Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH3:15])[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1C1CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 37% overall yield. FDMS m/e=380 (M+ of free base). α[D]589 =-14.83 (c=0.81, methanol).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12]>C(O)C>[OH:13][CH:10]([CH2:11][OH:12])[CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCC(O)CO
Solvent: CCO
Product: O=C1N=C(NCC(O)CO)CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (2.0 g) in ethanol (20 mL) was added 3-aminopropane-1,2-diol (1.00 g), and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration and washed with ethanol to give the title compound (1.56 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C@H:8]([CH:27]([CH3:29])[CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([OH:17])[C:13]([CH3:26])([CH3:25])[CH2:12]1)=[O:10])=[O:6].[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C@@:14]2([OH:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@H:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([C:35]([O:34][CH3:33])=[O:36])=[CH:38][CH:39]=4)[CH:32]=[CH:31][CH:30]=3)=[O:6])[CH:27]([CH3:29])[CH3:28])[CH2:12][C:13]2([CH3:26])[CH3:25])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)[C@@H](NC(=O)c1cccc(Br)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccc(C(=O)N[C@@H](C(=O)N3CC[C@](O)(c4ccc(Cl)cc4)C(C)(C)C3)C(C)C)c2)cc1
Temperature: 60 °C
Yield: 79.2 %

Procedure:
3-Bromo-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)benzamide (50 mg, 0.096 mmol), 4-(methoxycarbonyl)phenylboronic acid (17 mg, 0.096 mmol), 1.5M cesium carbonate (0.192 ml, 0.287 mmol) and palladium(II) acetate (1.08 mg, 4.79 μmol) were dissolved in DMF (3 mL) in a microwave tube at 25° C. then heated at 60° C. for 30 minutes. The reaction was diluted with EtOAc then washed with water (4×). The organic layer was dried (sodium sulfate) and concentrated in vacuo to give methyl 3′-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)biphenyl-4-carboxylate (44 mg, 0.076 mmol, 80% yield) as a white solid. MS found: (M+H)+=577.32.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17](Cl)=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37].C1COCC1>C(OCC)(=O)C>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([NH:37][CH3:36])=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: Cc1cc2c(cc1F)c(C(=O)Cl)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn2)n(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A mixture of (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid (300 mg, 0.58 mmol) in SOCl2 (4 mL) was stirred at 66° C. for 2 h. Volatiles were removed by a stream of nitrogen followed by vacuum to give (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride as a solid. The above prepared (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride (100 mg, 0.188 mmol) was treated with a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) and stirred at room temperature for 5 min. The mixture was then treated with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated to give (S)-1-cyclopentyl-5-fluoro-N,6-dimethyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxamide (66 mg, 67%). MS m/z 527.3 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.18 (1H, br s), 8.30 (1H, dd, J=8.0 Hz, J=2.0 Hz), 7.73 (1H, d, J=8.5 Hz), 7.66 (1H, d, J=10.5 Hz), 7.28 (1H, br s), 6.26 (1H, br s), 5.91 (1H, d, J=9.5 Hz), 4.51-4.40 (1H, m), 4.15-4.10 (1H, m), 2.84 (3H, s), 2.43 (3H, d, J=1.5 Hz), 2.30-2.23 (2H, m), 2.10-1.90 (4H, m), 1.68-1.62 (2H, m), 1.42 (3H, d, J=8.5 Hz).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.S(=O)(=O)(O)O.[CH3:18]O>>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:18])=[O:10])=[CH:1][CH:2]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(O)cc1

Procedure:
51.2 g (312 mmol) of p-coumaric acid were dissolved in 330 ml of methanol and treated with 10 ml of concentrated sulphuric acid. The solution was heated under reflux for 2 hours. Subsequently the majority of the methanol (about 200 ml) was distilled off and the residue remaining behind was poured into 1.3 l of ice-water. The separated ester was filtered off under suction and washed in succession with cold water, with a small amount of cold NaHCO3 solution and again with cold water. Drying at 50° C. in a water-jet vacuum gave 51.1 g of methyl 3-(4-hydroxyphenyl)-acrylate in the form of a light brownish coloured powder. ##STR14##
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:21]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CN(Cc1cscn1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)CN(Cc1cscn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.8 %

Procedure:
To a cooled (0° C.) solution of 4-{isobutyl-[(thiazol-4-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (540 mg, 1.53 mmol, 1 eq.) in anhydrous dichloromethane (3 ml), is added anisole (2.5 g, 23 mmol, 15 eq.) and trifluoroacetic acid (2.6 g, 23 mmol, 15 eq.). The reaction is allowed to warm to room temperature and stirred for 4-5 hours. The reaction mixture is loaded on a SCX-2 column. The column is first washed with methanol and then the base eluted with 20% 2N NH3 in methanol in dichloromethane. The solvents are removed in vacuo to afford isobutyl-(piperidin-4-yl)-[(thiazol-4-yl)methyl]-amine (387 mg). m/z=254 (M+1); 1H NMR (CDCl3): δ=8.27 (1H, d), 7.22-7.21 (1H, m), 3.86 (2H, d), 3.15 (2H, brd), 2.62-2.49 (3H, m), 2.30 (2H, d), 2.03 (1H, brs), 1.78 (2H, d), 1.66-1.59 (1H, m), 1.50-1.40 (2H, m), 0.86 (6H, d).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:9]2=[O:27])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][OH:37]>C(#N)C>[OH:37][CH2:36][CH2:35][N:5]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:9]2=[O:27])[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N(CCO)c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Temperature: 110 °C
Yield: 95.7 %

Procedure:
To a solution of benzyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.700 g, 1.802 mmol) in acetonitrile (20 ml), K2CO3 (0.498 g, 3.605 mmol) and 2-bromoethanol (0.509 ml, 7.21 mmol) were further added. The mixture was heated under MW irradiation at 110° C. for 2 hours. 2-Bromoethanol (0.272 ml, 3.734 mmol) and K2CO3 (0.268 g, 1.931 mmol) were added, and the reaction was heated under MW irradiation at 110° C. for additional 3 hours. The mixture was then diluted with acetonitrile, the insoluble inorganic salts were filtered off and the filtrate was evaporated to dryness. The crude was purified by trituration with Et2O affording benzyl 2-(5-(N-(2-hydroxyethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.746 g, 1.725 mmol, 96% yield, MS/ESI+ 432.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.C[Mg]Br.[F:20][C:21]([Si](C)(C)C)([F:23])[F:22].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:21]([F:23])([F:22])[F:20])([OH:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:5]2
Reactant: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Mg]Br
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1(O)C(F)(F)F

Procedure:
If 5-chloro-2-fluoro-2-methanesulfonylindan-1-one is, instead of methylmagnesium bromide, reacted with trifluoromethyltrimethylsilane and tetrabutylammonium fluoride in tetrahydrofuran, 5-chloro-2-fluoro-2-methyanesulfonyl-1-trifluoromethylindan-1-ol of molecular weight 332.7 (C11H9CIF4SO3); MS (ESI): 333.20 (MH+) is obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol (3.0 g, 13.8 mmol) in DCM (30 ml) was added Dess-Martin reagent (8.6 g, 20.6 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then washed with water and concentrated in vacuo. The crude residue was purified by flash chromatography (eluted with petroleum ether:EtOAc=100:1) to afford the title compound (1.6 g, 54%): 1H NMR (CDCl3, 400 MHz) delta 0.05 (s, 6H), 0.88 (s, 9H), 1.17 (s, 6H), 3.59 (s, 2H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:37][O:38][C:39](=[O:46])[C@@H:40]([CH2:42][CH2:43][S:44][CH3:45])[NH2:41]>C(Cl)Cl>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:18]([NH:41][C@@H:40]([C:39]([O:38][CH3:37])=[O:46])[CH2:42][CH2:43][S:44][CH3:45])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)[C@H](N)CCSC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
To Boc-tyrosine (16.9 g, 60 mmol) in 150 ml of methylene chloride (CH2Cl2) cooled to 0° C. under an argon (Ar) atmosphere were added 6.6 ml (60 mmol) of N-methylmorpholine (NMM). After cooling this vigorously stirred solution to -78° C., 7.9 ml (60 mmol) of isobutylchloroformate (IBCF) were added to this reaction. The mixture was allowed to warm to 20° C. before it was again cooled to -78° and another 7.9 ml (60 mmol) of NMM were added. (D)Methionine methyl ester hydrochloride (12.0 g, 60 mmol) was then added to the reaction in a single portion. The mixture was allowed to warm to room temperature and stir for an additional 18 hours (h). After filtering the reaction through diatomaceous earth, the filtrate was washed 3×100 ml 0.5N potassium bisulfate (KHSO4). The combined aqueous washed was extracted with CH2Cl2 (100 ml). The combined organic extracts were washed with 100 ml of brine, dried over sodium sulfate (Na2SO4) and stripped of all solvent under reduced pressure to produce the title product (25.1 g) as a light yellow glass. The material was used in subsequent reactions without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1ccc(OCCn2cncn2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(OCCn2cncn2)cc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
2-(4-nitrophenoxy) ethanol (3.0 g) was dissolved in THF (60 ml), triethylamine (2.74 ml) and methanesulfonyl chloride (1.4 ml) were added to the mixture, and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and a solution (15 ml) of the obtained residue in DMF was added dropwise to a solution (30 ml) of 1,2,4-triazole (1.0 g) and potassium carbonate (3.4 g) in DMF. The mixture was stirred for 16 hours at 90° C., and cooled to room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 1-[2-(4-nitrophenoxy)ethyl]-1,2,4-triazole (1.7 g). To 1-[2-(4-nitrophenoxy)ethyl]-1,2,4-triazole (1.6 g) was added 85% ethanol solution (48 ml), calcium chloride (0.38 g) and reduced iron (1.91 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[2-(1,2,4-triazol-1-yl)ethoxy]aniline (0.92 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:14][C:7]=2[C:6]=1[OH:22])=[O:4].[CH3:23]C1(C)CCCB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[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][O:2][C:3]([C:5]1[N:10]=[C:9]([CH3:23])[C:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:14][C:7]=2[C:6]=1[OH:22])=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(-c3ccc(F)cc3)csc2c1O
Reactant: CB1CCCC(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2c(-c3ccc(F)cc3)csc2c1O
Temperature: 100 °C
Yield: 56.8 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-3-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (77.9 mg, 0.204 mmol), example 32-a, trimethylboroxane (57.0 μL, 0.408 mmol), potassium carbonate (169 mg, 1.22 mmol), and tetrakis(triphenylphosphine)-palladium(0) (35.3 mg, 0.031 mmol) were suspended in 3.5 mL of anhydrous 1,4-dioxane. The reaction mixture was heated at 100° C. for 16 hours, cooled to room temperature, and diluted with ethyl acetate. The organic mixture was successively washed with water, saturated sodium bicarbonate, and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to produce 36.8 mg of a white solid. MS: (+) m/z 318.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][C@H:28]3[C@@H:32]([OH:33])[CH2:31][O:30][CH2:29]3)[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:27][C@H:28]3[C:32](=[O:33])[CH2:31][O:30][CH2:29]3)[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O[C@@H]3COC[C@@H]3O)CC2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O[C@@H]3COCC3=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3′-Fluoro-4′-{[4-(trans-4-{[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.39 g) was dissolved in acetonitrile (10 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.45 g) was added, and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 45%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH2:28][CH2:29][CH3:30])[C:7]=1[NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:31]>C(OCC)(=O)C.CO>[ClH:31].[ClH:31].[NH2:1][CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH2:28][CH2:29][CH3:30])[C:7]=1[NH2:8]
Reactant: CCCn1ncc(CN)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1ncc(CN)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-aminomethyl-1-propyl-5-tritylaminopyrazole (9.6 g) in a mixture of ethyl acetate (150 ml) and methanol (30 ml) was added 4N hydrochloric acid in ethyl acetate (24.2 ml), and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and dried in vacuo to give 4-aminomethyl-1-propyl-5-aminopyrazole dihydrochloride (3.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:18]=[C:19]=[S:20])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:19](=[S:20])[N:18]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1)[C:4]2=[O:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: S=C=NCC1CCCO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (8.0 g, 37.0 mmol), tetrahydrofurfuryl isothiocyanate (5.0 g, 34.9 mmol) and triethylamine (5.0 mL, 3.6 g, 35.6 mmol) in ethanol (48 mL) was heated at reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and filtered. The resulting filter cake was washed with 50 mL of cold ethanol, followed by 50 mL of hexanes to provide 10.8 g of the title compound of Step A as a solid melting at 230-232° C. 1H NMR (400 MHz, Me2SO-d6): δ 1.63-2.0 (m,4H), 3.58-3.68 (m,1H), 3.74-3.82 (m,1H), 4.32 (dd,1H), 4.39-4.50 (m,1H), 4.58 (dd,1H), 7.37 (d,1H), 7.91 (d,1H), 8.02 (s,1H), 13.1 (br s,1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]Cl)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:25]3[CH2:29][CH2:28][CH2:27][CH:26]3[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: c1cncc(C2CCCN2)c1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1[nH]c2ccc(OCCN3CCCC3c3cccnc3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
A mixture of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (Example 1, Step A, 0.400 g, 1.16 mmol), 3-pyrrolidin-2-yl-pyridine (0.345 mL, 2.33 mmol), K2CO2 (0.322 g, 2.33 mmol), and KI (0.019 g, 0.116 mmol) in 23 mL of acetonitrile was heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated to give a brown oil. The product was purified by flash column chromatography on silica gel (3% methanol:CH2Cl2) and triturated with diethyl ether/hexanes/CH2Cl2 to give 0.120 g (23.0%) of a light yellow solid: mp 126-127° C.; IR (KBr)3036, 2962, 2793, 1693, 1594, 1454, 1168, 1077 cm−1; 1HNMR (400 MHz, DMSO-d6) δ 1.40-1.52 (m, 1H, NCHCH2CH2CH2), 1.70-1.85 (m, 2H, NCHCH2CH2CH2 & NCHCH2CH2CH2), 2.10-2.18 (m, 1H, NCHCH2CH2CH2), 2.29-2.31 (m, 1H, NCHCH2CH2CH2),2.34-2.42 (m, 1H, NCHCH2CH2CH2), 2.46 (s, 3H, CCH3), 2.71 (t, J=6.35 Hz, 2H, OCH2CH2), 3.38-3.42 (m, 1H, NCHCH2CH2CH2), 3.82 (t, J=5.62 Hz, 2H, OCH2CH2), 5.26 (s, 2H, OCH2Ar), 6.64 (dd, J=8.79, 2.44 Hz, 1H, ArH), 7.17 (t, J=8.55 Hz, 1H, ArH), 7.28 (t, J=7.08 Hz, 3H, ArH), 7.35 (t, J=7.33 Hz, 2H, ArH), 7.46 (d, J=7.81 Hz, 2H, ArH), 7.73 (d, J=7.81 Hz, 1H, ArH), 8.39-8.40 (m, 1H, ArH), 8.51 (s, 1H, ArH), 11.70 (s, 1H, NH); MS(APCI+): m/z 456.2 (MH+). Anal. Calcd for C28H29N3O3: C, 73.79; H, 6.42; N, 9.22. Found: C, 73.42; H, 6.45; N, 9.11.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([O:11]C)=[O:10])[CH:5]=[CH:4][CH:3]=1.[OH-].[K+:20]>C1COCC1.CO>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[K+:20]
Reactant: COC(=O)C(c1cccc(Br)n1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])C(c1cccc(Br)n1)N1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of methyl (6-bromopyridin-2-yl)(morpholin-4-yl)acetate (1.98 g, 6.28 mmol) in THF (21 mL) and MeOH (7 mL) was added aqueous KOH (1.0 M, 6.91 mL, 6.91 mmol). The reaction was maintained at room temperature overnight and then concentrated to dryness to afford the title compound which was carried forward without purification.