Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.C[N:3]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[NH:6])[NH2:4].Br[C:14](=[CH2:25])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].N12CCCC1=NCC[CH2:27]2.C(OCC)(=O)C>CN(C)C=O.C1C=CC=CC=1>[CH3:27][N:6]1[CH2:25][CH:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[NH:4][N:3]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(Br)C(=O)OCc1ccccc1
Reactant: CN(N)C(=N)c1ccccc1
Reactant: C1CN=C2CCCN2C1
Agent: I
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CC(C(=O)OCc2ccccc2)NN=C1c1ccccc1

Procedure:
Benzenecarboximidic acid-N-methyl hydrazide monohydroiodide (0.43 g) in dry dimethylformamide (10 ml) and benzyl 2-bromo-prop-2-enoate (0.41 g) in benzene (2.5 ml) were cooled to 0° and stirred together under an atmosphere of nitrogen. A solution of 1,5-diazabicyclo[4.3.0]non-5-ene (0.4 ml) in dimethylformamide (5 ml) was added gradually and the mixture was stirred at 0° for a further 20 minutes. Ethyl acetate (100 ml) was added and the mixture was washed with brine (30 ml) and dried over magnesium sulphate. The solvent was removed at reduced pressure to yield the sub-title product (0.46 g) as an orange oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([C:7]2[N:8]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([CH3:20])=[CH:18][CH:17]=3)[C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: OCc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CO)cc1

Procedure:
1 g of 2-phenyl-4-chloro-5-hydroxymethylimidazole, together with 0.7 ml of p-methylbenzyl bromide and 3 g of potassium carbonate, was stirred in 10 ml of dimethylformamide at 30° C. for 2 days. The reaction solution was poured into 100 ml of water, and the precipitate deposited was chromatographed on a column of 30 g of silica gel, followed by eluting with chloroform. The initially eluted fraction was collected, and recrystallization from aqueous methanol yielded 0.5 g of 2-phenyl-4-chloro-5-hydroxymethyl-1-(4-methylbenzyl)imidazole as colorless, needle-formed crystals, m.p. 173°-175° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>S(=O)(=O)(O)O.O.C(O)CCC.C1(C)C=CC=CC=1>[C:7]([OH:9])(=[O:8])[CH2:2][CH2:3][CH3:4].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:5]1[CH:6]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: CCCC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
16.52 g of isoleucine was dissolved in a solution of 10 g of concentrated sulfuric acid, 20 mL water, 20 mL of butanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was then cooled to room temperature and washed with saturated aqueous sodium bicarbonate to neutralize acidic impurities, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting liquid distilled under vacuum to provide phenylalanine butyrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C:10](=[O:11])[CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][S:7]1)=[O:5])[CH3:2].[BH4-].[Na+].CC(C)=O.C(O)(=O)C>CCO>[CH2:1]([O:3][C:4]([C@H:6]1[CH:10]([OH:11])[CH:9]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][S:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1SCC(NC(=O)OC(C)(C)C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@@H]1SCC(NC(=O)OC(C)(C)C)C1O
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
The oxo-ester (13) (9.16 g, 31.7 mmole) in EtOH 90 mL was reduced with NaBH4 (844 mg, 22 mmole) added portion wise at −30° C. After 30 min at −30° C., acetone 8.7 mL followed with acetic acid 1.1 mL were added. The crude mixture was concentrated at 40° C. under 100 mbar, extracted with EtOAc and brine to pH 7. The solvent was removed under 0.1 mbar, crude 9.20 g (yield 99%) of (R)-ethyl-4-[(tert-butoxycarbonyl)amino]tetrahydro-3-hydroxy-2-thiophenecarboxylate.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(N(CC)CC)C.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Reactant: OCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCCCCCO)C1
Temperature: 50 °C
Yield: 55.7 %

Procedure:
To a stirred solution of (S)-3-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (40 g, 142.7 mmol) and triethylamine (59.6 mL, 428 mmol) in acetonitrile (1.1 L) at 40° C. under a nitrogen atmosphere was added 7-bromo-1-heptanol (24 mL, 146 mmol) in acetonitrile (100 mL) dropwise. The reaction mixture was heated to 50° C. for 9 hours. The reaction mixture was allowed to cool before removing the solvent under reduced pressure. The crude residue was dissolved in dichloromethane (500 mL) and the organic layer washed with saturated aqueous sodium bicarbonate (2×300 mL), followed by water (300 mL) and saturated aqueous sodium chloride (300 mL), and then dried over magnesium sulfate (10 g). The magnesium sulfate was filtered off and washed with dichloromethane (100 mL). The solvent was then removed in vacuo to give the crude product which was purified on a short column (SiO2) by varying the eluant from 19:1:0.1 to 3:1:0.1 CH2Cl2/MeOH/NH4OH to give 31.35 g of the title intermediate as a white solid (56% yield; >95% purity by HPLC Method A).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH2:28][CH2:29][O:30][CH3:31])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH2:28][CH2:29][O:30][CH3:31])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoate (1.08 g, Int. Patent Appl., Publication No. WO 9401420) and sodium hydroxide (253 mg) in methanol:water (1:1, 10 mL) was heated under reflux for 2 hours. After evaporation of the resultant mixture in vacuo, the residue was diluted with water, acidified to pH 5 with 2M hydrochloric acid and then extracted with ethyl acetate. Washing of the ethyl acetate extracts with water and drying (MgSO4) and evaporation gave the title compound as an oil which crystallised on trituration with diethyl ether/hexane. [Found C, 63.8; H, 6.5; N, 7.0%; M+ 414.1791. C22H26N2O6 requires C, 63.8; H, 6.3; N, 6.8%; M+ 414.1791]; δH (CDCl3) 2.91 (1H,dd), 3.15 (1H,dd), 3.34 (3H,s), 3.38 (3H,s), 3.41-3.69 (4H,m), 3.93 (2H,t), 4.05 (1H,dd), 4.21 (2H,t), 6.80 (2H,d) and 6.83-7.38 (6H m).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1.Cl.Cl.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:4].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:30]([CH3:38])[CH3:29])=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)Cn2c(-c3cccc(Cl)c3)nc3cccnc32)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.8 ml, 0.032 mole) was added dropwise (slowly) to a stirred and chilled solution of 2-(3-chlorphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.028 mole) in anhydrous dimethylformamide (100 ml). The reaction was heated at 55°-60° C. for 3 hrs, cooled to room temperature, and added dropwise to a stirred and chilled (5°-10° C.) suspension of N,N-dimethyl-p-phenylenediamine dihydrochloride (6.7 g, 0.032 mole) and triethylamine (12.9 g, 0.128 mole) in anhydrous dimethylformamide (200 ml). The reaction was stirred at room temperature over the weekend, filtered, and poured into ice water (600 ml). The mixture was filtered and the filter cake recrystallizd from ethanol giving 6.6 g (58%). The solid was coverted to the hydrochloride salt in isopropyl alcohol and concentrated hydrochloric acid to give 6.6 g of a white granular solid, mp. 229°-231° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[N:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]1[CH2:36][CH2:35][N:34]2[C:29](=[N:30][CH2:31]C[CH2:33]2)[CH2:28][CH2:27]1.[CH3:37]N(C=O)C>>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:29]2[N:34]([CH3:33])[C:35]3[CH:37]=[CH:28][CH:27]=[CH:26][C:36]=3[N:30]2[CH3:31])[S:10][C:9]1=[N:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: CN(C)C=O
Reactant: C1CCC2=NCCCN2CC1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2N(C)c3ccccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of the above salt (66 mg, 0.2 mmol) and 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile (70 mg, 0.2 mmol) in DMF was added DBU (62 mL, 2 equiv) and the solution was heated to 100° C. for 48 h. Evaporation of solvent under high vacuum gave a crude, which was purified by chromatography on silica gel eluting with EtOAc-hexane (1:1) to give the title compound (3.6 mg). 1H-NMR indicated one isomer. 1H-NMR (CDCl3): δ 7.46 (2H, m), 7.22–7.36 (8H, m), 6.46 (1H, d), 5.17 (2H, s), 4.44 (1H, t), 3.79 (3H, s), 3.01 (2H, m), 0.88 (3H, t); MS (ESI): 495 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[C:10]([F:25])=[C:11]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:39](=[S:41])=[S:40].Br[CH2:43]Br>CS(C)=O.O>[CH2:26]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:25])=[C:11]([C:16](=[O:24])[C:17](=[C:39]2[S:41][CH2:43][S:40]2)[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCBr
Reactant: S=C=S
Reactant: O=C(Cc1ccncc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(C(=C1SCS1)c1ccncc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a solution of 1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-pyridin-4-yl-ethanone (2.14 g, 4.994 mmol) in dry DMSO (22 mL) under nitrogen atmosphere solid potassium carbonate (2.07 g, 15 mmol, 3 eq) was added at room temperature, followed by carbon disulfide (0.9 mL, 15 mmol, 3 eq) and dibromomethane (1.05 mL, 15 mmol, 3 eq). The reaction mixture was stirred at room temperature for 3 hour and then poured into stirred iced water (150 mL). The aqueous phase was extracted with ethyl acetate (3 x 70 mL) and the combined organic layers were washed with water, dried and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (n-hexane/ethyl acetate 7:3 to 6:4) to obtain 1.26 g of 1-(3-dibenzylamino-2,6-difluoro-phenyl)-2-[1,3]dithietan-2-ylidene-2-pyridin-4-yl-ethanone as yellow solid (49%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:42](=[O:44])[CH3:43])[CH2:19][CH2:20]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1
Reactant: CON=C1C[C@@H](c2noc(CN3CCNCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C1C[C@@H](c2noc(CN3CCN(C(C)=O)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution containing 1 equivalent of (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime (Example 48) in dry DCM at 0° C. were added 1.5 equivalent of triethyl amine and 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phase was dried with magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography to give the expected product, (3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers, in 70% yield (94.4% purity by HPLC). The pure Z-isomer could be separated by flash-chromatography using cyclohexane/ethylacetate (1/1) as eluent, and was obtained in 40% yield (98.0% purity by HPLC).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[NH2:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:36][CH:37]5[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCC(NC(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 58.6 %

Procedure:
The product is prepared by following the procedure described in example 52c starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.315 g of tert-butyl (4-aminocyclohexyl)carbamate instead of the N-Boc-ethylenediamine used in example 52c. 0.237 g of tert-butyl (4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-amino}cyclohexyl)carbamate is obtained with the following characteristics:
Reaction SMILES: [CH2:1]([C:8]1[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cc2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2ccccc2)[nH]1

Procedure:
A mixture of Ethyl 5-benzylpyrrole-2-carboxylate (0.7 g, 3.05 mmol; Elder et al., Synthetic Communications, 19, 763-767 (1989)), ethanol (20 ml) and 1M sodium hydroxide (9.2 ml, 9.2 mmol) was stirred and heated under reflux for 3 h. The major part of the ethanol was removed and the remaining liquid was diluted with water, washed with ether, cooled in ice and acidified with concentrated hydrochloric acid. The mixture was extracted with ether. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to afford 0.567 g (92%) of an off white solid: mp. 130-134° C.; 1H NMR(CDCl3) δ8.87 (1H, brs), 7.37-6.95 (5H, m), 6.97 (1H, m), 6.07 (1H, m), 4.00 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=O)([O-:11])=[O:10].[O:21]1[CH2:26][C:25](=O)[CH2:24][C:23](=[O:28])[CH2:22]1>C(O)C>[Cl:20][C:19]1[CH:18]=[CH:17][C:14]([CH:15]2[C:24]3[C:23](=[O:28])[CH2:22][O:21][CH2:26][C:25]=3[NH:1][C:2]3[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]2=3)=[CH:13][C:12]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C1COCC(=O)C1
Reactant: Cn1oc(=O)cc1N
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 45A (0.085 g, 0.75 mmol), 3-nitro-4-chlorobenzaldehyde(0.14 g, 0.75 mmol) and 2H-pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol) were heated in 2 mL of ethanol for 2 days. The resulting mixture was allowed to cool to ambient temperature and filtered to provide the title compound as the filter cake (0.09 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]1=[O:19])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]=1[O:19][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:2]
Reactant: CCc1cc(-c2ccc(F)cc2)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(-c2ccc(F)cc2)ccc1C1=C(OC(=O)C(C)(C)C)C(C)(C)OC(C)C1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
To a solution of 4-(3-ethyl-4′-fluoro-biphenyl-4-yl)-2,2,6-trimethylpyran-3,5-dione (0.125 g, 0.35 mmol) in dichloromethane (5 ml) is added triethylamine (0.2 ml, 1.43 mmol) and the reaction mixture is cooled to 0° C. Pivaloyl chloride (0.2 ml, 1.63 mmol) is added slowly at 0° C. and the mixture is stirred at 0° C. for 5 hours. The reaction mixture is diluted with water and extracted with dichloromethane (3×25 ml). The organic extracts are combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to afford 2,2-dimethyl propionic acid 4-(3-ethyl-4′-fluorobiphenyl-4-yl)-2,2,6-trimethyl-5-oxo-5,6-dihydro-2H pyran-3-yl ester (130 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:31][CH2:32][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:34][CH2:35]2)[S:28][CH:29]=1
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 34.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (225 mg, 0.782 mmol), 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 103 mg (34.4%) of the desired product as a solid. mp 166-167° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:20]1CCOCC1.[OH-].[Na+:27]>O>[NH2:3][C:4]1[C:5]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:27]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(S(=O)c3ccccc3Cl)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1S(=O)c1ccccc1Cl

Procedure:
A mixture of 2-oxo-7-(2-chlorophenylsulfinyl)indoline (5.0 g.), dioxane (30 ml.), sodium hydroxide (2.5 g.) and water (30 ml.) was refluxed for 8 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water under heating and filtered. The filtrate was adjusted to about pH 4 with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in 1N sodium hydroxide (14.2 ml.) under heating and the solution was evaporated to dryness under reduced pressure. The oily residue was dissolved in ethanol (20 ml.) and crystallized with diethyl ether to give crystals of the captioned compound (2.9 g.). mp 248° to 251° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([O-:21])(=[O:20])=[O:19].[N+:22]([O-])([OH:24])=[O:23]>>[OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([N+:22]([O-:24])=[O:23])[C:3]=1[CH:4]=[O:5].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([O-:21])(=[O:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C=O)c1O
Agent: O=S(=O)([O-])c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C=O)c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Hydroxy-3-methoxybenzaldehyde-2-benzenesulfonate (50 g, 171 mM) is added to nitric acid (500 ml) at 0° C.-5° C. The solution is kept five minutes at 5° C. and then poured into ice-water (1.5 L). The crude product, a tan solid, is filtered, washed with cold water, alcohol, and then recrystallized from acetic acid (650 ml) to afford the product as a white solid; yield 30.3 g (52.6%); m.p. 152°-154° C.