Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]CC)=[O:33])[CH:26]=[N:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[N:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1
Reactant: CCOC(=O)c1cnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.9 %

Procedure:
To a stirred solution of ethyl 6-[4-({[3-(2,6-dichlorophenyl) -5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinoxalinecarboxylate (0.112 g, 0.20 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1 N sodium hydroxide (0.21 mL, 0.21 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3.5 hours. The solvent was removed in vacuo and water (5 mL) was added to the resulting solid. The pH of the aqueous mixture was adjusted to ˜3 (litmus paper) with 1 N HCl. The acidic aqueous mixture was extracted with ethyl acetate. The aqueous phase was separated and extracted a second time with ethyl acetate. The aqueous phase was separated and found to contain product according to thin layer chromatography. The pH of the aqueous phase was adjusted to ˜2 (litmus paper) with 1 N HCl. The acidic aqueous phase was combined with the aforementioned ethyl acetate extracts. The organic phase was separated, washed with water followed by brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give a yellow solid which was dried under high vacuum at room temperature to give 0.095 g (89%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinoxalinecarboxylic acid. 1H NMR (d6-DMSO, 400 MHz): δ 13.89 (br s, 1H), 9.40 (s, 1H), 8.32 (s, 1H), 8.24 (m, 2H), 7.81 (d, J=9 Hz, 2H), 7.62 (m, 2H), 7.53 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.89 (s, 2H), 3.47 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M−H)−.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>CO>[ClH:4].[CH2:24]([C:20]1[CH:19]=[C:18]([CH:15]2[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]2)[CH:23]=[CH:22][CH:21]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(Cc3ccccc3)c2)CC1
Solvent: CO
Product: Cl
Product: c1ccc(Cc2cccc(C3CCNCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2 mL of MeOH at 0° C. was added 0.17 mL of acetyl chloride. After warming to room temperature and stirring for 15 minutes, a solution of 71 mg (0.20 mmol) of 1-tert-butoxycarbonyl-4-((3-benzyl)phenyl)-piperidine (from Step E) was added. The reaction was stirred for 1 hour at room temperature. Volatiles were removed under reduced pressure to yield the title compound, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][C:2]([Br:1])=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:20]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc2ccc3c(-c4cccc(-c5ccccc5)c4)ccc4ccc1c2c43
Yield: 69.2 %

Procedure:
To a solution of 1,6-dibromopyrene (5.4 g, 15.0 mmol), [1,1′-biphenyl]-3-ylboronic acid (3.3 g, 16.5 mmol), and K2CO3 (10.4 g, 75.0 mmol) in 1,4-dioxane (320 mL) and water (50 mL) was bubbled with nitrogen for 15 min. Pd(PPh3)4 (0.87 g, 0.75 mmol) was then added to the mixture. The mixture was bubbled with nitrogen for 15 min. The resultant mixture was refluxed for 19 h. The reaction mixture was then extracted by DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography using 15% DCM/hexane (containing 0.25% triethylamine) to yield 1-([1,1′-biphenyl]-3-yl)-6-bromopyrene (4.5 g, 70% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.Cl[C:19]1[C:20]2[C:21]3[C@H:22]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][CH2:24][CH2:25][C:26]=3[S:27][C:28]=2[N:29]=[CH:30][N:31]=1>C1COCC1>[C:13]([O:12][C:11]([NH:10][CH:7]1[CH2:8][CH2:9][CH:4]([O:3][C:19]2[C:20]3[C:21]4[C@H:22]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][CH2:24][CH2:25][C:26]=4[S:27][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:5][CH2:6]1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CCOC(=O)C[C@@H]1CCCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCCc2sc3ncnc(OC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
NaH (60% dispersion in mineral oil, 438 mg, 10.95 mmol, 4.00 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)carbamate (710 mg, 3.30 mmol, 1.20 equiv) in freshly distilled THF at 50° C. for 30 min under nitrogen. Then a solution of ethyl 2-[(13S)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate (850 mg, 2.73 mmol, 1.00 equiv) in THF (10 mL) was added via syringe and stirred for 2 h at 60° C. After cooling, the reaction was quenched with brine, extracted with ethyl acetate (80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give 800 mg (60%) of ethyl 2-[(13S)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-13-yl]acetate as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:12](OCC)(=O)[C:13]([O:15]CC)=[O:14].[O-]CC.[Na+].Cl>C(O)C.C(O)(=O)C.O>[CH3:10][C:9]1[C:8](=[O:11])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)c1ccccc1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
2'-Hydroxypropiophenone (15.02 g) and diethyl oxalate (17.54 g) were added to a solution of sodium ethoxide in ethanol (prepared from 6.90 g of sodium and 200 ml of ethanol), and the mixture was heated for 2.5 hours while refluxing. The mixture was cooled, poured over 2N HCl (320 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to yield an oily substance (4.26 g). This oily substance was dissolved in acetic acid-concentrated hydrochloric acid (1:1, 30 ml) and heated for 1 hour while refluxing. After cooling, the reaction mixture was poured over water (150 ml) and stirred at room temperature for 10 minutes. The separated crystals were collected by filtration to yield 3-methyl-4-oxo-4H-1-benzopyran-2-carboxylic acid (2.62 g, 13%), which was then recrystallized from ethanol to yield colorless prisms having a melting point of 192° to 193° C.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH2:17].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.O>[CH2:1]([O:3][C:4]([NH:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccc2ccccc2c1
Yield: 84 %

Procedure:
A mixture of 16.7 g of ethoxycarbonyl chloride and 20 ml of methylene chloride is added dropwise to a mixture of 20.0 g of 2-naphthylamine, 17.6 g of sodium bicarbonate, 100 ml of water and 200 ml of methylene chloride under ice-cooling and stirring. The mixture is stirred overnight at room temperature. Chloroform is added to the mixture and the organic layer is separated, dried and treated with charcol. The residue is recrystallized from ethyl acetate-hexane to give 25.26 g of N-ethoxycarbonyl-2-naphthylamine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].O.C(O)(=O)C>N1C=CC=CC=1>[C:12]1([C:11]2[N:10]=[C:9]([S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[N:8]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.76 g (5 mmole) 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole, 1.1 g (10 mmole) of ethyl chloroformate in 10 ml pyridine was stirred at RT overnight. TLC showed some starting material, so another 0.6 g (5 mmole) of ethyl chloroformate was added and stirring was continued another 24 hours. The mixture was poured into water, neutralized with acetic acid and extracted three times with ether. The ether extracts were backwashed three times with water, then dried and concentrated. The last traces of pyridine were removed by pumping at 50° (0.5 mm). The residue was chromatographed on 150 g SilicAR CC-7, eluting with toluene to give, after recrystallization from hexane, 1.05 g (55%) of white product, mp 126.5°-127°.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH2:23])C([O:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[C:16]2[NH:17][C:18]([NH2:22])=[N:19][C:20](=[O:21])[C:15]=2[N:14]=[CH:13]1)=O)[CH3:3].[NH:24]([C:32]([O:34]C(C)(C)C)=O)[C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27]>C(N(CC)CC)C>[CH:13]1[N:12]([CH2:11][O:10][CH2:9][CH2:8][OH:7])[C:16]2[N:17]=[C:18]([NH2:22])[N:19]=[C:20]([OH:21])[C:15]=2[N:14]=1.[CH3:1][CH:2]([C@H:4]([NH2:23])[C:32]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:27])[CH3:28])=[O:34])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Product: Nc1nc(O)c2ncn(COCCO)c2n1

Procedure:
A mixture of Boc-Val and dicyclohexyl carbodiimide (DCC) in dimethylformamide (DMF) in a ratio of 1:2 DCC/Boc-Val was stirred for 1 hr at 0° C. under nitrogen atmosphere. A solution of acyclovir (1) and 4-N,N(dimethylamino)pyridine (DMAP) was added to the reaction mixture, stirred for 18 hrs and then filtered. The solvent of the filtrate was partially removed in vacuo and the impure solution was added dropwise to cold diethyl ether. The resulting precipitate (2) was filtered and dried, followed by acidolytic removal (treating Boc-Val-ACV with trifluoroacetic acid (TFA) for 30 min at 0° C.) of the Boc protecting group to yield Val-ACV (3). Compound (3) was neutralized by triethylamine (TEA) and treated with the amino acid anhydride of Boc-Val for about 5 hrs. The solvent was removed from the reaction mixture in vacuo and the reaction mixture was added dropwise to the cold diethyl ether. The resulting precipitate (4) was filtered, dried and the Boc group was deprotected (acidolytic removal) to yield the desired dipeptide ester of acyclovir Val-Val-ACV (5).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH:5]1[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:6]=1.C1(N)CCCCC1.[OH2:19]>>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:7]([OH:19])(=[O:8])/[CH:6]=[CH:5]\[C:10]([OH:9])=[O:11]
Reactant: O
Reactant: O=C1C=CC(=O)O1
Agent: C=CC=C
Solvent: NC1CCCCC1
Product: O=C(O)/C=C\C(=O)O
Reaction time: 1 h

Procedure:
of the same butadiene-maleic anhydride copolymer as in Example 11, 40g. of cyclohexylamine and 500 ml. of water were fed in a separable 1 liter flask equipped with a stirrer and a reflux condenser. A reaction was carried out for 1 hour at 100° C. under a nitrogen gas atmosphere to give a transparent, viscous, aqueous butadiene-maleic acid copolymer cyclohexylamine salt solution. To this aqueous solution was added over a period of 10 minutes a separately prepared aqueous solution of 56g. of magnesium acetate tetrahydrate in 100 ml. of water. After completion of the addition, heating was applied up to near 100° C. while a violent stirring was applied to the interior pf the flask, resulting in that there were deposited many solids in the form of small lumps. The solids were separated from the liquid phase by means of hot filtration and collected in a flask. Cooling of the flask in an ice-water bath resulted in that after 5 minutes the solids therein were completely converted into an aqueous solution. To the aqueous solution thus obtained there were repeatedly applied such heating and cooling operations. At every repetition the aqueous solution on heating was converted into a rubber-like matter and on cooling reverted to its original liquid phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.CN(C)[CH:28]=[O:29].[O:31]1CCCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([OH:31])=[C:4]([CH:3]=1)[CH:28]=[O:29]
Reactant: C1CCOC1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cl)cc1C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Product: O=Cc1cc(Cl)cc(C(F)(F)F)c1O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-2-fluorobenzotrifluoride (1.5 g, 7.5 mmol) was dissolved in dry tetrahydrofuran (THF; 10 mL), treated with tetramethylethylenediamine (TMEDA; 1.6 mL, 1.2 g, 11 mmol), cooled to −78° C. and treated in portions with n-butyl lithium (n-BuLi, 2.5 M in hexanes; 3.9 mL, 9.8 mmol). After stirring at −78° C. for 90 minutes (min), the mixture was treated with N,N-dimethylformamide (DMF; 770 microliters (μL), 730 mg, 10 mmol) and stirred for a further 30 min. The cooling bath was removed and mixture warmed to 25° C. over 30 min. The reaction was quenched by addition of satd ammonium chloride (NH4Cl) solution then diluted with diethyl ether (Et2O; 30 mL). The separated organic phase was washed with satd NaCl (10 mL), dried (Na2SO4) and evaporated. The residue was dissolved in dry methanol (CH3OH; 10 mL) and treated with 30% sodium methoxide solution in CH3OH (14 g). The mixture was stirred at 25° C. for 20 h, diluted with H2O (50 mL) and extracted with Et2O (2×40 mL). The combined organic phases were washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography using a 0 to 10% EtOAc gradient in hexane to give the benzaldehyde (1.1 g). This material (1.0 g, 4.2 mmol) was dissolved in dry CH2Cl2 (10 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 5 mL, 5 mmol). The mixture was allowed to warm to 25° C. and stirred for 22 h. After cooling to −45° C., the mixture was treated with H2O (5 mL), warmed to 25° C. and extracted with EtOAc (2×15 mL). The combined extracts were washed with satd NaCl solution (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography using a 0 to 10% EtOAc gradient in hexane to give the aldehyde (950 mg): 1H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H), 9.91 (s, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H); EIMS m/z 224.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C(OO[C:10](CC)([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)(=O)C=C.[S:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)([OH:24])(=[O:23])=[O:22].C(N(CC)CC)C>C(O)(=O)C>[NH:12]([C:10]1[NH:32][N:31]([C:28]2[CH:29]=[CH:30][C:25]([S:21]([OH:24])(=[O:22])=[O:23])=[CH:26][CH:27]=2)[C:1](=[O:3])[CH:2]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Reactant: C=CC(=O)OOC(C)(CC)Nc1ccccc1
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=c1cc(Nc2ccccc2)[nH]n1-c1ccc(S(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
Into 1.5 l of ethanol were dispersed 118 g of ethylβ-anilino-β-ethoxy acrylate and 94 g of p-sulfophenylhydrazine, and 150 g of triethylamine and glacial acetic acid were successively dropped thereinto while heating (95°-100° C.) and stirring. After heating (95°-100° C.) and stirring for 5 hours, the reaction solution was concentrated under reduced pressure. To the residue so concentrated were added 50 ml of water and 120 ml of ethanol containing 35% by wt. hydrogen chloride to provide a uniform solution. This uniform solution was allowed to stand in a refrigerator for one day and one night. The crystals of the objective compound which precipitated had a melting point of 290° to 291° C. and weighed 145 g.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:23][CH:22]3[C:24]([OH:26])=O)[CH:19]=2)[NH:14][CH:13]=1)=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C@@H:21]3[CH2:23][C@H:22]3[C:24]([N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)=[O:26])[CH:19]=2)[NH:14][CH:13]=1)=[O:11]
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c2ncc(C3CC3C(=O)O)cc12
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)[C@@H]2C[C@H]2c2cnc3[nH]cc(C(=O)Cc4cccc(F)c4F)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-{3-[(2,3-Difluoro-phenyl)-acetyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-cyclopropanecarboxylic acid, (93 mg, 0.26 mmol), was combined with DIEA, (67 mg, 0.52 mmol), and HBTU, (113 mg, 0.3 mmol) in 1 mL DMF and stirred at rt for ˜15 min. Then N-methyl piperazine, (26 mg, 0.26 mmol), was added and the reaction stirred at rt for 4 hours. The DMF was evaporated under vacuum, water added and the suspension extracted with dichloromethane. The solvent was evaporated under vacuum and the residue purified by silica chromatography, (eluent: 5% methanol/DCM), affording trans-2-(2,3-Difluoro-phenyl)-1-{5-[2-(4-methyl-piperaz ine-1-carbonyl)-cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-ethanone, (35 mg, Rf 0.5) and the cis isomer (16 mg, Rf 0.3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.[N+:23]([C:26]1[CH:39]=[CH:38][C:29]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C=O)C>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]([CH2:2][C:3]2[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:38][CH:39]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Temperature: 50 °C
Yield: 55.7 %

Procedure:
To a solution of the product of Example 149D (1.09 g, 2.97 mmol) and N-(4-nitrobenzyl)aniline (0.677 g, 2.97 mmol) dissolved in DMF (10 mL) was added potassium carbonate (1.23 g, 8.9 mmol) and the mixture heated at 50° C. for 1 hour. After cooling, the solution had dichloromethane added to it and the mixture extracted with water. The organic extract was then dried, filtered, concentrated and purified by chromatography (silica gel, 0-2% methanol in dichloromethane) to afford 0.85 g (56%) of the title compound. MS (ESI) m/z 514 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[N:20]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:19][N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[C:8]([N:20]([CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH:9]=2)[CH2:18][CH2:17]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester (12.1 g, 25.7 mmol), trifluoroacetic acid (48.5 mL) and dichloromethane (195 mL) was stirred at room temperature for 2 hours. The volatiles were then evaporated, the residue taken up with diethylether and evaporated again. The procedure was repeated for 5 times, then the solid was triturated with diethylether, filtered and dried in oven at 40° C. affording the title compound as a pale brown solid (13.4 g).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][C:17](=[O:20])[CH:18]=[CH2:19]>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[CH:1]1([C:7](=[O:8])[CH2:19][CH2:18][C:17](=[O:20])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: C=CC(C)=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)C1CCCCC1
Temperature: 85 °C
Yield: 27.1 %

Procedure:
To a solution of cyclohexanecarbaldehyde (3.22 mL, 26.7 mmol) in ethanol (9.5 mL) was added triethylamine (7.46 mL, 53.5 mmol), but-3-en-2-one (2.22 mL, 26.7 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (1.35 g, 5.35 mmol). The reaction mixture was heated at 85° C. for 18.5 hours. The reaction was then concentrated under vacuum and the resulting residue was extracted with ethyl acetate (3×50 mL). The organic layer was dried (sodium sulfate), filtered and concentrated to an orange residue which was purified on silica gel using an automated system (ISCO 120 g, 20 mL/min) and 0 to 45% ethyl acetate in hexanes over 60 minutes as the eluent. The product was isolated as a yellow oil (1.32 g, 7.24 mmol, 27% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 2.68-2.73 (m, 4H), 2.35-2.42 (m, 1H), 2.19 (s, 3H), 1.85-1.89 (m, 2H), 1.76-1.79 (m, 2H), 1.65-1.69 (m, 1H), 1.17-1.39 (m, 5H).