Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccsc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccsc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 4-(3-methoxycarbonylthiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g, 13 mmol, 1.0 eq.) and Pd(OH)2/C (1.0 g, 1.4 mmol, 0.1 eq.) in MeOH (150 mL) was degassed and purged with hydrogen (3×). The mixture was hydrogenated (1 atm) at room temperature overnight, then the vessel was evacuated and purged with nitrogen, and the material was filtered and washed with MeOH (100 mL). The filtrate was concentrated then again allowed to hydrogenate at 1 atm at room temperature overnight. Filtering again as above, and concentrating the filtrate provided 4-(3-methoxycarbonylthiophen-2-yl)piperidine-1-carboxylic acid t-butyl ester (3.2 g) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(NCc3ccccc3)c2n1
Product: c1ccc(CNc2ncnc3c(N4CCSCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 118 from 8-benzylamino-2-chloro-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 94°-96° C.) and piperazine.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:19]=[CH:18][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])=[CH:24][CH:23]=1.[Br-].Cl>O.CN(C=O)C>[C:3]([C:7]1[CH:19]=[CH:18][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][N:14]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[C:29](=[O:38])[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:36]4=[O:37])=[CH:26][CH:27]=3)[C:13]2=[O:17])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CN2CCNC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(CBr)cc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(N4C(=O)c5ccccc5C4=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (approximately 60% strength suspension in oil, 140 mg, approximately 3.5 mmol) was added portionwise to a solution of 1-(4-tert-butylbenzyl)imidazolidin-2-one (C) (730 mg, 3.15 mmol) in abs. DMF (15 mL) under a blanket of argon within a period of 10 min. The reaction mixture was stirred for 60 min at RT and a solution of 2-(4-bromomethylphenyl)-isoindol-1,3-dione (B) (1 g, 3.16 mmol) in abs. DMF (20 mL) was then added within a period of 60 min. The reaction mixture was stirred at RT over a period of 3 h, then heated to 100° C. over a period of 1 h, cooled, and added to a mixture of ice water (300 mL) and 2N hydrochloric acid solution in H2O (20 mL). The resulting mixture was stirred for 30 min and then extracted with DCM (4×20 mL). The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo. Following purification, by column chromatography, of the residue (SiO2, cyclohexane/EtOAc 1:1), the desired product 2-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}isoindol-1,3-dione (E) was obtained as vitreous solid matter (680 mg, 46% of theory).
Reaction SMILES: [CH2:1]=[O:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH:16]3[CH2:18][CH2:17]3)[C:12](=[O:15])[NH:13][N:14]=2)=[CH:6][CH:5]=1>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH:16]3[CH2:18][CH2:17]3)[C:12](=[O:15])[N:13]([CH2:1][OH:2])[N:14]=2)=[CH:8][CH:9]=1
Reactant: C=O
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Solvent: O
Product: O=c1n(CO)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7 ml of a 37% strength solution of formaldehyde in water were added to 1000 mg (4.24 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A], and the mixture was stirred at RT for 20 h. The precipitated solid was filtered off with suction and washed with water. Drying under high vacuum gave 878 mg (62% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].Cl[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:24][C:23]1[C:18]([N:14]2[CH2:15][CH2:16][CH:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1Cl)C1CCNCC1
Reactant: Clc1cccnc1Cl
Product: O=S(=O)(c1ccccc1Cl)C1CCN(c2ncccc2Cl)CC1
Yield: 51.1 %

Procedure:
Using the procedure from Example 7A, 4-[(2-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 2,3-dichloropyridine (173 mg, 1.16 mmol) to afford the title compound (110 mg), a white solid, in 51% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:30]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:31])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
250 mg (0.74 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 143 mg (0.96 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to General Method 3. Yield: 276 mg (88% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([OH:22])=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[C:27]2[Cl:33].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:33][C:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([NH:23][C:20]([C:13]3[CH:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])[CH2:17][C:16](=[O:18])[NH:15][C:14]=3[CH3:19])=[O:22])[CH:25]=2)[NH:29][N:28]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.4 %

Procedure:
The product of Step 2 (200 mg, 0.63 mmol, 1.00 equiv), 5-amino-3-chloroindazole (106 mg, 0.63 mmol, 1.0 equiv), and EDC (145 mg, 0.757 mmol, 1.20 equiv) were suspended in 1.75 mL DMF. Et3N (0.106 mL, 0.757 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-80% CH3CN/H2O—NH4OH to pH 10 over 17 minutes, retention time 12.41 min) to provide 60 mg (20%) of the title compound as a white solid. MS (ES+) m/e 467 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:9]2[C:8]([CH3:10])=[CH:7][S:6][C:5]=2[S:4][C:3]=1[CH:11]=O.[CH3:13][N:14]1C2C(=CC=CC=2)C=C1C=O>>[CH3:1][C:2]1[C:9]2[C:8]([CH3:10])=[CH:7][S:6][C:5]=2[S:4][C:3]=1[CH2:11][NH:14][CH3:13]
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: Cc1csc2sc(C=O)c(C)c12
Product: CNCc1sc2scc(C)c2c1C
Yield: 53 %

Procedure:
According to the procedure of Preparation 24 (a), except substituting 3,4-dimethylthieno[2,3-b]thiophene-2-carboxaldehyde (0.5 g, 2.5 mmole) for the 1-methylindole-2-carboxaldehyde, the title compound (0.28 g, 53%) was prepared as a colorless oil: MS (ES) m/e 212 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OC)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:22]
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-phenyl-1,2-thiazino [5,6-b]-indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 9 from methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and aniline in toluene; M.p.: 269°-270° C. (decomposition);
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH2:13][CH:12]=1)C.[CH:15]([NH2:18])([CH3:17])[CH3:16]>CCOCC>[CH:15]([NH2:18])([CH3:17])[CH3:16].[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:14])=[O:3])[CH2:12][CH:13]=1
Reactant: CCOC(=O)CCCCCCC1=CC1
Solvent: CCOCC
Solvent: CC(C)N
Product: O=C(O)CCCCCCC1=CC1

Procedure:
A solution of 7-cycloprop-1-enyl-heptanoic acid ethyl ester in 5 ml of ether was treated with 0.1 g of isopropyl amine at room temperature. The solvent was stripped to give 40 mg of 7-cycloprop-1-enyl-heptanoic acid isopropylamine salt.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][C@H:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C@@H:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: C[C@H]1CO1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[C@H](O)Cn1ccc2cc(F)ccc21
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.95 g of 5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (S)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with 7 ml of water. The mixture was diluted with 180 ml of ether, washed twice with 90 ml of water each time and with 50 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 28 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 1.15 g (84%) of (S)-1-(5-fluoro-indol-1-yl)-propan-2-ol as a light brown oil.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[NH:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[C:17]([S:18](=[O:20])(=[O:21])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[NH:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(N)c1

Procedure:
The mixture of 1.5 g of 4-(3-acetamidophenoxy)-3-n-butylamino-5-sulfamoylbenzoic acid and 15 ml of2 N aqueous sodium hydroxide is refluxed for 5 hours under nitrogen. After cooling it is filtered, the filtrate acidified with glacial acetic acid and hydrochloric acid to a pH of 2-3, the precipitate collected and recrystallized from ethanol, to yield the 4-(3-aminophenoxy)-3-n-butylamino-5-sulfamoylbenzoic acid of the formula ##SPC16##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=2)[CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)[CH:16]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(O)cc3C)c2)cc1
Yield: 98.4 %

Procedure:
A solution of methyl 3-(4-{[2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propanoate (3.78 g, 8.21 mmol) and p-toluenesulfonic acid monohydrate (0.156 g, 0.821 mmol) in methanol (60 mL) was stirred at room temperature for 2 hrs. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (3.04 g, yield 98%) as a colorless viscous oil.
Reaction SMILES: [CH:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][C:9]([CH3:30])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+]>>[N:33]([CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:9]([O:8][C:7]2[CH:31]=[CH:32][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)([CH3:30])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1)=[N+:34]=[N-:35]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(C(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(C(C)C)cc1
Yield: 98.8 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)-3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methylpropionate (0.64 g), which is the product of Reference example 9(e), and sodium azide (0.27 g) and the reaction mixture was treated to afford the desired compound (0.56 g) as a syrup.
Reaction SMILES: [CH:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)[OH:5])([CH3:3])[CH3:2]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[F:18][C:13]([F:19])([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([CH:1]([CH3:2])[CH3:3])=[O:5])=[CH:7][CH:8]=1)[C:14]([F:15])([F:17])[F:16]
Reactant: CC(C)C(O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CC(C)C(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1

Procedure:
The preparation of pentafluoroethoxy-substituted phenyl alkyl ketones is accomplished following the procedure of Belous et al., J. Org. Chem. (U.S.S.R.) 7, 1521 (1971). According to that procedure, p-bromophenol is allowed to react with trifluoroacetic anhydride in the presence of sulfur tetrafluoride and hydrogen fluoride, to yield pentafluoroethoxy-4-bromobenzene. This compound is allowed to react with isobutyraldehyde in the presence of n-butyllithium to yield the intermediate alcohol, isopropyl p-(pentafluoroethoxy)phenyl carbinol. This alcohol is oxidizied with chromium trioxide in the presence of aqueous acetic acid to yield the ketone, isopropyl p-(pentafluoroethoxy)phenyl ketone.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>C1COCC1>[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[N:10]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COc1cncc(Cl)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A flame-dried round bottom flask was charged with a suspension of 95% NaH (1.1 eq) in anhydrous THF (0.3 M). The stirring mixture was cooled to 0° C. in an ice-water bath and 2-methyl-1-propanol (1 eq) was added drop wise via syringe. After 30 min 2,6-dichloropyrazine (1 eq) was added, the reaction was warmed to rt and stirred for 3 h. The crude mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed once each with H2O and brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was dissolved in CH2Cl2, loaded onto a SiO2 column, and purified by flash chromatography (9:1 hexanes/EtOAc eluent) to give 2-chloro-6-isobutoxypyrazine. LC/MS (m/z): 187.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.IC.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH3:21])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(Cl)c21
Reaction time: 10 h
Yield: 31.4 %

Procedure:
To a mixture of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (150 mg, 0.55 mmol) and iodomethane (254 mg, 2.22 mL) in anhydrous DMF (2 mL) was added anhydrous K2CO3 (380 mg, 2.75 mmol). The reaction mixture was stirred for 10 h and concentrated under reduced pressure. The residue was purified by prep HPLC to give the title compound as a yellow oil (49.1 mg. Yield: 31%). 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.22-7.23 (d, J=4.0 Hz, 1H), 7.14-7.15 (d, J=4.0 Hz, 1H), 5.45-5.48 (m, 1H), 4.03-4.09 (m, 2H), 3.81 (s, 3H), 3.21-3.25 (m, 1H), 2.39-2.45 (m, 1H), 1.14-1.17 (m, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>C(O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(OCCOC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(OCCOc2ccc(C(=O)O)cc2)CC1

Procedure:
A solution of 21-5 (1.6 g, 4.1 mmol), ethanol (41 mL), and 1N NaOH (21 mL) was stirred at ambient temperature for 20 hours. The reaction was then concentrated and the residue dissolved in H2O and then washed with ether. The aqueous phase was acidified with 5% KHSO4 and then extracted with EtOAc. The EtOAc portion was washed with 5% KHSO4 and brine, dried (MgSO4), and concentrated to furnish 21-6 as a white solid. TLC Rf =0.68 (silica, acetone);
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[N:11]1([C:17]([S:19][CH3:20])=[S:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:14]1[CH2:15][CH2:16][N:11]([C:17]([S:19][CH3:20])=[S:18])[CH2:12][CH2:13]1
Reactant: CSC(=S)N1CCNCC1
Reactant: CSc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2SC)CC1
Yield: 30.9 %

Procedure:
In 20 ml of ethanol, 2.1 g (12.2 mmol.) of 2-methylthiobenzyl chloride, 2.17 g (12.3 mmol.) of methyl 1-piperazinecarbodithioate and 1.30 g (12.3 mmol.) of sodium carbonate were refluxed under heating for 2 hours. Ethanol was distilled off under reduced pressure. The residue was extracted with ether, after addition of water. The ether portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over silica gel column, to give 1.18 g of the desired compound as a yellow oil, yield 31%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[C:8]([O:47][CH3:48])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:46])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:45])[CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl.C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:49][S:50]([CH3:53])(=[O:51])=[O:52])[C:8]([O:47][CH3:48])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:46])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:45])[CH2:31][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)CN5CCN(C(=O)OC(C)(C)C)CC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)CN5CCNCC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
160 mg tert-butyl 4-(2-{4-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazin-1-yl}-2-oxo-ethyl)-piperazine-1-carboxylate are dissolved in 5 ml dichloromethane, combined with 1 ml of a 5 M solution of hydrogen chloride in isopropanol and stirred for 12 hours at ambient temperature. Then the solvents are eliminated in vacuo and the residue is divided between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and then dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on aluminium oxide (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[C:8](N1C=CN=C1)([N:10]1[CH:14]=[CH:13]N=C1)=[S:9].COC(OC)CN>C1(C)C=CC=CC=1>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][N:1]1[CH:13]=[CH:14][NH:10][C:8]1=[S:9]
Reactant: NCc1cccs1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: COC(CN)OC
Solvent: Cc1ccccc1
Product: S=c1[nH]ccn1Cc1cccs1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Under a blanket of nitrogen, 11.3 g (0.1 mol) 2-aminomethylthiophene is added to 19.6 g (0.11 mol) 1,1'-thiocarbonyldiimidazole in 200 ml anhydrous toluene at 0° C. the reaction is held at 0° C. for 4 hours. Then 10.5 g (0.1 mol) aminoacetaldehyde dimethyl acetal is added and the reaction is warmed at 80° C. for 2 hours. The toluene is removed and the residue dissolved in 100 ml ethanol, 15 ml water and 15 ml concentrated HCl. The mixture is refluxed 5 hours, cooled and poured into 1L ice. After recrystallization (1/1 EtOH/H2O) the desired product is obtained as white shiny crystals, mp 128°-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=[O:2].O.NN>O1CCCC1.[Rh]>[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([NH:1][OH:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Agent: [Rh]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: ONc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 99.5 %

Procedure:
To a mixture of 4-nitrobiphenyl (400 mg, 2.008 mmol) and 5% rhodium on carbon (15 mg, 0.146 mmol) in tetrahydrofuran (15 ml), hydrazine hydrate (0.200 ml, 2.61 mmol) was added, and gas evolution was observed. The reaction mixture was stirred at RT for 25 minutes, then it was partitioned between diethyl ether (90 ml) and brine (20 ml), and the phases were separated. The aqueous phase was extracted with diethyl ether (90 ml), and the combined organic extracts were dried (Na2SO4) and concentrated to give 370 mg of the desired compound (89% purity) and about. The mixture was used as such for the next step.