Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:20]([OH:32])[C@@H:19]([CH2:33][OH:34])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].N1C=CN=C1>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C@@H:20]([OH:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of 5.05 (8.90 g, 18 mmol) in DMF (60 mL) was treated with tert-butyldimethylsilyl chloride (6.8 g, 45.2 mmol) and imidazole (3.1 g, 45.2 mmol). After stirring for 8 h, the reaction was concentrated in vacuo. The residue was redissolved in CH2Cl2 then washed with H2O. The organic layer was dried over Na2SO4, decanted, and concentrated in vacuo. The residue was purified by silica gel chromatography (10% EtOAc/petroleum ether) to afford the title compound (10.5 g, 17.4 mmol, 96%). 1H NMR (600 MHz, CDCl3): δ ppm 7.38 (d, J=7.0 Hz, 2H, PhH), 7.33 (t, J=7.6 Hz, 2H, PhH), 7.30-7.26 (m, 3H, PhH, PMPH), 6.85 (d, J=8.2 Hz, 2H, PMPH), 4.92, 4.73 (ABq, J=11.1 Hz, 1H each, OCH2Ph), 4.68, 4.64 (ABq, J=11.4 Hz, 1H each, OCH2PMP), 4.34 (d, J=7.9 Hz, 1H, H-1), 4.04-3.98 (m, 1H, OCHHCH2SiMe3), 3.94 (br s, 1H, H-4), 3.89 (dd, J=10.3, 6.2 Hz, 1H, H-6), 3.82 (dd, J=10.4, 5.7 Hz, 1H, H-6), 3.80 (s, 3H, OMe), 3.64-3.54 (m, 2H, H-2, OCHHCH2SiMe3), 3.45 (dd, J=9.4, 3.2 Hz, 1H, H-3), 3.38 (t, J=6.0 Hz, 1H, H-5), 2.50 (br s, 1H, OH), 1.03 (t, J=8.5 Hz, 2H, OCH2CH2SiMe3), 0.90 (s, 9H, SiCMe3), 0.082, 0.078 (s, 3H each, SiMe2), 0.02 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 159.41, 138.99, 130.26, 129.56, 128.35, 128.14, 127.62, 113.93, 103.33, 80.55, 79.34, 75.23, 74.56, 72.18, 67.24, 66.75, 62.50, 55.33, 25.97, 18.59, 18.41, −1.32, −5.23, −5.28; HRMS calcd for C32H56NO7Si2 [M+NH4]+: 622.3595. found 622.3580.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1csc(N)n1
Agent: Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(NC(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate hydrobromide (80 g), pyridine (52.5 g) and dichloromethane (800 ml) was added acetyl chloride (27.3 g) dropwise at 0° C., and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with water (500 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with ethyl acetate to give ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate (60 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][OH:24])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:6])([F:25])[F:26])[CH:9]=1)(=[O:15])=[O:16])(=[O:4])=[O:3]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCCCC1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
Methanesulfonyl chloride (1 eq), dissolved in methylene chloride (2 ml/mmol) was added dropwise to a cooled solution (0° C.) of (1-(3-(trifluoromethyl)phenyl-sulfonyl)piperidin-2-yl)methanol (1.1 eq) in methylene chloride (4 ml/mmol) and triethylamine (2.5 eq). When the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature until, according to thin layer chromatography control, the reaction was complete. Hydrogen chloride solution (0.5 mol/l, 2 ml/mmol) was added, the mixture was stirred for 15 min, the phases were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. Yield: 43%
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Cl)[N:7]=1.[CH3:14][O-:15].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:15][CH3:14])[N:7]=1
Reactant: CN(C)CCNc1cccc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(NCCN(C)C)n1
Yield: 80.9 %

Procedure:
A solution of 2-(2-dimethylaminoethylamino)-6-chloropyridine (10.0 g, 0.05 mole) in dimethylformamide (50 ml) containing sodium methoxide (3.5 gm, 0.065 mole) is heated at 110°-120° for two hours. The solution is cooled and the sodium chloride filtered. After removing the solvent in vacuo, the residue is dissolved in dilute hydrochloric acid (10%), washed with methylene chloride, made alkaline with sodium carbonate and the product is extracted into methylene chloride. After drying this solution over anhydrous sodium sulfate and filtering through charcoal, the solvent is removed under vacuum to give the oily product (7.9 g). This is used without further purification in the succeeding step.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.CCOCC>[CH3:27][O:26][C:24](=[O:25])[NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][CH:14]=[C:13]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)Cl
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC1(c2c[nH]c3c(NC(=O)OC)cccc23)CCc2cc(F)ccc21
Yield: 35.8 %

Procedure:
Dissolve 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine (0.35 g, 1.19 mmol) in pyridine (3 ml). Add methyl chloroformate (0.10 ml, 1.31 mmol, 1.1 equivalents) and stir at room temperature under nitrogen overnight. Dilute with ether, wash with 1N aqueous hydrochloric acid (2×), dry over anhydrous sodium sulfate, filter, and concentrate solution in vacuo. Purify the residue on silica eluting with 0 to 75% ethyl acetate/hexanes over 30 minutes to provide the title compound as a white solid (0.15 g, 36%). LC-MS m/z 353.1 (M++1).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1N.C(OCC)C.[ClH:20]>O.[Cu]Cl>[Cl:20][C:7]1[C:6]([Cl:5])=[C:11]([CH3:12])[CH:10]=[CH:9][C:8]=1[F:13]
Reactant: Cl
Reactant: Cc1ccc(F)c(N)c1Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(F)c(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Sodium nitrite (0.172 g, 2.5 mmol) was added to a stirred solution of 2-chloro-6-fluoro-3-methyl-phenylamine (0.400 g, 2.5 mmol) in water (20 ml) and 37% aqueous hydrogen chloride (5 ml) at −5° C. The mixture was stirred at −5° C. for 5 minutes and then added in one pot to a solution of copper (I) chloride (0.742 g, 7.5 mmol) in 37% aqueous hydrogen chloride (5 ml) whilst maintaining the temperature at −5 to 0° C. The reaction mixture was heated to 38° C. and stirred for 1 hr then the mixture was cooled and diethyl ether (20 ml) was added. The organic phase was separated and washed with 1N aqueous hydrogen chloride and then with water. The organic layer was then dried over sodium sulphate and concentrated in vacuo. The crude residue was purified by flash silica column chromatography, eluting with petroleum ether, to give 2,3-dichloro-1-fluoro-4-methylbenzene (0.090 g, 0.5 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH2:12][CH2:13][CH2:14][OH:15])[CH3:11])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)[CH3:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH3:11])[CH2:12][CH2:13][CH2:14][O:15][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[C@H:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:32])[CH2:23][CH2:24]3)[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN(CCCO)c1nc(Cl)c(C#N)cc1F
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)c(C#N)cc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 2-chloro-5-fluoro-6-[(3-ydroxypropyl)(methyl)amino]nicotinonitrile (Example 311) (0.50 g, 2.05 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.25 9, 1.14 mmol) in THF (9 mL) were added PPh3 (0.54 g, 2.05 mmol) and ADDP (0.52 g, 2.05 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.41 g, 81%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.29 (d, 1H), 7.04 (d, 1H), 6.73 (d, 1H), 6.66 (dd, 1H), 4.16 (q, 2H), 3.99 (t, 2H), 3.82 (t, 2H), 3.51 (qt, 1H), 3.25 (d, 3H), 2.95-2.78 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.12 (qt, 2H), 1.82-1.72 (m, 1H), 1.29 (t, 3H).
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[N:32]([CH3:1])[CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: C1CN2CCN1CC2
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 70 °C
Yield: 17.4 %

Procedure:
DABCO (111 mg) was added to a solution of 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E13) (100 mg) in dimethyl carbonate (3 mL) and DMF (2 mL). The resulting mixture was heated at reflux for 5 days. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in THF (3 mL) and water (3 mL). Sodium hydroxide (40 mg) was added to the mixture. The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitate was purified by Mass Directed Auto Prep to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E14) (18 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.60 (2H, t), 2.96 (2H, t), 3.62 (3H, s), 5.44 (1H, m), 7.17 (1H, t), 7.19 (1H, s), 7.43 (1H, d), 7.80 (1H, d), 8.57 (1H, d), 8.95 (1H, d), 12.10 (1H, br s). MS (ES): C22H21ClN4O4 requires 440; found 441.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23]C(=O)OCC=C)[CH:22]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:30])=[C:21]([CH:22]=2)[NH2:23])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a solution of 2-propen-1-yl {5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (35 g, 78.4 mmol) in DCM (400 mL), HOAc (11.3 g, 188 mmol), Pd(PPh3)2Cl2 (1.1 g, 1.57 mmol) were added. Then tri-n-butyl tin hydride (34.2 g, 117 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by added the saturated NaHCO3 (400 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (500 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (200 mL) to afford the title compound (18.3 g, 64.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=5.5 Hz, 1H), 6.96-7.03 (m, 3H), 6.78-6.83 (m, 1H), 2.30-2.60 (br, 2H), 1.48 (s, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].O>CCCCCC>[Cl:12][CH2:11][CH2:10][CH2:9][N:4]1[N:5]=[CH:6][CH:7]=[N:3]1.[Cl:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: ClCCCBr
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: ClCCCn1ccnn1
Product: ClCCCn1nccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.38 %
Yield: 24.15 %

Procedure:
A suspension of sodium hydride (1.55 g, 30.8301 mmol, 60% in oil) in hexane was allowed to stand, and after removing the supernatant, dimethylformamide (25 ml) was added thereto to forma suspension and 1H-1,2,3-triazole (1.5 ml, 25.8867 mmol) was added dropwise while cooling on ice. This was stirred at room temperature for 5 minutes to thorough dissolution, and then 1-bromo-3-chloropropane (2.82 ml, 28.4754 mmol) was added and the mixture was stirred at room temperature for 8 hours. After adding water while cooling on ice, the mixture was extracted with diethyl ether and then with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the isomers were separated by NH silica gel column chromatography (hexane-ethyl acetate) and purified to obtain low polarity 2-(3-chloropropyl)-1,2,3-triazole (0.429 g, 2.9466 mmol, 11.38%) and high polarity 1-(3-chloropropyl)-1,2,3-triazole (0.910 g, 6.2504 mmol, 24.15%) as colorless oils.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH:11]1([N:17]=[C:18]=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:20]I>CN(C=O)C.O>[CH:11]1([NH:17][C:18]([S:19][CH3:20])=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CC#N
Reactant: S=C=NC1CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)=C(NC1CCCCC1)SC
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of ethyl cyanoacetate (2.07 g, 18.3 mmol) in DMF (40 ml) was added under ice-cooling sodium hydride (0.77 g, 19.2 mmol). After stirring for one hour, cyclohexyl isothiocyanate (2.59 g, 18.3 mmol) was added dropwise. After stirring under ice-cooling for 1.5 hours, methyl iodide (2.60 g, 18.3 mmol) was added dropwise. After stirring at room temperature for 15 hours, water (400 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (100 ml×2). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a yellow oily substance (4.76 g) from the fraction from hexane-ethyl acetate (4/1). Yield=97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.NC(N)=[S:13].[OH-].[Na+].Cl[CH2:18][C:19]([OH:21])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][CH2:18][C:19]([OH:21])=[S:13]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: NC(N)=S
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(=S)CCc1ccc(Cl)c(Cl)c1
Yield: 83 %

Procedure:
A mixture of 19.5 (0.1 mol) of 3,4-dichlorobenzyl chloride and 7.6 g (0.1 mol) of thiourea in 50 ml of water is heated under reflux for 30 minutes, with stirring, and then, at 60°-70° C., a solution of 16 g (0.4 mol) of NaOH in 25 ml of water is run in; the mixture is heated under reflux for 15 minutes and a solution of 15 g (0.15 mol) of chloroacetic acid, 7 g of sodium carbonate and 50 ml of water are run in at 60°-70° C., and the reaction mixture is maintained under reflux for 1 hour. The mixture is acidified, whilst cold, with concentrated HCl, and is extracted with ether, and the ether extract washed with water, dried and evaporated. The residue is taken up in petroleum ether and the product filtered off. 21 g (yield 83%) of the stated product are obtained. Melting point 63°-64° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([N:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH3:29].C(OC(C)C)(C)C.C(O)C>C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[O:32])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCN(CCC)C1CCc2cccc(OCCNC(=O)N(CC)CC)c2C1
Reaction time: 2 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially introduced into 20 ml of toluene. 0.77 g (5.5 mmol) of diethylcarbamoyl chloride was then added dropwise, and the mixture was stirred for 2 h at +100° C. The mixture was then filtered and evaporated. The product was obtained by chromatography over silica gel 60, 40-63 μm, using diisopropyl ether/ethanol, 3:2.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:17]([CH:30]=[CH2:31])[CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.CCOCC>[NH2:19][CH2:18][C@H:17]([N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:30]=[CH2:31]
Reactant: C=C[C@H](CN1C(=O)c2ccccc2C1=O)N(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: C=C[C@H](CN)N(OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
A solution of (R)-tert-butyl benzyloxy(1-(1,3-dioxoisoindolin-2-yl)but-3-en-2-yl)carbamate (Intermediate 155, 80 g, 189.36 mmol) and hydrazine hydrate (47.4 g, 946.86 mmol) in MeOH (800 mL) was stirred at rt overnight. The mixture was diluted with ether and filtered. The filtrate was evaporated and the residue was purified by silica gel column and eluted with MeOH/DCM (0-10%) to give the title compound (44.3 g, 80%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)OCC(O)=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36](CN)[OH:37].F[P-](F)(F)(F)(F)F.N1([O:56][C:57](N(C)C)=[N+:58]([CH3:60])[CH3:59])C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:30]1([C:13]2[N:14]([S:16]([C:19]3[CH:29]=[CH:28][CH:27]=[C:21]([O:37][CH2:36][C:57]([N:58]([CH3:60])[CH3:59])=[O:56])[CH:20]=3)(=[O:17])=[O:18])[CH:15]=[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:12]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: NCCO
Reactant: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)O)c2)c1)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2C2=CCCCC2)c1
Reaction time: 1 h

Procedure:
2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(cyclohex-1-en-1-yl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid 8b (69 mg, 0.14 mmol) was dissolved in 15 mL of N, N-dimethylformamide, followed by addition of ethanolamine (16.7 mg, 0.27 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (104 mg, 0.27 mmol) and N,N-diisopropylethylamine (53 mg, 0.41 mmol), and then the reaction solution was stirred for 1 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system C to obtain the title product tert-butyl ((5-(cyclohex-1-en-1-yl)-1-((3-(2-(dimethylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 8c (55 mg, a colorless oily product) in 76% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]#[CH:26])[CH:24]=1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]#[C:26][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=2)[CH:24]=1
Reactant: COc1cc(I)ccc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
Dissolve 1-fluoro-4-iodo-2-methoxybenzene, (prepared as described in PREPARATION 47), (480 mg, 1.9 mmol) in triethylamine (7 mL, 53 mmol) and add 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.8 mmol) followed by bis(triphenylphosphine)palladium (II) dichloride (51 mg, 0.07 mmol) and copper (I) iodide (28 mg, 0.15 mmol). Stir for 18 h at room temperature, concentrate, and purify by silica gel chromatography, eluting with 3:1 hexanes:ethyl acetate. Further purify on silica gel, eluting with 100% dichloromethane, to give the title compound as a white solid (450 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl([O-])(=O)=O.[K+].[I-:20].[K+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([I:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [O-][Cl+2]([O-])[O-]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ccc(Cl)cc2)cc1I
Temperature: 80 °C
Yield: 89208.8 %

Procedure:
To a solution of 4′-chlorobiphenyl-4-ylamine (2.03 g, 0.01 mmol) in a mixed solvent system of methanol (10 ml) and distilled water (40 ml) is added potassium chlorate (0.830 g, 6.77 mmol) and potassium iodide (3.32 g, 0.02 mol). After heating the reaction mixture to 80° C., concentrated hydrochloric acid (0.60 ml) is added, and the mixture is further heated overnight at this temperature. The solution is cooled to room temperature and the crude product is extracted with diethyl ether (×3), followed by washing of the combined organic fractions with 5% aqueous sodium thiosulfate solution and distilled water. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give a dark solid, which is triturated with hexanes to afford 4′-chloro-3-iodobiphenyl-4-ylamine (2.94 g) as light brown solid.