Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:4]1[CH:5]=[C:6]([C:17](O)=[O:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:9]=1)[CH3:2].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32]>>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:17]([C:6]1[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:5]=1)=[O:18])[CH3:32]
Reactant: CCN(C(=O)C(C)C)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: CC(N)c1cnccn1
Product: CCN(C(=O)C(C)C)c1cc(C(=O)NC(C)c2cnccn2)cc(-c2ccc(C)cc2)c1

Procedure:
5-(Ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid was reacted with 1-pyrazin-2-yl-ethylamine following the procedure of step 5 of Example 1 to give 5-(ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=431.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=[O:22])[C:16]=12)=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([C:7]([NH:14][C:15]2[C:16]3[C:21](=[O:22])[O:20][C:18](=[O:19])[C:17]=3[CH:23]=[CH:24][CH:25]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: Nc1cccc2c1C(=O)OC2=O
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To prepare the required acid chloride, 27.77 g of 2-chloro-5-thiophenecarboxylic acid (0.171 mol) are suspended in 50 ml of thionyl chloride (0.685 mol) and stirred at 90° C. for 90 min (after 15 min, a clear solution is formed). The resulting solution is concentrated under reduced pressure, twice subjected to azeotropic distillation with toluene, dissolved in 60 ml of toluene and, over a period of 40 min and at 20° C., added dropwise to a solution of 17.98 g (110.2 mmol) of 3-aminophthalic anhydride in 200 ml of pyridine. The mixture is stirred at RT overnight, the pyridine is evaporated under reduced pressure and the residue is twice stirred with toluene and re-evaporated. 11 of ethyl acetate and 0.51 of KH2PO4 buffer (pH=4–5) are added and the mixture is then shaken vigorously and filtered off with suction, and the solids are washed with ethyl acetate, pressed thoroughly dry and dried under reduced pressure over P2O5. The mother liquor is extracted three times with ethyl acetate and evaporated and the residue is stirred with ethyl acetate and filtered off with suction. This gives a total of 19.77 g (58.3% of theory) of the target compound of m.p. 195° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH2:39])=[S:38])[CH3:29]>>[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:38])[CH3:29]
Reactant: CCc1ccccc1NC(N)=S
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CCc1ccccc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-ethylphenyl)thiourea isolated as a white solid (0.104 g, 35%): 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.13 (s, 1H), 9.42 (s, 1H), 8.15-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.67-7.57 (m, 2H), 7.56-7.45 (m, 2H), 7.39 (dt, J=7.7, 1.4 Hz, 1H), 7.33-7.25 (m, 1H), 7.25-7.17 (m, 2H), 7.09-6.96 (m, 1H), 3.47 (q, J=6.5 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.58-2.51 (m, 2H), 1.11 (t, J=7.5 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 555 ([M+H]+), 553 ([M−H]−).
Reaction SMILES: [I-].[I-].[Sm+2].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C@:11]2([C@H:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][CH:29]=[O:30])[C:15](=[O:16])[C:14]3[C:17]([O:24][CH2:25][CH3:26])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[CH:20][C:13]=3[O:12]2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C@:11]23[C@H:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:28][C@H:29]([OH:30])[C@@:15]2([OH:16])[C:14]2[C:17]([O:24][CH2:25][CH3:26])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[CH:20][C:13]=2[O:12]3)=[CH:7][CH:6]=1
Reactant: CCOc1cc(OCC)c2c(c1)O[C@@](c1ccc(Br)cc1)([C@@H](CC=O)c1ccccc1)C2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(Br)cc3)[C@H](c3ccccc3)C[C@H](O)[C@@]21O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
178 ml (17.9 mmol) of a 0.1 M solution of samarium diiodide in THF is cooled to 0° C. under argon, and a solution of 2.60 g (5.10 mmol) of (S*,R*)-3-[2-(4-bromophenyl)-4,6-diethoxy-3-oxo-2,3-dihydrobenzofuran-2-yl]-3-phenylpropanal in 30 ml of degassed THF is added dropwise. The mixture is stirred at 0° C. for 1 h and at RT for 1 h. An ice-cold saturated sodium potassium tartrate solution with 10% potassium carbonate is added, the phases are separated, the aqueous phase is extracted three times with dichloromethane, and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Column chromatography on silica gel 60 (mobile phase: toluene/ethyl acetate 95:5) results in 1.55 g (58% of theory) of the product as racemic mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1cccc2ccccc12
Yield: 82.9 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.0 g, 25 mmole), naphthaleneboronic acid (4.0 g, 23 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (50 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (5.4 g, 83%) were obtained.
Reaction SMILES: [CH:1]12[CH2:9][CH:6]3[CH:7]([CH2:8]1)[CH:3]([O:4][CH:5]3[OH:10])[CH2:2]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH:5]1[CH:6]2[CH2:9][CH:1]3[CH2:8][CH:7]2[CH:3]([CH2:2]3)[O:4]1)(=[O:13])[CH3:12]
Reactant: OC1OC2CC3CC1C2C3
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1OC2CC3CC2C1C3
Temperature: 50 °C
Yield: 87.9 %

Procedure:
A mixture of 14 g of 4-oxatricyclo[4.2.1.03,7]nonan-5-ol, 12 g of pyridine and 14 g of acetic anhydride was heated at 50° C. for 5 hours. The reaction mixture was concentrated. The concentrate was purified by distillation, obtaining 16 g (yield 88%) of the target compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]([O:28][CH2:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:19])[NH2:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1.C([O-])(=O)C.[Na+].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]([O:28][CH2:29][C:30](=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])=[O:19])[NH:17][CH2:43][C:42]1[CH:45]=[CH:46][C:39]([Cl:38])=[CH:40][CH:41]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@H]1CCC[C@H]1C(=O)OCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=C(NCCC[C@H](NCc1ccc(Cl)cc1)C(=O)N[C@H]1CCC[C@H]1C(=O)OCC(=O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a mixture of 2-oxo-2-phenylethyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate hydrochloride (0.30 g) and methylene chloride (6.0 ml) were added 4-chlorobenzaldehyde (87 mg), sodium acetate (53 mg), and sodium borohydride (215 mg) at room temperature, followed by stirring at room temperature over one night. To a reaction mixture was added a saturated sodium bicarbonate solution under ice-cooling to adjust the pH to about 7, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-oxo-2-phenylethyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(4-chlorobenzyl)-L-ornithyl}amino)cyclopentanecarboxylate (0.34 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>N1C=CC=CC=1>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Brc1ccccn1
Solvent: c1ccncc1
Product: NCCCNc1ccccn1
Yield: 69.5 %

Procedure:
2-Bromopyridine (20 g), 1,3-diaminopropane (47 g) and pyridine (13 ml) were heated together under reflux for 2.5 hr. The mixture was stripped to remove the excess of diaminopropane and the residue taken up in water. The pH was adjusted to 14 and extracted with chloroform. The extracts were dried (K2CO3), stripped and the residue distilled at reduced pressure to give 2-(3-aminopropylamino)pyridine (13.3 g; 70%) b.p.0.02 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccncc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.88 g of 3-chloroisonicotinic acid, 5 ml of thionyl chloride and 20 mg of DMF was heated to reflux for three hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give 3-chloroisonicotinic acid chloride. The resultant 3-chloroisonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 1.14 g of triethylamine and 8 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and then stirred while heating at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.87 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[F:12][C:13]([F:23])([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:14][OH:15].[OH-].[K+]>CN(C)C=O>[F:12][C:13]([F:23])([C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])[CH2:14][O:15][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(COCC(F)(F)C(F)(F)C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
100.0 g (0.58 mol) of 3-nitrobenzyl chloride and 128.3 g (0.62 mol, 1.05 equivalents) of 2,2,3,3,4,4,4-heptafluorobutanol(purity: 96%) were dissolved in 300 ml of dimethylformamide. To the resultant mixture 49.0 g (0.88 mol, 1.5 equivalents) of KOH pellets were added while the mixture was being cooled in a water bath. The reaction temperature is elevated to 43° C. and thereafter gradually restored to room temperature, and the reaction was completed after 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(Cl)cc1
Product: ClCCCOc1ccc(Cl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-chlorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>CO>[CH3:11][CH:12]1[NH:13][CH2:14][CH2:15][N:16]([C:3]2[C:4](=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:17]1
Reactant: CC1CNCCN1
Reactant: COc1cccccc1=O
Solvent: CO
Product: CC1CN(c2cccccc2=O)CCN1
Yield: 70.6 %

Procedure:
A solution of 2-methoxy-2,4,6-cycloheptatrien-1-one (6.8 g) and 2-methylpiperazine (5 g) in methanol was refluxed for 16 hr and evaporated. The residue (11 g) was chromatographed on silica gel (250 g) using methanol and the eluate was evaporated to give 7.2 g of 2-(3-methyl-1-piperazinyl)-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [Na].[CH2:2]([O:5][NH:6][C:7](=[C:11]1[C:16](=[O:17])[CH:15](OC)[C:14]([CH3:21])([CH3:20])[C:13](=C=O)[C:12]1=[O:24])[CH2:8][CH2:9]C)[CH:3]=[CH2:4]>>[CH2:2]([O:5][NH:6][C:7](=[C:11]1[C:12](=[O:24])[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]1=[O:17])[CH2:8][CH3:9])[CH:3]=[CH2:4]
Reactant: C=CCONC(CCC)=C1C(=O)C(=C=O)C(C)(C)C(OC)C1=O
Agent: [Na]
Product: C=CCONC(CC)=C1C(=O)CC(C)(C)CC1=O

Procedure:
sodium salt of 2-[1-(N-allyloxyamino)-butylidene]-5,5-dimethyl-4-methoxy-carbonyl-cyclohexane-1,3-dione
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]([N+:25]([O-])=O)=[CH:17][C:16]=1[N+:28]([O-])=O)[C:10](=[O:14])[O:11][CH2:12][CH3:13].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:28][C:16]1[CH:17]=[C:18]([NH2:25])[CH:19]=[C:20]([C:21]([F:23])([F:24])[F:22])[C:15]=1[N:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:10](=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(=O)N(c1ccc(Cl)cc1Cl)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: CCOC(=O)N(c1ccc(Cl)cc1Cl)c1c(N)cc(N)cc1C(F)(F)F
Reaction time: 2 h
Yield: 97 %

Procedure:
Ethyl 2,4-dichlorophenyl[2,4-dinitro-6-(trifluoromethyl)phenyl]carbamate (1.4027 g) was dissolved in methanol (80 ml), and to the solution was added titanium(III) chloride solution (27.731 g) under ice-cooling. The reaction mixture was stirred for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (600 ml), and the mixture was extracted 2 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1.1863 g, 97%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH2:11])[N:3]=[CH:2]1.[N:12]1([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([NH:11][C:10]3[CH:9]=[CH:8][S:7][C:6]=3[C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:30])=[CH:26][CH:27]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccsc1-c1cscn1
Reactant: O=C(O)Cc1ccc(OCCCN2CCCCC2)cc1
Product: O=C(Cc1ccc(OCCCN2CCCCC2)cc1)Nc1ccsc1-c1cscn1

Procedure:
The title compound was prepared from 2-(thiazol-4-yl)thiophen-3-amine and 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetic acid using protocol X. Method[7], MS(ESI) 442.1 [M+H], Retention time=3.586 min; 1H-NMR (300 MHz, CDCl3) δ 10.8 (s, 1H), 8.54-8.53 (m, 1H), 8.13-8.11 (m, 1H), 7.33-7.30 (m, 2H), 7.25-7.17 (m, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.08 (t, J=4.95 Hz, 2H), 3.74 (m, 3H), 3.28-3.21 (m, 2H), 2.72-2.61 (m, 2H), 2.40-2.20 (m, 6H), 2.05-1.91 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][CH:20]=[C:21]([CH:23]=O)[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][CH:31]([CH3:34])[CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:28])[CH3:29])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][CH:20]=[C:21]([CH2:23][NH:33][CH2:32][CH:31]([CH3:34])[CH3:30])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(C=O)cnc2[nH]1
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CNCc1cnc2[nH]c(-c3cc(OCc4ccccc4)ccc3OC(C)C)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
A solution of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-6-carbaldehyde (50 mg) and 2-methylpropan-1-amine (14 mg) in 10% acetic acid-dichloromethane (2 ml) was stirred at room temperature for 20 min. Sodium triacetoxyborohydride (55 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with water and concentrated. The residue was purified by preparative HPLC. Saturated aqueous sodium hydrogencarbonate solution was added to the obtained fraction to neutralize the mixture, and the mixture was extracted with dichloromethane. The extract was concentrated to give the title compound (32 mg, yield 56%) as colorless crystals. melting point 101-103° C. purity 97%. M+H: 445. 1H NMR (CDCl3) δ: 0.92 (6H, dd, J=6.6, 1.7 Hz), 1.49 (6H, dd, J=5.9, 1.6 Hz), 1.70-1.85 (1H, m), 2.50 (2H, d, J=6.8 Hz), 3.97 (2H, s), 4.71-4.78 (1H, m), 5.15 (2H, s), 6.98-7.08 (2H, m), 7.31-7.50 (5H, m), 8.05 (1H, s), 8.18 (1H, s), 8.33 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.CO.C1COCC1>[NH2:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: COC(=O)Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Nc1cc(Cl)cc(Cl)c1N
Yield: 42.5 %

Procedure:
Methyl (3,5-dichloro-2-nitrophenyl)carbamate (79 mg, 0.3 mmol) prepared in Step 1 was added with THF (1.5 mL, 0.2 M), followed by stirring. In a separate vial, sodium hydrosulfite (603 mg, 2.7 mmol, 9.0 eq) and sodium bicarbonate (227 mg, 2.7 mmol, 9.0 eq) were dissolved in H2O (3 mL, 0.1 M), and the solution thus obtained was added to a solution of methyl (3,5-dichloro-2-nitrophenyl)carbamate. MeOH (0.5 mL) was added to the solution, and the mixture was subjected to a reaction at room temperature for 2 hours. Upon completion of the reaction, THF and MeOH were removed by distillation under reduced pressure, and the residue thus obtained was extracted with ethyl acetate (30 mL x 2), dried over MgSO4, and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EtOAc/Hex=1:4) to obtain the title compound (30 mg, yield: 43%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][C:6]=1[CH3:15])=[O:4].[OH-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[C:6]=1[CH3:15])=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1c(C)[nH]c2ncc(F)cc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A cooled (0-5° C.) suspension of 5-fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (9.0 g, 43.2 mmol), powdered sodium hydroxide (5.4 g, 133.9 mmol) and benzyltriethylammonium chloride (0.2 g, 0.86 mmol) in dichloromethane (100 mL) was treated over ca. 5 minutes with benzenesulfonyl chloride (9.5 g, 6.9 mL, 54.0 mmol). The reaction mixture was allowed to stir at 0-5° C. for 20 minutes then allowed to warm to ambient temperature and stirred for 24 hours. The solid was removed by filtration through celite and the cake washed with dichloromethane. The filtrate was evaporated and the resultant residue triturated with diethyl ether to afford the title compound as a cream solid (14.0 g, 93%). 1H NMR (400 MHz, CDCl3): 8.27 (dd, J=2.8, 1.1 Hz, 1H), 8.18-8.18 (m, 2H), 7.97 (dd, J=8.7, 2.8 Hz, 1H), 7.61-7.61 (m, 1H), 7.52-7.51 (m, 2H), 3.94 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([CH2:30]O)[N:27]([CH3:29])[N:28]=2)=[CH:20][C:19]=1[C:32]([F:35])([F:34])[F:33].CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:30][C:26]3[N:27]([CH3:29])[N:28]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:32]([F:34])([F:33])[F:35])[CH:20]=4)[CH:25]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(F)c(C(F)(F)F)c2)cc1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(F)c(C(F)(F)F)c4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[5-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(#N)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:5][C:6]1([CH3:11])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1(C)CCCC1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](CC1(C)CCCC1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 25 %

Procedure:
2-Benzyloxycarbonylamino-3-(1-methylcyclopentyl)-propionic acid methyl ester (7.6 g, 23.8 mmol) was dissolved in a mixture of acetonitrile (82 mL) and 0.2 M aqueous NaHCO3 (158 mL) and Alcalase 2.4 L (1.1 mL) was added and the reaction mixture was stirred vigorously for 8 h. The reaction mixture was then evaporated at 30° C. to remove acetonitrile, and the aqueous residue was washed with ether. The ethereal layer was concentrated to yield 1.9 g of 2(R)-benzyloxycarbonylamino-3-(1-methylcyclopentyl)-propionic acid methyl ester. The aqueous phase was filtered with Celite, the pH was adjusted to 3 with 6 N HCl, and the solution was extracted with ethylacetate. The ethyl acetate layer was dried and evaporated to yield 1.4 g of 2(S)-benzyloxycarbonylamino-3-(1-methylcyclopentyl)propionic acid.