Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCC(=O)CC1C=C(OC)C=CC=1.COC(OC)CC(=O)CC1C=CC(F)=CC=1.CO[C:34]([C:36]1[O:37][CH:38]=[CH:39][C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:35]>>[O:37]1[CH:38]=[CH:39][C:40]2[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=3[C:34](=[O:35])[C:36]1=2.[O:37]1[CH:38]=[CH:39][C:40]2[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:34][C:36]1=2
Reactant: COC(=O)c1occc1-c1ccccc1
Agent: COC(CC(=O)Cc1ccc(F)cc1)OC
Agent: COCCC(=O)Cc1cccc(OC)c1
Product: O=C1c2ccccc2-c2ccoc21
Product: c1ccc2c(c1)Cc1occc1-2

Procedure:
Synthetic substrates 8H-indeno[2,1-b]furan-8-one and 8H-indeno[2,1-b]furan and their derivatives are prepared in accordance with the following. Substituted and unsubstituted 3-arylfuran-2-carboxylic acids are prepared according to a general procedure of Burgess, J. Org. Chem., 21, 102 (1956), wherein, 4,5-dimethoxy-1-phenyl-2-butanone and related 2' to 4' substituted phenyl analogs (e.g., 4,4-dimethoxy-1-(4'-fluorophenyl)-2-butanone, prepared according to the general procedure of Royals and Brannoch, J. Amer. Chem. Soc., 75, 2050 (1953)) are converted into 3-phenylfuran-2-carboxylic acid methyl ester (e.g., 3'-(4'-fluorophenylfuran-2-carboxylic acid methyl ester) by the Darzens glycidic ester condensation (Darzens, Compt. Rend., 139, 1214 (1904)). This rearrangement of the glycidic ester yields the furoic ester. The furoic ester can be hydrolyzed in alkaline methanolic solution to yield, for example, 3-(4'-fluorophenyl)-furan-2-carboxylic acid. The furoic acid product can be cyclized via the aroyl chloride in the presence of stannic chloride or aluminum chloride to yield the ketone, e.g., 6-fluoro-8H-indeno [2,1-b]furan-8-one. This ketone can be derivatized in accordance with Method V. Hydantoin derivatization (Method I) yields the spiro-hydantoin, e.g., spiro-(6-fluoro-8H-indeno[2,1-b]furan-8,4'-imidazolidine)-2',5'-dione. Reduction according to methods cited in Method VIII yields the corresponding 8H-indeno[2,1-b]furan derivative which can be derivatized in accordance with Methods II, III and IV into the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide. Furthermore, the spiro-derivatives may be further derivatized according to Method VI.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C@@H:9]([C:17]([OH:19])=O)[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([CH2:8][C@H:9]([NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[C:17]2=[O:19])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOc1ccc2c(c1)C(=O)[C@@H](NC(=O)C(F)(F)F)C2
Reaction time: 1 h

Procedure:
O-Ethyl-N-trifluoroacetyl-L-tyrosine (XIII, Example 17, 1.52 g, 5 mmol) and ferric chloride (0.89 g, 5 mmol) are suspended in methylene chloride (36 mL). Trifluoroacetic anhydride (2.12 mL, 15 mmol) is added over 1 hr at 20-25°. The reaction is stirred for 1 hr and then quenched with water (36 mL). The organic layer is separated and mixed with methanol (7 mL). The mixture is cooled to −20° for 1 hr and then filtered to give the same title compound as EXAMPLE 4.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][CH2:7][CH2:8][C:9]([CH2:12]O)=[C:10]([CH3:11])[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.CS([Cl:29])(=O)=O.C(OCC)C>ClCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][CH2:7][CH2:8][C:9]([CH2:12][Cl:29])=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1=C(CO)CCOc2ccc(Br)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=C(CCl)CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 125 %

Procedure:
To a solution of (7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepin-4-yl)methanol from step H6 (1.53 g, 5.68 mmol) in dichloromethane (10 mL) was added DIPEA (2.98 mL, 17.1 mmol) followed by methanesulfonyl chloride (0.886 mL, 11.4 mmol) at 0° C. The mixture was allowed to gradually warm up to rt. After 18 h at rt, diethyl ether (50 mL) was added, the mixture was washed with water, and the organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to give 7-bromo-4-(chloromethyl)-5-methyl-2,3-dihydrobenzo[b]oxepine (2.05 g, 7.13 mmol, 125% yield). The crude material was used in the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 7.40 (d, J=2.4 Hz, 1H), 7.36-7.32 (m, 1H), 6.96 (s, 1H), 4.56 (t, J=6.3 Hz, 2H), 4.37 (s, 2H), 2.34 (t, J=1.0 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (11.4 mmol; 4.65 g) in THF (30 mL) and methanol (20 mL) was added a 1M solution of sodium hydroxide (28.4 mmol; 28.4 mL) and the resulting mixture was heated to reflux for 48 hours. The resulting mixture was then evaporated and a 1N hydrochloric acid solution (200 mL) was added to the residue. A white precipitate formed that was separated via filtration to yield 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. MS (ESI) m/z 395.76 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:16]C1C=CC(CCl)=CC=1.[Mg].C(OCC)(=O)C(OCC)=O>>[Cl:16][C:6]1[CH:5]=[CH:4][C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2][CH:7]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccc(Cl)cc1
Yield: 74 %

Procedure:
The title compound was prepared as described for B4 using 4-chlorobenzyl chloride (1.250 g, 7.76 mmol), magnesium (0.208 g, 8.54 mmol) and diethyl oxalate (2.269 g, 15.53 mmol). The product was isolated in the form of colorless oil in 74% yield and used instantly in next step.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([C:13]([OH:15])=[O:14])[O:11][C:10](=[O:16])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:18]1NCC(C(O)=O)O1.[OH-].[K+].Cl.[CH3:29][CH:30]([OH:32])[CH3:31]>ClCCl>[C:30]([O:32][C:10]([NH:9][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:12]([OH:11])[C:13]([OH:15])=[O:14])=[O:16])([CH3:18])([CH3:31])[CH3:29]
Reactant: CC(C)O
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@H](C(=O)O)O1
Reactant: O=C1NCC(C(=O)O)O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To (4S,5R)-4-benzyl-2-oxo-5-oxazolidinecarboxylic acid obtained in the same manner as in Example 4 (2.39 g) were added 2-propanol (6.7 ml) and 8N aqueous potassium hydroxide solution (6.7 ml), and the mixture was stirred at 90° C. for 3 hr. The mixture was cooled to room temperature and adjusted to pH=8 with 6N aqueous hydrochloric acid solution. To the reaction mixture was added di-tert-butoxycarbonate (2.83 g) dissolved in 2-propanol (6.7 ml) and the mixture was stirred at room temperature for 12 hr. After adjusting the mixture to pH=3, dichloromethane (20 ml) was added to extract the mixture. The solvent of the organic layer was removed under reduced pressure to give crude crystals of (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (2.88 g). The crude crystals were analyzed by HPLC to confirm that (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid (2.55 g, yield 80%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].Br[C:13]#[N:14].O>C(O)C>[N+:1]([C:4]1[C:5]2[NH:11][C:13]([NH2:14])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: N#CBr
Solvent: O
Solvent: CCO
Product: Nc1nc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 1.53 g (10 mmol) of 3-nitro-benzene-1,2-diamine in ethanol (20 mL) was added 1.3 g (12.5 mmol) of BrCN and water (5 mL). The mixture was refluxed for 1.0 h. After cooling to room temperature, the solvent was concentrated, then the residue was dissolved in water, the pH was adjusted to 8.0 with sat. NaHCO3 solution. The resulting solid was filtered, washed with water and dried under vacuum to afford 1.42 g (80%) of the 7-nitro-1H-benzoimidazol-2-ylamine. LCMS: 179 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].ClC(Cl)C.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[Cl:14][C:15]([Cl:20])([Cl:19])[C:16]([O:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[O:17]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Hydroxyethylmethacrylate (13.0 g) was placed in a 250 ml, three-necked, round-bottomed flask, fitted with a stirrer, air condenser and two dropping funnels, as well as a thermometer. The apparatus was placed in an ice/salt freezing bath. Dichloroethane (100 ml) was added, followed by the simultaneous dropwise addition of triethylamine (10.1 g) and trichloroacetyl chloride (18.2 g). During the addition the temperature was not allowed to rise above 2° C. After the addition was complete, the mixture was stirred for a further 6 hours, during this time the temperature rose gradually to room temperature. The mixture stood overnight, and the precipitated salt was filtered off, and the residue was washed thoroughly with dichloroethane. The washings and the filtrate were combined and the solvent was removed on a rotary evaporator. The residue still contained some solid. It was dissolved in ether, the ether solution was washed with water (3 times). The solution was then dried (MgSO4), filtered, and the solvent was removed under vacuum. The residue was distilled under high vacuum, collecting the fraction, boiling between 84°-90° C./0.1 mm (16 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH3:13][O:14][C:15]([C:17]1[C:22]([NH:23][C:10](=[O:12])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: O=C(O)Cc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1nccnc1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nccnc1NC(=O)Cc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
To a solution of (3,5-dichloro-pyrid-2-yl)-acetic acid (Example 5.1) (5.7 g) and 3-amino-pyrazine-2-carboxylic acid methyl ester (4.65 g) in dichloromethane (120 ml) were added successively triethylamine (8.5 ml) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (“BOP-Cl”) (7.5 g). The reaction mixture was stirred at ambient temperature for 24 hours. The organic phase was washed successively with water, aqueous sodium hydrogen carbonate (1M), and brine. The organic phase was dried over magnesium sulfate and concentrated to give 3-[2-(3,5-dichloro-pyrid-2-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (6.37 g). 1H-NMR (400 MHz, CDCl3): 4.04 (s, 3H), 4.35 (s, 2H), 7.77 (s, 1H), 8.39 (s, 1H), 8.49 (s, 1H), 8.56 (s, 1H), 11.02 (s, 1H) ppm.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)([CH2:10][CH2:11][C:12]([O:14]C)=O)[CH2:4][CH2:5][C:6]([O:8]C)=O)#[N:2].C[O:27]C1C=C(CC#N)C=CC=1OC>>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[C:3]1([CH2:10][CH2:11][C:12](=[O:14])[NH:2][C:1]1=[O:27])[CH2:4][CH2:5][C:6]2=[O:8]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC)c1
Product: COc1cc2c(cc1OC)C1(CCC(=O)NC1=O)CCC2=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
Unpurified dimethyl γ-cyano-γ-(3,4-dimethoxyphenyl)pimelate, prepared from 334 grams of 3,4-dimethoxyphenylacetonitrile as described by Horning et al., J. Am. Chem. Soc., 74, 773 (1942), was added with stirring to 3.0 kg of polyphosphoric acid. This reaction mixture was stirred at 110° C. for 2 hours and poured into 6.0 liters of crushed ice with stirring. The resulting solid was filtered and recrystallized from isopropyl alcohol-water to give 65.8 grams (18%) of 2,3-dihydro-6,7-dimethoxyspiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 269°-271° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Cl:27])=[CH:15][C:14]=1[C:28]1[O:32][N:31]=[C:30]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[C:29]=1[NH2:38])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:36]([NH:35][C:33]([C:30]1[C:29]([NH:38][C:1](=[O:3])[CH3:2])=[C:28]([C:14]2[CH:15]=[C:16]([Cl:27])[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:13]=2[O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:32][N:31]=1)=[O:34])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1N
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1NC(C)=O
Reaction time: 5 h

Procedure:
To a solution of acetyl chloride (1.45 mmol) in DCM were added 5-[2,4-bis(benzyloxy)-5-chlorophenyl]-4-amino-N-ethylisoxazole-3-carboxamide (1.45 mmol, 700 mg) and TEA (1.74 mmol, 0.24 ml) dropwise. The mixture was stirred for 5 h, diluted with DCM and washed HCl 1N. The organic extract was dried and filtered. Solvents were removed under vacuo to give the crude residue that was purified by flash chromatography on silica gel.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10](O)=O)=[O:7])(C)(C)C.[CH3:13][N:14](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(N[CH:52]1CC[CH2:55][N:54]([C:58]2[C:59]3[CH:66]=[CH:65][N:64](S(C4C=CC(C)=CC=4)(=O)=O)[C:60]=3[N:61]=[CH:62][N:63]=2)[CH2:53]1)C1C=CC=CC=1.Cl>CN(C=O)C.CCOC(C)=O>[N:61]1[C:60]2[NH:64][CH:65]=[CH:66][C:59]=2[C:58]([N:54]2[CH2:53][CH2:52][CH2:10][CH:9]([NH:8][C:6](=[O:7])[CH2:13][NH2:14])[CH2:55]2)=[N:63][CH:62]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(NCc5ccccc5)C4)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NCC(=O)NC1CCCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)acetic acid (0.7 g, 4 mmol), HATU (1.5 g, 4 mmol), Et3N (1.1 mL, 4 mmol) in DMF (60 mL) was added N-benzyl-1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (1.8 g, 40 mmol). After stirring at RT for 4 h, the solution was diluted with EtOAc and washed with water, aq. citric acid and aq. NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to a solid. The Boc protected amine was dissolved in 1,4-dioxane (10 mL) and treated with 4 N HCl (10 equiv.) at rt for 5 h. The solvent was concentrated in vacuo to afford N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-aminoacetamide as a solid which was used without any additional purification.
Reaction SMILES: [C:1]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)/C=C\C(O)=O.ClC1[N:31]=[N:30]C2CCNCC=2C=1.C(Cl)(=O)CCC>C(#N)C>[C:1]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([NH:30][NH2:31])=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: CCCC(=O)N1CCc2nnc(Cl)cc2C1
Agent: CCCC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC#N
Product: CCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 6-butyryl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, requires as starting material, may be produced in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and butyric acid chloride. Reaction time 27 hours. M.P. 130°-133° from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]2)=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]2)=[CH:8][C:9]=1[N:10]([C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-cyclohex-2-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg) and MeOH (3 mL) cooled to 0° C. was added NaBH4 (15 mg) in one portion. Reaction was complete in 5 min. HCl (0.1 N, 0.5 mL) was added until it was acidic. It was evaporated and then extracted with DCM, washed with saturated NaHCO3 solution, brine, dried (MgSO4) and evaporated. The crude was purified by chromatography over silica gel (hexane:EtOAc-1:1 as eluent) yielding pure 5-Cyclohex-2-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (12 mg, 26%) in two steps.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:8]([Cl:13])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Cl)sc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)sc1C(=O)Cl

Procedure:
8.8 g of 2-chloro-4-methylthiazole-5-carboxylic acid was suspended in 7 ml of thionyl chloride, and one drop of N,N-dimethylformamide was added. The mixture was heated under reflux for 1 hour, and then the excess of thionyl chloride was evaporated under reduced pressure. Benzene (10 ml) was added, and the mixture was evaporated under reduced pressure. This procedure was repeated three times to give 9.7 g of 2-chloro-4-methylthiazole-5-carboxylic acid chloride which was used in the following reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24].C(N(CC)C(C)C)(C)C.O>C1COCC1>[CH3:21][O:20][C:3]1[C:4]([CH:14]([OH:19])[C:15]([F:18])([F:16])[F:17])=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:7][C:2]=1[NH:1][C:23](=[O:24])[O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1c(N)cc(N2CCOCC2)cc1C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(N2CCOCC2)cc1C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a solution of 1-(3-amino-2-methoxy-5-morpholinophenyl)-2,2,2-trifluoroethanol (2.35 g, 7.67 mmol) in THF (20.4 mL), 2,2,2-trichloroethyl chloroformate (1.14 mL, 8.28 mmol), N,N-diisopropylethylamine (4.02 mL, 23.0 mmol) was added, and the mixture was stirred at 0° C. for 15 minutes. Water was added to the reaction solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20-60/40) to obtain 3.45 g (93% yield) of the captioned compound.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1>C(=O)=O.CC(C)=O>[NH2:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:1])=[O:17])=[CH:10][CH:9]=1
Reactant: CO
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C/c1ccc(N)nc1

Procedure:
To methanol (5 ml) in dry ice-acetone bath was added thionyl chloride (0.41 ml) dropwise over 5 minutes. After (E)-3-(6-Aminopyridin-3-yl)acrylic acid (700 mg) was added to the mixture, the reaction mixture was heated at reflux for 1 hour, and the solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The precipitate was collected by vacuum filtration and washed with isopropyl ether to give methyl (E)-3-(6-aminopyridin-3-yl)acrylate (725 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc(Cl)ccc1C=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1C=Nc1ccccc1
Yield: 32.7 %

Procedure:
A mixture of 4-chloro-2-methylbenzaldehyde (3.5 g, 22.6 mmol) and aniline (2.11 g, 22.6 mmol) in toluene (40 ml) was heated at reflux in a Dean-Stark apparatus for 1 hour. The mixture was cooled and evaporated in vacuo to leave an oily residue. The residue was redissolved in ether, washed with 5% sodium bicarbonate solution. The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford an oily residue which was purified by distillation via a Kugelrohr apparatus (oven temperature 160° C., 0.5 mm) to provide the title compound (4.0 g, 7.4 mmol, 77%) as a viscous oil; pmr(CDCl3) δ2.5(3H,s), 6.3~7.5(7H,m), 7.95(H,d), 8.6(H,s).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)[N:22]=[C:21]4[NH:32][CH:33]=[CH:34][C:20]=34)[CH:18]=2)=[CH:9][CH:8]=1.[OH-].[Na+].O.CC(O)=O>CO>[CH3:31][C:27]1[N:26]=[C:25]([C:23]2[N:22]=[C:21]3[NH:32][CH:33]=[CH:34][C:20]3=[C:19]([C:17]3[CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:6][NH:5][CH2:4][C:3]([OH:35])=[O:2])=[CH:8][CH:9]=4)[CH:14]=[N:15][CH:16]=3)[CH:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CNCc1ccc(-c2cncc(-c3cc(-c4cccc(C)n4)nc4[nH]ccc34)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(-c2cc(-c3cncc(-c4ccc(CNCC(=O)O)cc4)c3)c3cc[nH]c3n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-{5-[6-(6-methyl-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyridin-3-yl}-benzylamino)-acetic acid methyl ester (Example 133) (1 eq, 0.216 mmol, 100 mg) in MeOH (10 ml) is added aqueous NaOH solution (1 M, 25 eq, 5.39 mmol, 5.39 ml). The resulting mixture is stirred for 1 h at r.t. Water is added, then the mixture is adjusted to pH 4 using AcOH, then washed with DCM/isopropanol (3:1). The aqueous layer is concentrated in vacuo, and the remaining residue is purified by column chromatography (DCM/MeOH/NH3) and subsequent reversed phase HPLC giving the title compound; [M+H]+=450; 1H-NMR (400 MHz, CD3OD): δ 9.01 (m, 1H), 8.92 (m, 1H), 8.52 (m, 1H), 8.31 (d, 1H), 8.25 (s, 1H), 7.98-7.87 (m, 3H), 7.69-7.62 (m, 3H), 7.40 (d, 1H), 6.73 (d, 1H), 4.32 (s, 2H), 3.70 (s, 2H), 2.69 (s, 3H).