Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:30])[CH:16]([NH:25][C:26](=[O:29])[CH2:27][OH:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:13][O:14][C:15](=[O:30])[CH:16]([NH:25][C:26](=[O:29])[CH2:27][O:28][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3(4-hydroxy phenyl) propionic acid (10 grams, 60.17 mmol) and 2-(2-hydroxy-acetylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester 3 (15.2 grams, 60.07 mmol) in anhydrous dichloromethane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide (31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 6, which can be purified in an appropriate solvent.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][CH2:12][C:13]1[N:18]=[C:17]2[S:19][C:20]3[CH2:21][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24][C:25]=3[C:16]2=[C:15]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[C:14]=1[Cl:43].O>N1C=CC=CC=1>[CH2:26]([N:22]1[CH2:23][CH2:24][C:25]2[C:16]3[C:17]([S:19][C:20]=2[CH2:21]1)=[N:18][C:13]([CH2:12][NH:11][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)=[C:14]([Cl:43])[C:15]=3[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CNC(=O)c3cccnc3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Nicotinoyl chloride hydrochloride (0.18 g) was added to a solution of the compound (0.29 g) obtained in Example 18B in pyridine (4 ml), the mixture was stirred at room temperature for 1 hour, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-2-(nicotinoylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.2 g, 51%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 124 to 125° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)/[N:9]=[CH:10]/N(C)C.C[Si]([CH:27]=[C:28]=[O:29])(C)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[C:28](=[O:29])[CH:27]=[CH:10][N:9]=1
Reactant: C[Si](C)(C)C=C=O
Reactant: Cc1ccc(N=C(/N=C/N(C)C)c2ccccc2Br)cc1F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2c(-c3ccccc3Br)nccc2=O)cc1F
Temperature: 23 °C
Reaction time: 120 h

Procedure:
A solution of 2-bromo-N-[(1E)-(dimethylamino)methylidene]-N′-(3-fluoro-4-methylphenyl)benzenecarboximidamide (1-3, 500 mg, 1.38 mmol, 1.0 equiv) in ethyl acetate (5 mL) was treated with a solution of (trimethylsilyl)ketene (0.39 mL, 2.76 mmol, 2 equiv) in toluene (5 mL). The reaction mixture was stirred at 23° C. for 5 days. The resulting mixture was concentrated, and the residue was purified via reverse-phase HPLC (Acetonitrile:H2O gradient with 0.1% TFA present) to afford 2-(2-bromophenyl)-3-(3-fluoro-4-methylphenyl)pyrimidin-4(3H)-one (1-4) as a dark orange solid. 1H NMR (500 MHz, CD3OD) δ 8.12 (d, 1H, J=6.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.46 (d, 1H, J=7.6 Hz), 7.32 (t, 1H, J=7.6 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.20-7.08 (m, 3H), 6.67 (d, 1H, J=6.6 Hz), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl>[CH2:46]([NH:53][C:23]([CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:17]1)=[O:24])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)NCc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.15 mmol) was added to the solution at 0° C. After 1 h, benzylamine (12 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(2-benzylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (19 mg, 32%) as a white solid: ESI-LRMS m/e calcd for C28H33ClN4O4S [M+] 556.2, found 557.4 [M+H+]; 1H NMR (400 MHz, CDCl3), δ ppm 1.04-1.22 (m, 2H, CH2), 1.42-1.93 (m, 8H, 4×CH2), 2.13-2.29 (m, 1H, CH), 2.67 (t, J=6.2 Hz, 2H, COCH2), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.6 Hz, 1H, CH), 4.31 (t, J=6.2 Hz, 2H, NCH2), 4.36 (d, J=5.5 Hz, 2H, NCH2Ar), 5.91 (t, J=5.5 Hz, 1H, NH), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.06-7.13 (m, 2H, Ar), 7.21-7.26 (m, 3H, Ar), 7.28 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1 h, Ar), 8.67 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][C:2]1[NH:14][CH2:13][CH2:12][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][CH:7]=[CH:6]3.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH2:12][CH2:13][N:14]1[C:15](=[O:17])[CH3:16]
Reactant: CC1=C2N=c3ccccc3=C2CCN1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C1c2[nH]c3ccccc3c2CCN1C(C)=O

Procedure:
To a solution of harmalan (1 mmol) in pyridine (2 ml) is added acetic anhydride (1.1 eq). After acid hydrolysis and extraction with ethyl acetate, the crude product is flash-chromatographed (eluent: EtOAc/pet. ether; 50/50). The 1-methylene-2-acetyl-1,2,3,4-tetrahydro-β-carboline elutes off first.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)(=[O:3])[CH3:2].Cl.[N:15](OC(C)(C)C)=[O:16]>C(Cl)Cl.O1CCOCC1>[CH:10]([N:8]1[C:7](=[O:13])[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[N:15]/[OH:16])=[CH:9]1)([CH3:11])[CH3:12]
Reactant: CC(=O)c1ccc(=O)n(C(C)C)c1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)/C=N/O)ccc1=O
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
5-Acetyl-1-isopropyl-2(1H)-pyridone was dissolved in CH2Cl2 (300 ml). The solution was cooled to −30˜−25° C. To the cooled solution were added 4N hydrogen chloride in dioxane (55.3 ml) and t-butyl nitrite (10.4 g) at −30˜−25° C. The temperature of the reaction mixture was raised to 20-25° C. The mixture was stirred at the same temperature for 3 hours. The precipitated crystal was collected by filtration, and dried in the air at ambient temperature, to give (1E)-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)(oxo)acetaldehyde oxime (14.0 g).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][OH:26])[S:18][C:17]=1[C:28]([NH2:30])=[O:29].O[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][O:26][C:32]2[CH:40]=[CH:39][C:35]([C:36](=[O:37])[NH2:38])=[CH:34][CH:33]=2)[S:18][C:17]=1[C:28]([NH2:30])=[O:29]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C(N)=O)cc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (23 mg, 0.116 mmol) was added to a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (see Example 12) (25 mg, 0.105 mmol), 4-hydroxy-benzamide (15 mg, 0.116 mmol), and Ph3P (30 mg, 0.116 mmol) in THF (2.5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated and triturated with 2:1 EtOAc:MeOH giving the title compound (7 mg, 19%) as an orange solid, m.p.>250° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[S:19][C:18]([C:20]3[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[S:19][C:18]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2nnc(C(=O)CCCCCCc3ccccc3)s2)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-c2nnc(C(=O)CCCCCCc3ccccc3)s2)n1
Yield: 101.1 %

Procedure:
The title compound was prepared from 12f (8.7 mg, 0.021 mmol) following general procedure A. Preparative thin layer chromatography (SiO2, 0-2% AcOH-EtOAc) afforded the title compound (8.4 mg, 100%) as a white solid: 1H NMR (acetone-d6+0.1% TFA, 500 MHz) δ 8.64 (dd, 1H, J=1.8, 7.2 Hz), 8.34 (m, 2H), 7.25 (m, 2H), 7.20 (dd, 2H, J=3.0, 5.1 Hz), 7.14 (t, 1H, J=7.2 Hz), 3.28 (t, 2H, J=7.3 Hz), 2.62 (t, 2H, J=7.7 Hz), 1.80 (m, 2H), 1.65 (m, 2H), 1.45 (m, 4H); 13C NMR (acetone-d6+0.1% TFA, 150 MHz) δ 195.2, 174.9, 171.9, 166.1, 150.4, 150.1, 144.5, 141.6, 130.2, 130.1, 128.9, 127.4, 126.4, 40.7, 37.4, 33.2, 31.3, 30.6, 25.4; HRMS-ESI-TOF m/z 396.1380 ([M+H]+, C21H21N3O3S requires 396.1376).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:31]3[N:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]3=[N:29][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12][CH2:13][CH2:14]3)=[CH:9][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(N)nn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 78 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (0.67 g, 1.50 mmol), 3-amino-6-methoxypyridazine (CAS Registry No. 7252-84-8, 0.23 g, 1.80 mmol, 1.2 eq), N,N-diisopropylethylamine (0.74 mL, 1.50 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10 g) in isopropanol (78 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure to give tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.55 g, 78% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].Cl[C:34]([O:36][CH3:37])=[O:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[O:36][CH3:37])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 0.034 mmol), methyl chloroformate (2.6 μL, 034 mmol) and diisopropylethyl amine (30 μL, 0.17 mmol) in anhydrous DMF (1.5 mL) was stirred under nitrogen at ambient temperature overnight. The crude reaction mixture was evaporated in vacuo and purified by reverse phase chromatography eluting with 10-90% aqueous CH3CN containing 0.1% formic acid to provide the product as a white solid: 1H NMR (CDCl3) δ 10.29 (2H, b), 8.57 (1H, s), 7.36 (1H, s), 7.13-7.18 (2H, m), 7.00-7.05 (2H, m), 5.60 (2H, b), 4.23 (2H, t, J=7 Hz), 4.13 (2H, s), 3.67 (3H, s), 3.63 (2H, b), 3.56 (2H, q, J=7 Hz), 3.11 (2H, b), 1.74-1.81 (2H, m), 1.24 (3H, t, J=7 Hz); ES+ MS: 501 (M+H+).
Reaction SMILES: [CH:1]1([CH:7]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:8][C:9]([NH:11][CH3:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1([CH:7]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:8][CH2:9][NH:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC(=O)CC(c1c[nH]c2ncccc12)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1c[nH]c2ncccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a RT solution of 3-cyclohexyl-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide (170 mg, 0.95 mmol) in THF (10 mL) was added LAH (1 M in THF, 1.5 mL). The mixture was stirred at RT overnight, and an additional LAH (1 M in THF, 2 mL) was added. The resulting mixture was refluxed for 4 hours and then quenched by addition of freshly ground Na2SO4.10H2O (3 g). After stirring for 1 hour, the solids were filtered off and the filtrate was concentrated and purified via preparative HPLC to give [3-Cyclohexyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-methyl-amine. MS M+H=272.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]=1.N>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][N:7]=[CH:6]2)=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: C1=NCCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To concentrated sulfuric acid (70 ml) was added 15 g of potassium nitrate, followed by adding a solution of 18 g (0.14 mol) of 3,4-dihydroisoquinoline in concentrated sulfuric acid (70 ml) at −15 degrees over 20 minutes. After stirring at room temperature for 1 hour, the mixture was heated at 60 degrees for 40 minutes. The reaction mixture was poured onto ice water, and the mixture was basified with aqueous ammonia and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. To the residue were added decalin (100 ml), nitrobenzene (100 ml) and Pd-Black (2 g), followed by heating at 200 degrees in a stream of nitrogen overnight. The reaction mixture was washed with ethyl acetate and extracted with 2 N hydrochloric acid. The aqueous layer was washed with ethyl acetate, followed by adding an aqueous sodium hydroxide. The resulting precipitates were collected by filtration and washed with water, to give 14.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[CH:16]=[CH:17][N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:21])=O>C(=O)(O)[O-].[Na+]>[Cl:21][C:13]1[N:12]2[CH:16]=[CH:17][N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
12.0 g (42.84 mmol) of 7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-ol are introduced into 131.6 g (858.27 mmol) of phosphoryl chloride and heated at 120° C. for 5 h. A clear solution is produced after 10 min. The mixture is allowed to cool, and then 2000 ml of saturated aqueous sodium bicarbonate solution are cautiously added. Towards the end, about 100 g of solid sodium bicarbonate are also added, and the mixture is stirred at pH 7 for 10 min. The precipitate is filtered off with suction, thoroughly washed with water, suspended in a little isopropanol and sucked dry. It is then washed once more with petroleum ether and dried under high vacuum at 50° C. 11 g (81% of theory) of the product are obtained as a solid.
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[CH:7]=[C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]2=[C:10]2[C:19]=1[O:18][C:17]1[C:12](=[CH:13][C:14]([O:20]C)=[CH:15][CH:16]=1)[O:11]2>ClCCl>[OH:5][C:6]1[CH:7]=[C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]2=[C:10]2[C:19]=1[O:18][C:17]1[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=1)[O:11]2
Reactant: COc1ccc2c(c1)Oc1c(c(O)cc3ccccc13)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(c1)Oc1c(c(O)cc3ccccc13)O2
Reaction time: 4 h

Procedure:
Under an inert atmosphere, 0.1 ml of boron tribromide is added dropwise to 90 mg of 6-hydroxy-10-methoxy-7,12-dioxabenz[a]anthracene in solution in 3 ml of dichloromethane at 0° C. After 4 hours, the mixture is hydrolyzed. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The bis-hydroxylated compound is purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate).
Reaction SMILES: [CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([O:29]CC3C=CC=CC=3)[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21](=[O:29])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(OCc3ccccc3)nc3ccccc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(=O)[nH]c3ccccc23)CC1
Yield: 3.4 %

Procedure:
150 mg of 10% palladium-carbon was added to 11 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl}carbonyl-2-benzyloxyquinoline (obtained in Reference Example 2) in 20 ml of ethanol. The mixture was stirred at room temperature at a hydrogen pressure of 1 atm. for 1 hour. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether and then re- crystallized from ligroin-ethyl acetate to obtain 0.3 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl}carbonylcarbostyril as a white powder having a melting point of 155°-158° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:32]=[CH:31][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][NH:27][C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1.[CH3:33]I>CN(C=O)C>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH3:33])[C:26]4=[O:30])[CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:31][CH:32]=2)=[N:6][N:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCNC2=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCN(C)C2=O)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride suspension (0.16 g, 50%) was added to a stirring solution of (R)-(+)-Methyl 3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-5-((2-oxopyrrolidin-3-yl)oxy)benzoate (1.5 g) (Intermediate 20) in dry DMF taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube, at room temperature. The reaction mixture was stirred at the same temperature for 15 min. Methyl iodide (0.20 mL) was added and stirred till the reaction completed. The reaction mixture was quenched with ice-water, extracted with DCM. All organic layers were combined, washed with water, brine, dried over sodium sulphate, filtered and concentrated in vacuum to get the thick liquid product. The liquid was triturated with EtOAc:hexane to get the white solid product (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(=O)(=O)(O)O.[CH:22]1([CH2:28][CH2:29]O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.S1(CCCC1)(=O)=O>CO>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([C:6]([O:8][CH2:29][CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:7])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: OCCC1CCCCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
After charging 50 parts of 4-chloro-3,5-dinitrobenzoic acid, 0.3 part of 98% sulfuric acid, 78 parts of cyclohexaneethanol and 50 parts of sulfolane into a flask, the mixture was heated to 100 to 110° C., and was maintained at the same temperature for 8 to 10 hours. After checking the disapearance of 4-chloro-3,5-dinitrobenzoic acid by HPLC, the reaction mass was cooled to room temperature under atmospheric pressure, and to the mass was 240 parts of methanol, and was stirred for 30 minutes. The resulting mixture was filtrated to obtain crystals, and the crystals were washed with 40 parts of methanol and then dried to obtain 58 parts of 2-cyclohexylethyl 4-chloro-3,5-dinitrobenzoate.