 (M+H).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][N:13]=[C:14]=[S:15]>O1CCOCC1>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][NH:13][C:14]([NH:2][NH2:3])=[S:15]
Reactant: NN
Reactant: Fc1ccc(Br)c(CN=C=S)c1
Solvent: O
Solvent: C1COCCO1
Product: NNC(=S)NCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of hydrazine hydrate (80%, 2.22 g, 35.5 mmol) in 1,4-dioxane (20 mL) at 0° C. was added a solution of 1-bromo-4-fluoro-2-(isothiocyanatomethyl)benzene (13, 3.16 g, 12.8 mmol) in 1,4-dioxane (5 mL) The mixture was stirred at RT for 2 h. Ice cold water (100 mL) was added. The precipitated solid was collected by filtration, washed with water, and dried over P2O5 overnight to provide N-(2-bromo-5-fluorobenzyl)hydrazinecarbothioamide (14). MS: m/z, 278 (100%, M+1), 280 (100%), 300 (10%, M+23), 302 (10%).
Reaction SMILES: Cl.Cl.[C@H]1(CN2C[CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.NC1C=C[C:48]([CH2:51][CH2:52][OH:53])=[CH:47]C=1>>[OH:53][CH2:52][CH2:51][C:48]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[C:29]([O:32][CH2:33][C:34]2[C:38]4[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=4[O:36][CH:35]=2)[CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:18][CH:47]=1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Product: O=C(Nc1ccc(CCO)cc1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 42 from 4-(5-Chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97) and 2-(4-amino-phenyl)-ethanol.
Reaction SMILES: Cl.[NH2:2][C:3]([CH2:33][OH:34])([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:19]=2)=[CH:13][C:12]=1[Cl:32])[CH2:4][C:5](O)=[O:6].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C.ClCCl>[ClH:32].[NH2:2][C:3]([CH2:33][OH:34])([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:19]=2)=[CH:13][C:12]=1[Cl:32])[CH2:4][CH2:5][OH:6]
Reactant: NC(CO)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)CC(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC(CO)(CCO)CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Reaction time: 0.08 h

Procedure:
To a dichloromethane solution (8 mL) of the compound of Example 147 (569 mg), triethylamine (303 μL) was added and the mixture was stirred for 5 min. While the mixture was chilled in an ice bath, Boc2O (358 mg) was added and the mixture was stirred for 1 hour. 4N hydrochloric acid was added to adjust the pH of the mixture to 2 to 1. This was followed by the addition of ethyl acetate and a saturated aqueous solution of sodium chloride to separate the mixture into an organic phase and an aqueous phase. The organic layer was dried over anhydrous sodium sulfate, was concentrated, and was dried in a vacuum pump to give a yellow oil. This product was dissolved in DMF (8 mL). To this solution, potassium carbonate (451 mg) and methyl iodide (135 mL) were added and the mixture was stirred at room temperature for 2 hours. The mixture was then extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and was concentrated. The residue was purified on a silica gel column chromatography (hexane:ethyl acetate=3:1). While chilled in an ice bath, the resultant oil was dissolved in THF (10 mL). To this solution, lithium tetrahydroborate (40.4 mg) and ethanol (1.5 mL) were added and the mixture was stirred in an ice bath for 10 min and at room temperature for the subsequent 1 hour. Following addition of water, 4N hydrochloric acid was added to adjust the pH of the mixture to 2 to 1. Ethyl acetate and water were added to separate the mixture into an organic phase and an aqueous phase. The organic layer was dried over anhydrous sodium sulfate and was concentrated. The residue was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1). Methanol hydrochloride (4 mL) was added to the resultant oil and the mixture was left overnight at room temperature. Subsequently, the solvent was removed to give the desired product as a colorless amorphous (70.0 mg).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[NH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(Cl)CCl>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Indomethacin (500 mg, 1.40 mmol) was taken up in 10 mL of CH2Cl2 along with tert-butyl 2-aminoethylcarbamate (223 mg, 1.40 mmol) and EDC (295 mg, 1.54 mmol). The resulting reaction mixture was stirred at room temperature for 18 and diluted with CH2Cl2 (10 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 550 mg of tert-butyl 2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethylcarbamate (79% yield).