Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11](I)([F:13])[F:12]>CN(C)C=O.O.[Cu]>[F:10][C:11]([F:13])([F:12])[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(C(F)(F)F)c1

Procedure:
A solution of 5-iodo-m-xylene (2.3 g) in dimethylformamide (DMF)(30 ml) and copper bronze (0.65 g) in a stainless steel tube is cooled and treated with trifluoromethyliodide (15 g). The tube is sealed and heated at 130°-140° C. in a rocking autoclave for 6 hours. After cooling and venting, the reaction mixture is diluted with water and extracted with n-hexane (2×200 ml). The combined hexane extracts are washed with aqueous NaHCO3 and water. After drying over MgSO4, the solvent is removed under reduced pressure. The residue is subjected to chromatography over silica gel to yield purified 5-(trifluoromethyl)-m-xylene.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14]([N:16]1[CH2:20][CH:19]2[CH2:21][C:22](=[O:24])[CH2:23][CH:18]2[CH2:17]1)=[O:15])[CH3:12].[O:25]=[CH:26][CH2:27][S:28][C:29](=[S:33])[O:30][CH2:31][CH3:32].C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1.O.[Cl-].[Cl-].[Zn+2]>[CH2:11]([O:13][C:14]([N:16]1[CH2:17][CH:18]2[CH:23]([CH:26]([OH:25])[CH2:27][S:28][C:29]([O:30][CH2:31][CH3:32])=[S:33])[C:22](=[O:24])[CH2:21][CH:19]2[CH2:20]1)=[O:15])[CH3:12]
Reactant: CCOC(=S)SCC=O
Reactant: CCOC(=O)N1CC2CC(=O)CC2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC(=O)C(C(O)CSC(=S)OCC)C2C1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
A 1M solution of Lithium bis(trimethylsilyl)amide in THF (LHMDS) (6.08 ml, 6.08 mmol) was added to anhydrous THF (4 ml) and the mixture was cooled to −30° C. under N2. Next, a solution of 5-Oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester (1.0 g, 5.07 mmol) in THF (10 ml) was added dropwise over 15 minutes and the mixture was stirred for an additional 15 minutes. Next, a 0.5M solution of ZnCl2 (15.2 ml, 7.6 mmol) was added over 15 minutes and the reaction mixture was stirred for an additional 30 minutes. The reaction temperature was lowered to −70° C. and a solution of dithiocarbonic acid O-ethyl ester S-(2-oxo-ethyl) ester (913 mg, 5.57 mmol) in THF (1 ml) was added dropwise over 25-30 minutes. After 3 hours at −70° C., a solution of acetic acid (2.5 ml) in toluene (7.5 ml) was added and the reaction mixture was warmed to 0° C. The reaction mixture was diluted with H2O (7.5 ml) and the organic layer separated, dried (MgSO4), and concentrated providing oily brown residue that was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% ethyl acetate to 100% ethyl acetate) to give the subtitle product as an oil (756 mg, 41%).
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(N[C:26](=[O:38])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=5[F:37])C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[O:60]1[CH2:65][CH:64]=[C:63]([C:66]2[NH:83][C:69]3[N:70]=[CH:71][N:72]=[C:73]([C:74]4[C:75]([CH3:82])=[C:76]([NH2:81])[CH:77]=[C:78]([F:80])[CH:79]=4)[C:68]=3[CH:67]=2)[CH2:62][CH2:61]1>>[O:60]1[CH2:61][CH:62]=[C:63]([C:66]2[NH:83][C:69]3[N:70]=[CH:71][N:72]=[C:73]([C:74]4[C:75]([CH3:82])=[C:76]([NH:81][C:26](=[O:38])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=5[F:37])[CH:77]=[C:78]([F:80])[CH:79]=4)[C:68]=3[CH:67]=2)[CH2:64][CH2:65]1
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)O)cc2F)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Example 22 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])=[CH:5][CH:4]=1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20].O>C1(C)C=CC=CC=1>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][C:9](=[CH:10][S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:20]
Reactant: CCOC(CN)OCC
Reactant: COc1ccc(C(=O)CS(=O)(=O)C(F)(F)F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(CNC(=CS(=O)(=O)C(F)(F)F)c1ccc(OC)cc1)OCC

Procedure:
A solution of 4'-methoxy-2-[(trifluoromethyl)sulfonyl]acetophenone (6.0 g, 0.021 mol) in toluene is treated with aminoacetaldehyde diethyl acetal (2.8 g, 0.021 mol), heated at reflux overnight with removal of water, and concentrated in vacuo to obtain the title product as an oil. This oil is used in Example 4 without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](OC)[CH:13]=2)[NH:8][CH:7]=1.O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=1>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:32][C:27]([C:21]3[C:20]4[C:24](=[CH:25][CH:26]=[CH:18][CH:19]=4)[NH:23][CH:22]=3)=[CH:28][CH2:29]2)=[CH:7]1
Reactant: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: COc1ccc2[nH]cc(CCCCCl)c2c1
Product: C1=C(c2c[nH]c3ccccc23)CCN(CCCCc2c[nH]c3ccccc23)C1

Procedure:
of 3-(4-chlorobutyl)-5-methoxyindole with 4-(5-hydroxyindol-3-yl)-1,2,5,6-tetrahydropyridine:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.[CH:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20].O>O1CCCC1>[CH3:20][CH:19]([CH3:21])[CH2:18][C:17]([C:10]1[S:9][CH:13]=[CH:12][C:11]=1[C:14]([OH:16])=[O:15])=[O:22]
Reactant: CC(C)CC=O
Reactant: O=C(O)c1ccsc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium diisopropylamide (86 mmol) in tetrahydrofuran (30 ml) was added at 0° C. to a solution of thiophene-3-carboxylic acid (5 g) in tetrahydrofuran (50 ml). Isovaleraldehyde (4.6 ml) was added as a solution in tetrahydrofuran (30 ml) at 0° C. The reaction mixture was stirred at 25° C. for 3 hours and then water (100 ml) was added and the tetrahydrofuran was removed in vacuo. The aqueous residue obtained was extracted with ethyl acetate and the aqueous phase added to potassium permanganate (12.3 g) and warmed to 60° C. for 1.5 hours. The mixture was filtered, allowed to cool to ambient temperature, and then acidified with dilute hydrochloric acid. The acidic aqueous mixture was extracted with ethyl acetate and the organic extract dried and evaporated to give the sub-title compound as an oil (5.3 g).
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[C:3]2[CH:6]=[C:7]([C:9](O)=O)[CH:8]=[C:2]12.[CH3:12][O:13][C:14]1[C:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1.C([O-])(=O)/C=C/C([O-])=O>>[S:1]1[CH2:5][CH:4]=[C:3]2[CH:6]=[C:7]([CH2:9][N:26]3[CH2:27][CH2:28][N:23]([C:15]4[C:14]([O:13][CH3:12])=[CH:22][C:18]5[CH2:19][CH2:20][O:21][C:17]=5[CH:16]=4)[CH2:24][CH2:25]3)[CH:8]=[C:2]12
Reactant: O=C(O)C1=CC2=CCSC2=C1
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc2c(cc1N1CCN(CC3=CC4=CCSC4=C3)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from (cyclopenta[b]thien-5-yl)carboxylic acid (Preparation 8) and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 186°-190° C. (ethanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:5](O)[CH:4]=[C:3]1[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].C(O)=[O:16]>O>[CH3:1][C:2]1([CH3:14])[C:3]2([CH2:13][CH:12]([OH:16])[CH2:11][CH2:10][CH2:9]2)[CH:4]=[CH:5][CH2:6][CH2:7]1
Reactant: O=CO
Reactant: C=CCCCC1=CC(O)CCC1(C)C
Solvent: O
Product: CC1(C)CCC=CC12CCCC(O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enol (810 mg) obtained in Step 3 was added formic acid (60 mL), followed by stirring the reaction mixture at room temperature for 2 hours and then at 50° C. for 3 hours. After cooling down to room temperature and adding water, the reaction mixture was extracted with chloroform. The organic layer was washed with water, dried and concentrated. The residue was reduced in the same condition as in Step 3 to give 11,11-dimethyl-spiro[5.5]undec-7-en-2-ol (340 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH2:22]([O:29][CH2:30][CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(O)C>[CH2:22]([O:29][CH2:30][CH2:31][NH:32][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCCOCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCOCc3ccccc3)cc2c1=O
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A mixture of 318 mg (1 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 605 mg (4.0 mmol) of 2-benzyloxy-ethylamine and 3.2 ml of ethanol is heated at 120° C. in a closed vial in a microwave reactor for 10 minutes. After cooling to room temperature, 1M aqueous hydrochloric acid is added until a pH value of ˜3 is reached. The resulting mixture is extracted with ethyl acetate. The organic phase is separated, washed with water and brine, dried over magnesium sulfate and evaporated. Chromatography of the residue on silica with dichloro-methane-methanol (93:7) and crystallization from tetrahydrofuran-hexane gives 261 mg (58%) of the title compound as red crystals, m.p. 204° C. (decomp.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[OH:12].B1([O-])O[O:14]1.O.O.O.O.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[NH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2]([CH3:1])=[O:14])[C:4]=1[OH:12]
Reactant: CSc1cccc([N+](=O)[O-])c1O
Reactant: [O-]B1OO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1cccc(N)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of 2-methylthio-6-nitrophenol (410 mg, 2.21 mmol) in acetic acid (15 ml) was added sodium perborate tetrahydrate (1.00 g, 6.50 mmol) and the mixture was stirred at room temperature for 2 hours. To the reaction solution was then added zinc powder (7 g, 0.107 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with a saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; chloroform) to provide 234 mg (yield 62%) of 2-amino-6-methanesulfinylphenol as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=O>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1]/[C:11](/[CH3:13])=[CH:10]\[C:9]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccccc1N
Product: COC(=O)/C=C(/C)Nc1ccccc1C
Reaction time: 8 h

Procedure:
In a manner similar to that previously described, 96.4 grams (0.9 mole) of o-toluidine is added dropwise to a solution of 116 grams (1 mole) of methyl acetoacetate and the reaction mixture allowed to stand overnight to obtain methyl 3-(2-methylphenyl)aminocrotonate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[O:10][N:9]=1)(=[O:3])[CH3:2].N1[CH:33]=[CH:32][CH:31]=CC=1>ClCCl>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:1]([O:4][CH2:5][CH:32]([CH3:31])[CH3:33])=[O:3])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Reactant: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCOc1noc(N(C(=O)OCC(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2-{[5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-4-iodo-3-isoxazolyl]oxy}ethyl acetate (Preparation 4) (9.44 g) in dichloromethane was added pyridine (1.65 mL) followed by the slow addition of isobutylchloroforomate (2.41 mL) over 10 minutes. The reaction mixture was stirred at room temperature for one hour. The solvent was removed in vacuo to yield the crude material. This was purified using column chromatography (300 g silica, compound loaded with dichloromethane (15 mL) using a gradient elution of hexane (100% to 75%) and ethyl acetate (0% to 25%) to yield the desired compound as a yellow oil (7.70 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:7]=O)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1.Cl>C(O)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: Cl
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Br)cc32)cc(C(C)C)c1OCCN1CCOCC1
Reaction time: 12 h
Yield: 12.4 %

Procedure:
A mixture of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.4 g), 5-bromo-2-oxindole (0.27 g) and pyrrolidine (0.5 ml) in ethanol (2 ml) was held in a sealed tube at 100° C. for 12 hours. The mixture was then added to 1N hydrochloric acid (100 ml) and the solids removed by filtration and washed with more water (50 ml). The solids were then dissolved in ethyl acetate (200 ml), the solution washed with 1N hydrochloric acid (75 ml) and brine (75 ml), dried with magnesium sulfate and concentrated. The crude solid was chromatographed (silica, 4:4:1 dichloromethane: hexanes: methanol) to give 80 mg (13%) of 5-bromo-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a reddish-brown solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(N)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CC(=O)NNc1ccc(N=Cc2ccccc2)cc1
Temperature: 75 °C

Procedure:
1-Acetyl-2-(4-aminophenyl)hydrazine (8.25 g, 0.05 mole) and benzaldehyde (5.3 g, 0.05 mole) were mixed in ethanol (50 ml). The mixture was stirred thoroughly and was warmed to approximately 75° C for one-half hour. The addition product precipitated out of the reaction mixture. The mixture was chilled in ice and then filtered. The solid was washed with ether and dried. The product was a white cyrstalline powder. Yield 12.0 g (94%), m.p. 172°-174° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[OH:35]O>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:35])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(B4OC(C)(C)C(C)(C)O4)ccc(F)c32)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 4, 1.31 g, 2.8 mmol) is suspended in acetic acid (8 mL) and hydrogen peroxide solution (35% in water, 0.97 mL, 11.2 mmol) is added. The mixture is stirred for 1 hour then diluted with water and extracted with ethyl acetate. The organic extracts are washed with water and brine, dried over sodium sulfate and the solvent removed. The residue is dried under vacuum to give the title compound (Yield 0.95 g). LC (METHOD 6): tR=0.57 min; Mass spectrum (ES+): m/z=357 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:23][CH2:24][N:25]([S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[CH2:26][CH2:27]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCNCC4)ncc3O2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCN(c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)CC1

Procedure:
The title compound is prepared by treatment of 4-(5-piperazin-1-yl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester with isopropylsulfonyl chloride in dichloromethane in the presence of triethylamine. LC (method 10): tR=1.48 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18].O>ClCCl>[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18]
Reactant: COC(=O)c1sccc1N
Reactant: CCC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (0.68 g; 4.3 mmol) in pyridine (0.52 mL; 6.4 mmol) and anhydrous dichloromethane (15 mL), was added a solution of 51 (1.0 g; 4.3 mmol) in dichloromethane (3 mL). After stirring 16 hours at room temperature, the reaction was mixed with water (50 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×10 mL), and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes (0 to 25% v/v gradient elution) to yield the title product as a white solid (0.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:7][CH2:6]2.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:16])=[O:17])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1N)N(S(=O)(=O)c1ccc(C)cc1)CC2
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A yellow slurry of 5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-6-nitro-2,3-dihydro-1H-indole (16.1 g, 46 mmol) and NiCl2.6H2O (3.29 g, 13.9 mmol) in THF (150 mL) and MeOH (300 mL) was treated with NaBH4 (5.2 g, 139 mmol) in small portions. The resulting mixture was stirred for 1 h, concentrated onto Celite and purified by column chromatography using 0-10% MeOH (containing 0.2% NH3)/CH2Cl2to obtain 5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-amine as white solid (11.94 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H), 2.63 (t, J=8.15 Hz, 2H), 3.66 (s, 3H), 3.77 (t, J=8.06 Hz 2H), 4.79 (s, 2H), 6.58 (s, 1H), 6.94 (s, 1H), 7.34 (d, J=7.87 Hz, 2H), 7.62 (d, J=7.87 Hz, 2H); ESIMS (M+H)+=320.12.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]\[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]\[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccco2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(/C=C(/C(=O)O)c2ccco2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
Combine (E)-2-(fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester (112 mg, 0.19 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (5 mL). After 2 hours, evaporate in vacuo, add dichloromethane and evaporate in vacuo to give the title compound.
Reaction SMILES: CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:36]([OH:38])=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[C:39]1([CH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:56])[C@@H:50]([CH2:52][CH2:53][S:54][CH3:55])[NH2:51])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1.C(OCC)(=O)C>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:36]([NH:51][C@@H:50]([C:49]([NH:48][CH2:47][CH2:46][CH2:45][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:56])[CH2:52][CH2:53][S:54][CH3:55])=[O:38])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:27][CH:26]=1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CSCC[C@@H](N)C(=O)NCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
N-methylmorpholine (485 mg.), then a solution of pivalyl chloride (579 mg.) in tetrahydrofuran (5 ml.), were added to a solution of N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine in tetrahydrofuran (35 ml.) maintained at -20° C., and the mixture was stirred at that temperature for about 10 minutes. A solution of N-(3-phenylpropyl)-D-methioninamide (1.50 g.) and N-methylmorpholine (485 mg.) in tetrahydrofuran (60 ml.) was then added, and stirring was continued at -20° C. for two hours and then at room temperature overnight. Ethyl acetate (150 ml.) was added. The mixture was washed three times with saturated aqueous sodium bicarbonate, three times with aqueous citric acid (5%), twice with water and twice with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum. Crystallization of the residue from ethyl acetate-hexane afforded as a white solid [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N-(3-phenylpropyl)-D-methioninamide (680 mg.; m.r. 158°-159° C.; [α]D25 +55.4°, c=1 methanol).