Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[N+:15]([O-])=O)=[C:4]([N+:18]([O-])=O)[CH:3]=1.Cl.[Sn].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([C:8]2[C:9]([NH2:15])=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Br)ccc1-c1ccc(Br)cc1N
Temperature: 100 °C
Yield: 72.1 %

Procedure:
To a solution of 4,4′-Dibromo-2,2′-dinitro-biphenyl (15.0 g, 37.3 mmol) in ethanol (abs., 186 cm3) was added 32% w/w aqueous HCl (124 cm3). Tin powder (17.6 g, 147 mmol) was added portion-wise over 10 minutes and the reaction mixture was heated to reflux at 100° C. for 2 hours. After cooling, the mixture was poured into ice water (ca. 400 cm3) and then basified with 20% w/w aqueous NaOH solution (150 cm3). The product was extracted with diethyl ether and the organic layer washed with brine, dried over anhydrous MgSO4 and evaporated to dryness. Purification by recrystallization from ethanol afforded the title compound (9.2 g, 72%) as light brown crystals (Found: C, 42.1; H, 3.0; N, 8.0. C12H10Br2N2 requires C, 42.2; H, 3.0; N 8.2%); νmax/cm−1 (Neat solid) 792, 994, 1406, 1477, 1608, 3210, 3357, 3443; δH(400 MHz, CDCl3) 6.92 (6H, s, ArH), 3.78 (4H, brs, NH2); δC(100 MHz, CDCl3) 118.1, 121.7, 122.0, 122.7, 132.2, 145.4; m/z (ES) 340.9283 ([M+H)+. C12H11Br2N2 requires 340.9284), 343.1 (100%), 263.1 (80), 185.1 (25).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH2:12])[C:4]=2[O:3]1.C(N(C(C)C)C(C)C)C.Cl[C:24]([O:26]C)=[O:25]>O1CCCC1>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH:12][C:24]([OH:26])=[O:25])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(NN)c2O1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(NNC(=O)O)c2O1
Reaction time: 1 h

Procedure:
17.8 g of (1C) thus prepared and 12.9 go f ethyldiisopropylamine were dissolved in 200 ml of tetrahydrofuran. 9.45 of methyl chloroformate was added drop-by-drop to the stirred solution, and the resulting mixture was stirred for one hour. The solvent then was evaporated, the residue was washed with water, extracted with ether, and the extract was dried. Part of the ether was evaporated from the extract and the remaining solution was cooled. The resulting solid was collected to give the methyl ester of 2-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)hydrazine-carboxylic acid (1D), as a white solid, m.p.: 101°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:41][C:40]([SH:42])=[N:39][N:38]=2)=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[O:41][C:40]([SH:42])=[N:39][N:38]=4)=[CH:35][CH:36]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: Nc1ccc(-c2nnc(S)o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(-c5nnc(S)o5)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 19.6 %

Procedure:
A mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (100 mg, 0.245 mmol), 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol (53 mg, 0.27 mmol), EDCI (94 mg, 0.49 mmol) and DMAP (90 mg, 0.735 mmol) in 5 mL of DMF was stirred at room temperature for 40 hours. The mixture was poured into water and extracted with EtOAc (3×10 mL). The water layer was allowed to stand overnight then filtered to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)benzamide (28 mg, 19.5%) as white solid. 1H NMR (300 MHz, DMSO): δ 10.67 (s, 1H), 10.20 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 9.61 (d, 1H, J=7.8 Hz), 8.10 (d, 1H, J=8.1 Hz), 7.96-7.93 (m, 3H), 7.83-7.68 (m, 4H), 7.55 (d, 1H, J=6.6 Hz), 6.99 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.74 (s, 3H). LC-MS: 584 [M+H]+, 582 [M−H]−, tR=1.61 min. HPLC: 96.43% at 214 nm, 96.83% at 254 nm, tR=4.60 min.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][CH3:46]>CN(C=O)C>[CH3:46][O:45][CH2:44][CH2:43][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(O)ccc5c34)c1C)C2
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(N4Cc5ccc(C)cc5C4=O)c3C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 40-2, 30 mg, 0.065 mmol) and potassium carbonate (18 mg, 0.130 mmol) in DMF (1.0 mL) was stirred at rt for 30 min, then was treated with 1-bromo-2-methoxyethane (14 mg, 0.098 mmol). The mixture was heated at 90° C. for 4 h, cooled to rt and concentrated under vacuum. The residue was purified by preparative HPLC to provide 7-(2-methoxyethoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (12.5 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1H, s), 8.17 (1 H, br. s.), 7.95 (1H, d, J=7.9 Hz), 7.54-7.64 (3H, m), 7.49 (3H, t, J=8.0 Hz), 7.27-7.38 (2H, m), 7.00 (1H, d, J=7.9 Hz), 6.91 (1H, d, J=8.8 Hz), 6.59 (1H, dd, J=8.8, 2.4 Hz), 4.91 (2H, d, J=3.3 Hz), 4.12 (2H, dd, J=5.5, 3.1 Hz), 3.63-3.75 (2H, m), 3.33 (3H, s), 2.44 (3H, s), 1.83 (3H, s). Mass spectrum m/z 520.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:11]=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7]
Reactant: O=C(CBr)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: N#Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1H-Pyrrole-2-carbonitrile (0.84 ml; 9.42 mmol) and 1-{4-[4-(2-bromo-acetyl)phenyl]-piperidin-1-yl}-2,2,2-trifluoro-ethanone (2.74 g; 7.25 mmol) are dissolved in acetone (25 ml). To this clear brown solution potassium carbonate (2 g; 14.49 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is filtered off by suction and washed with acetone. The filtrate is evaporated to dryness. The residue is purified by flash chromatography to afford 1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carbonitrile as pale off-white crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[C:7]2=[O:14].[Cl:15][C:16]1[CH:27]=[C:20]2[C:21](OC(=O)[NH:25][C:19]2=[CH:18][CH:17]=1)=[O:22].CO>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:27]=[C:20]2[C:19](=[CH:18][CH:17]=1)[N:25]=[C:8]1[C:7](=[O:14])[C:6]3[C:10]([N:9]1[C:21]2=[O:22])=[CH:11][CH:12]=[C:4]([F:3])[CH:5]=3
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(F)ccc2-n2c1nc1ccc(Cl)cc1c2=O
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (10 mmol, 40 mg 60%) in 4 mL of DMF was added 10 mmol of 5-fluoroisatin in 2 mL of DMF. After 15 min, a solution of 5-chloroisatoic anhydride in 3 mL of DMF was added. The reaction mixture was stirred for 18 h, methanol (0.5 mL) and 20 mL of chloroform was added and the organic solution was washed with water, dried (MgSO4) and concentrated to give a residue which was purified by silica gel chromatography (CHCl3 :CH3OH). Yield 77%: mp 280°-282° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[N:3]1.C([Li])CCC.C(O[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(C)C>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[C:6]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)=[C:5]([CH3:7])[CH:4]=[N:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cnn(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1,4-Dimethyl-1H-pyrazole (50 mg, 0.5 mmol) was stirred in THF (2 mL) and cooled to 0° C. A solution of 1.6 M n-butyllithium in hexanes (390 mL) was added dropwise by syringe and the mixture was allowed to warm to room temperature for 2 h. The mixture was cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110 mL, 0.52 mmol) was added dropwise by syringe. The mixture was stirred at −78° C. for 15 min. and at 0° C. for 3 h. The mixture was diluted with EtOAc and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel using EtOAc in hexanes gave the sub-title compound. LCMS calc. for C11H20BN2O2 (M+H)+: m/z=223.2. found: 223.0.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:9][N:8]=1.CN([CH:23]=[O:24])C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[C:10]1[CH:11]=[CH:12][C:7]([CH:23]=[O:24])=[N:8][CH:9]=1)[CH3:16]
Reactant: CN(C)C=O
Reactant: CCOC(OCC)c1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(OCC)c1ccc(C=O)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
To toluene (3 mL) were added dropwise at −78° C. n-butyllithium (2.6 mol/L solution in n-hexane, 0.94 mL, 2.43 mmol) and a solution of 2-bromo-5-(diethoxymethyl)pyridine (575 mg, 2.21 mmol) obtained in Step 1 of Reference Example 42 in toluene (2 mL), and the mixture was stirred at −78° C. for 30 minutes. THF (2 mL) was added to the resulting suspension and the mixture was stirred at −78° C. for 30 minutes. DMF (0.51 mL, 6.63 mmol) was added and the mixture was stirred for 30 minutes allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 5-(diethoxymethyl)picolinaldehyde (149 mg, 32% yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)=[CH:3][N:4]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: O=C(O)Cc1ccc(S)cc1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccc(CC(=O)O)cc3)s2)c(C(=O)C2CCCC2)c1
Yield: 28.2 %

Procedure:
(4-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-phenyl)-acetic acid (140 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and (4-mercapto-phenyl)-acetic acid (336 mg, 2 mmol) following the general procedure Y.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(F)ccc2c1OCCO2
Solvent: CN(C)C=O
Product: Nc1c(F)cc(Cl)c2c1OCCO2
Yield: 61.4 %

Procedure:
In a flask were placed 3.05 g (0.018 mole) of 5-amino-6-fluoro-1,4-benzodioxane and 40 mL of N,N-dimethylformamide. To this solution was added in a dropwise manner a solution of 2.65 g (0.0198 mole) of N-chlorosuccinimide in N,N-dimethylformamide while maintaining the temperature at ambient conditions. The solvent was evaporated under reduced pressure, leaving a residue which was passed through a column of silica gel, eluting with methylene chloride/heptane (1:1 ). Product-containing fractions were combined and the solvent evaporated, yielding 2.25 g of 5-amino-8-chloro-6-fluoro-1,4-benzodioxane as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O.[OH-].[Na+]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][CH2:3][OH:4])=[C:8]([C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: OCCOc1ccc(Br)cc1C(F)(F)F
Yield: 80.3 %

Procedure:
2-Bromoethanol (10.37 g) was added to a mixture of 4-bromo-2-(trifluoro-methyl)phenol (20 g) and potassium carbonate (22.94 g) in Acetonitrile (150 ml). The above reaction mixture was refluxed overnight, then diluted with ethyl acetate (500 ml), water (300 ml) the 0.5M sodium hydroxide (300 ml). Organic layer was separated and dried over magnesium sulphate, solvent removed under reduced pressure to give white solid (19 g), NMR consistent with product. 1H NMR (CDCl3) δ: 7.69 (d, 1H), 7.58 (dd, 1H), 6.91 (d, 1H), 4.15 (t, 2H), 3.97 (t, 2H).
Reaction SMILES: [C:1]([C:3]1[C:7](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5](=[O:19])[C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:22][CH:21]=1)#[N:2].O1CCCC1.Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[C:1]([C:3]1[C:7](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5](=[O:19])[C:4]=1[C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCCCCCN1C(=O)C(c2ccc(N(CCCCCC(=O)OC)CC(CC)CCCC)cc2)=C(C#N)C1=C(C#N)C#N
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCCCN1C(=O)C(c2ccc(N(CCCCCC(=O)O)CC(CC)CCCC)cc2)=C(C#N)C1=C(C#N)C#N
Yield: 87.5 %

Procedure:
The prepared methyl 6-((4-(4-cyano-5-(dicyanomethylene)-1-hexyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenyl)(2-ethylhexyl)amino)hexanoate (7.5 g, 12.8 mmol) and tetrahydrofuran (50 ml) were loaded into a flask and stirred. Hydrochloric acid (20 ml, 3 N) was added thereto, and the mixture was allowed to react at 65° C. for 24 hours with stirring. The reaction product was transferred into a separate funnel, and was then added with water and dichloromethane, after which the organic layer was isolated therefrom, dehydrated using sodium sulfate, and then distilled under reduced pressure. Subsequently, the obtained material was separated through silica column chromatography, thus obtaining 6.4 g of a dark blue solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=C[N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].[N:17]1C2NC=C(C(=O)C)C=2C=CN=1>>[C:1]([C:4]1[C:12]2[CH:11]=[CH:10][N:9]=[N:17][C:7]=2[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2nnccc12
Reactant: CC(=O)c1cn(CC(=O)O)c2cnccc12
Product: CC(=O)c1cn(CC(=O)O)c2nnccc12

Procedure:
was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3-c]pyridin-1-yl)-acetic acid in Scheme A15 from 1-(7H-pyrrolo[2,3-c]pyridazin-5-yl)-ethanone (prepared according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 220.1 [M+H]+, 178.0 [MH-CH3CO]+, 218.1 [M−H]−, 437.2 [2M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].CO>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ncc([C@@H]3CCCO3)[nH]2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(-c2ncc([C@@H]3CCCO3)[nH]2)cc1C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask was added a solution of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.3, 400 mg, 1.33 mmol, 1.00 equiv) and sodium hydroxide (300 mg, 7.50 mmol, 5.63 equiv) in a solvent mixture of methanol and H2O (20/10 mL). The resulting solution was stirred for 2 h at 70° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residual aqueous layer was washed with 2×50 mL of ethyl acetate. The pH of the aqueous layer was adjusted to 5-6 with hydrogen chloride (aq., 6 M), then extracted with 3×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 340 mg (90%) of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as a yellow solid.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:16]N1C(=O)CCC1=O.[Na+].[Cl-]>C(Cl)(Cl)Cl>[Cl:16][C:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ON=C(Cl)c1ccccc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To benzaldehyde oxime (12.2 g, 0.1 mol) in chloroform was added catalytic amount of pyridine, followed by N-chlorosuccinimide (13.35 g, 0.1 mol) at room temperature. The reaction mixture was stirred for 1.5 h, then saturated aqueous NaCl was added. The organic phase was washed with saturated aqueous NaCl (twice) and dried with MgSO4. The solvent was removed under reduced pressure. 13.85 g α-chlorobenzaldehyde oxime was obtained. The yield was 87%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.Cl.CO>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:16][CH2:17]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
1,1-Dimethylethyl (1-{2-[7-(methyloxy)-2-oxo-1(2H)-quinolinyl]ethyl}-4-piperidinyl)carbamate (2.25 g; 5.61 mmol) was dissolved in a mixture of chloroform (20 ml) and HCl (15 ml) and stirred at rt under argon for 1 hour. The salts were dissolved in MeOH and a small amount of toluene added, all the solvents were then removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until a neutral pH was reached. The resin was filtered off and the solvent removed and the crude residues were purified by column chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient, to give the desired product (900 mg; 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][N:26]1[CH:30]=[C:29]([Sn](CCCC)(CCCC)CCCC)[CH:28]=[N:27]1.O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:29]1[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3cnn(C)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 53.7 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 1-methyl-4-tributylstannanyl-1H-pyrazole (0.1 mL, 0.31 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., water and EtOAc were added. 1 M HCl was added until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (50% EtOAc/CH2Cl2, then 100% EtOAc+1% AcOH) to give 44 mg of the title compound. MS: (+) m/z 391.29 (M+1).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])C.CN(C(ON1N=NC2C=[CH:22][CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:7]1([N:3]2[CH2:2][CH2:1][C:6]3([CH2:22][CH2:23][NH:24][CH2:19]3)[CH2:4]2)[CH2:8][CH2:9]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: C1CC2(CCN(C3CC3)C2)CN1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To an ice-cold solution of acid S3 (0.612 mmol) and DIPEA (1.3 mmol) in THF (2.5 ml) was added HATU (0.612 mmol) and the reaction mixture was stirred for 15 min. Then a solution of amine A12 (0.735 mmol) in THF (1 ml) was added slowly and allowed to stir at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography using 1-5% MeOH in DCM as eluent. Yield: 50% 2. To a solution of step-1 product (180 mg) in MeOH (5 ml) was added 1N NaOH solution (5 ml) at 0° C. Then the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography on neutral alumina using 1-10% MeOH in DCM as eluent. m/z=530.7 [MH]+