Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][C@@H:30]([CH2:33][F:34])[CH2:29]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1.N#N>C(OCC)(=O)C.C(O)C.C(OCC)(=O)C.[Pd]>[F:34][CH2:33][C@@H:30]1[CH2:31][CH2:32][N:28]([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][N:14]3[C:15]4[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=4)[C:12]([CH3:49])=[C:13]3[C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)=[CH:20][CH:21]=2)[CH2:29]1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCN3CC[C@@H](CF)C3)cc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CC[C@@H](CF)C3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A solution of (R)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indole (263 mg, 0.40 mmol) in ethyl acetate/ethanol (4:1, 6 mL) was degassed with three vacuum/N2 cycles. To this solution was added 10% Pd on carbon (120 mg, 0.11 mmol) and then the needle of a H2 balloon was placed into the reaction flask. The mixture was stirred at room temperature for 15 hrs then diluted with ethyl acetate, filtered through Celite and concentrated. The residue was dried further on high vacuum to give 171 mg of (R)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 8.69 (s, 1H), 7.16 (d, 2H), 7.06 (d, 1H), 6.85 (d, 2H), 6.80 (d, 1H), 6.75 (s, 4H), 6.57 (dd, 1H), 5.10 (s, 2H), 4.35-4.30 (m, 1H), 4.23-4.18 (m, 1H), 3.94 (t, 2H), 2.70 (t, 2H), 2.62 (t, 1H), 2.56-2.40 (m, 3H), 2.38-2.31 (m, 1H), 2.10 (s, 3H), 1.87-1.76 (m, 1H), 1.40-1.31 (m, 1H). LCMS: 475.2 (M+H)+.
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]1[CH:14]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:25][CH2:26][C:27](O)=[O:28])[C:16]2=[O:30])[CH2:13][CH2:12][C:11](=[O:31])[NH:10]1.ClC(OCC)=O.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>C1COCC1>[CH:38]1([NH:41][C:27](=[O:28])[CH2:26][NH:25][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[C:23](=[O:24])[N:15]([CH:14]2[CH2:13][CH2:12][C:11](=[O:31])[NH:10][C:9]2=[O:8])[C:16]3=[O:30])[CH2:40][CH2:39]1
Reactant: O=C(O)CNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NCC(=O)NC4CC4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
N-Methylmorpholine (0.15 g, 1.5 mmol) was added to a stirred suspension of [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]acetic acid (0.50 g, 1.5 mmol) in 50 mL THF under nitrogen at room temperature. Ethyl chloroformate (0.16 g, 1.5 mmol) was then added. Following 30 minutes stirring at room temperature, cyclopropylamine (0.086 g, 1.5 mmol) was added, and stirring proceeded for 21 hours. The solvent was evaporated in vacuo, and the dark yellow residue was dissolved in ethyl acetate (200 mL) and washed with sat. sodium bicarbonate (2×100 mL), water (100 mL), 1N citric acid (2×100 mL), water (100 mL) and brine (100 mL). The organic phase was dried (MgSO4) and evaporated to provide 0.15 g (27%) of the product as a yellow solid: mp 240-242° C.; 1H NMR (DMSO-d6) δ 0.39-0.45 (m, 2H), 0.59-0.73 (m, 2H), 2.02-2.06 (m, 1H), 2.45-2.70 (m, 3H), 2.96-2.83 (m, 1H), 3.88 (d, J=5.3 Hz, 2H), 5.07 (dd, J=12.5 Hz, J=5.3 Hz, 1H), 6.83-6.92 (m, 2H), 7.07 (d, J=7.0 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 5.57, 22.13, 22.26, 30.96, 44.92, 48.59, 109.77, 110.88, 117.42, 132.02, 136.17, 145.80, 167.28, 168.68, 169.46, 170.07, 172.77; Anal. calcd. for C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C, 58.16; H, 4.64; N, 14.84.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][N:22](CC3C=CC=CC=3)[CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Yield: 69.8 %

Procedure:
To the solution of 5-Phenyl-3-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole-7-carboxamide (2.66 g, 6.5 mmol) in ethanol (150 mL) and acetic acid (3 mL) was added Pd(OH)2 (20% by weight on carbon) (0.8 g,) at ambient temperature. The solution was stirred under 1 atm of hydrogen for 2 days. The reaction mixture was then filtered through Celite, neutralized with 5% sodium hydroxide solution, and extracted with ethyl acetate. The solvent was removed under reduced pressure to yield the desired product (1.45 g, 70%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:30])[CH2:10][CH2:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:17][CH:16]=1.[C:31]([O:35][C:36](=[O:49])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][NH2:48])([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([O:35][C:36](=[O:49])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][NH:48][C:9](=[O:30])[CH2:10][CH2:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:20]=1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)cc1

Procedure:
A solution of 4-[4-(3,5-dioxo-hexyl)-phenylcarbamoyl]-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 g, 3.6 mmol), 3-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-propionic acid tert-butyl ester (1.0 g, 3.6 mmol) and DIEA (1.3 μL, 7.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The solvent was removed in vacuo and the residual oil purified using column chromatography EtOAc/MeOH (95:5) to give the title compound as a transparent oil, (M+1)=579.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:28])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[CH3:28]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C(F)(F)F)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=385.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:10])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Nc1ccccn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminopyridine (2.0 mL, 21.25 mmol) in DCM (35 mL) at 0° C. was added a solution of 4-nitrophenyl chloroformate (4.28 g, 21.25 mmol) in DCM (35 mL) and pyridine (1.73 mL, 21.25 mmol, anhydrous). After the addition was completed, the reaction mixture was stirred at RT for 16 h under an atmosphere of nitrogen. A white precipitated was observed and it was collected by filtration. The filtrate was washed with DCM (3×50 mL) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 260 (M+H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:23])[CH3:22])[C@@H:16]([CH3:24])[CH2:15][NH:14]2.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>ClCCCl>[C:21]([N:17]1[C:18]2[C:13](=[CH:12][C:11]([Br:10])=[CH:20][CH:19]=2)[N:14]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:15][C@@H:16]1[CH3:24])(=[O:23])[CH3:22]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
N,N-Diisopropylethylamine (0.973 mL, 5.57 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.500 g, 1.858 mmol) and isopropyl chloroformate (1.0 M in toluene, 2.79 mL, 2.79 mmol) in 1,2-dichloroethane (10.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.558 g, 85%) as an off-white solid. MS (ESI, pos. ion) m/z 355, 357 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[NH:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2.Cl.N1C=CC=CC=1>O.C([O-])(O)=O.[Na+]>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[N:30]=[C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[NH:28][N:27]=5)[CH2:22][CH2:21]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:3](=[O:2])[C:4]=3[CH:5]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1nccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 5-methoxy-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridine (725 mg, 1.31 mmol) and pyridine hydrochloride (6.9 gm, ˜60 mmol) was heated at 150° C. for ten minutes. The cooled residue was dissolved in the minimum amount of water and neutralized with aqueous NaHCO3. The precipitated solid was collected by filtration and purified by column chromatography on silica gel eluting with 1-14% methanol/ethyl acetate (sat'd NH4OH). The isolated product was digested in methanol/acetonitrile to give pure product. 1H NMR (500 MHz, DMSO-d6): δ 11.58 (1H, d, J=4.8 Hz), 8.68 (1H, br s), 8.39 (1H, s), 8.03 (1H, d, J=7.3 Hz), 7.50 (2H, t, J=6.5 Hz), 7.31-7-33 (5H, m), 7.24-7.25 (4H, m), 6.79 (2H, d, J=7.3 Hz), 3.50 (2H, s), 2.84 (2H, br d, J=10.5 Hz), 2.72 (1H, m), 2.08 (2H, br t, J=11 Hz), 1.95 (2H, br d, J=11.6 Hz), 1.77 (2H, m). m/e (m+1): 540.3, 270.9 [(m+2)/2].
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[NH4+:15]>>[C:7]([C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:10]([NH2:15])=[O:11])([OH:9])=[O:8]
Reactant: [NH4+]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
30 g (0.155 mol) of 3-nitrophthalic anhydride are introduced in portions into 180 ml of conc. ammonium solution and the resulting solution is heated at 100° C. with stirring for 45 min. The mixture is evaporated in a rotary evaporator and co-distilled twice with toluene, and the residue is dried in a high vacuum. It is stirred with EA, and the beige precipitate is filtered off with suction and dried in vacuo over P2O5. 31.8 g of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)s1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C(=O)O)s2)cccc1[N+](=O)[O-]
Yield: 85.6 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (10 g, 35.85 mmol), 5-bromothiophene-2-carboxylic acid (6.68 g, 32.2 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.59 g, 71.6 mmol) were dissolved in the solvent mixture of 200 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 mL of water and adjusted to pH 3 with 1 N hydrochloric acid. The mixture was filtered and the filter cake was washed with 50 mL of the solvent mixture of n-hexane/ethyl acetate (V:V=1/1) and dried to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)thiophene-2-carboxylic acid 12a (7.7 g, yield 77%) as a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].CO[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:11]>>[OH:7][CH:4]([CH2:5][OH:6])[CH2:3][N:2]([CH3:1])[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[N:29][CH:28]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:11]
Reactant: CNCC(O)CO
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CN(CC(O)CO)C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 9 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-methylamino-propane-1,2-diol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (9%) as sticky yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH:16]([N:19](C(C)C)CC)(C)C.Cl.CN>O1CCCC1>[CH3:16][NH:19][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 1 h

Procedure:
Combine 3,4,5-trimethoxybenzoyl chloride) (2.9 g, 17.0 mmol) and tetrahydrofuran (170 mL) and cool to 0° C. Add diisopropylethylamine (5.92 mL, 34 mmol). Add methylamine hydrochloride (1.26 g, 18.7 mmol). Allow to stir for 1 hour and concentrate in vacuo. Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane to give N-methyl-3,4,5-trimethoxybenzamide: TLC Rf =0.45 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I>C1COCC1>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
To a solution of 6-nitroindazole (8 g) in THF (200 ml) was added NaH (2.5 g) at 0° C. The reaction was stirred for 30 min and MeI (3.7 ml) was added and stirred at RT overnight. The reaction was quenched with water and extracted with EtOAc twice, then was further purified by column chromatography to give 1-methyl-6-nitro-1H-indazole which was hydrogenated with an H2 atmosphere in the presence of Pd/C (400 mg) to give 1-methyl-6-amino-1H-indazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)N3CCCCC3)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 90.4 %

Procedure:
4.7 g (15.7 mmol) (2S,4R)-4-Hydroxy-2-(piperidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 300 ml CH2Cl2 were treated with 4.5 g (23.6 mmol, 1.5 eq) p-toluene sulfonylchloride in the presence of 2.88 g (23.6 mmol, 1.5 eq) DMAP at RT for 48 h. The solution was washed with 1M KHSO4, water, 5% aq. NaHCO3 solution, water and brine, dried over Na2SO4 and was concentrated. Flash chromatography yielded 6.42 g (90%) (2S,4R)-2-(Piperidine-1-carbonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)=[O:15]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[NH:11])[N:9]([CH2:13][C:14]([C:16]3[CH:21]=[C:20]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=3)=[O:15])[N:10]=2)[N:7]=1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)Cn2nc3ccc(Cl)nn3c2=N)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamin (W2.001a; 30 mg) was initially charged in DMF (3.5 ml) at RT while stirring, and 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone (O1.002; 58 mg) predissolved in DMF (0.5 ml) was added dropwise. The reaction mixture was stirred at RT for 30 min and was then heated to 60° C. for 5 h. After standing overnight, the solvent was removed under reduced pressure and the residue was purified by means of preparative HPLC (met. A). The clean product fractions were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 28 mg of the title compound were obtained. LC-MS rt: 1.28 min [M+H]+: 416.1 (met. a)
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=1[CH3:34])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=3[CH3:34])[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cccc(N=C=O)c1C
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(C)c3C)c(=O)n(C3CCCC3)c12
Yield: 16.5 %

Procedure:
1-Cyclopentyl-3-(2,3-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (22 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-2,3-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O.Cl>CCO.[Fe]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH3:8]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(C)c1O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)c(C)c1O
Temperature: 95 °C
Yield: 74.4 %

Procedure:
To a solution of 1-(2-hydroxy-3-methyl-4-nitro-phenyl)-ethanone (720 mg, 3.7 mmol) in EtOH (30 mL) are consecutively added Fe powder (4 g, 74 mmol), water (7.2 mL), and conc. HCl (145 μL). The reaction mixture is heated at 95° C. for 4 h. The iron is filtered through celite and the filtrate poured slowly into saturated aqueous NaHCO3. After the bubbling subsides, the mixture is extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried over Na2SO4, and concentrated. The residue is purified by 25% EtOAc/hexane. Obtained is the title compound as a white solid (455 mg). LC-MS (m/e): 166 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:9][C:8]2=[O:22])=[C:4]([F:25])[CH:3]=1.Br[C:27]1[CH:35]=[CH:34][C:30]2[S:31][CH:32]=[CH:33][C:29]=2[CH:28]=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:27]3[CH:35]=[CH:34][C:30]4[S:31][CH:32]=[CH:33][C:29]=4[CH:28]=3)[CH:10]=[CH:9][C:8]2=[O:22])=[C:4]([F:25])[CH:3]=1
Reactant: Brc1ccc2sccc2c1
Reactant: CC1(C)OB(c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)OC1(C)C
Product: O=c1ccc(-c2ccc3sccc3c2)cn1Cc1ccc(Cl)cc1F
Yield: 5.9 %

Procedure:
According to Scheme 17 Step 2: The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1 eq, 1.26 mmol, 0.40 g) and 5-bromobenzo[b]thiophene (1.5 eq, 0.29 mmol, 0.06 g) according to the procedure described for Example 1 Step 2. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 90/10 and by crystallization with diisopropyl ether/pentane to afford the title compound (17 μmol, 6.4 mg, 9%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=[O:15]>>[CH3:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:17]1[CH:18]=[N:19][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Cc1cc(I)ccc1N
Reactant: O=C(O)c1ccnc(F)c1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)O

Procedure:
synthesized as intermediate 1 by reacting 4.7 mmol of 2-methyl-4-iodoaniline with 7.0 mmol 2-fluoroisonicotinic acid. LC/MS [(5.3 min; 355 (M+1)]. See detailed procedure in Example 3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(N)cc1
Reaction time: 12 h
Yield: 94.6 %

Procedure:
A mixture of N-(4-nitrophenyl)propanamide (10 g, 51.5 mmol), 10% palladium on carbon (1 g), methanol (500 ml) and tetrahydrofuran (100 ml) was stirred under hydrogen atmosphere for 12 hours, insoluble substances were removed by filtration, and the filtrate was concentrated to give 8.00 g (94.8%) of the desired product as an oil.