Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:30]=[C:31]=[O:32])[CH:28]=[CH2:29]>N1C=CC=CC=1>[CH2:27]([NH:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:32])[CH:28]=[CH2:29]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C=CCN=C=O
Solvent: c1ccncc1
Product: C=CCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.07 g, 0.18 mmol) was dissolved in pyridine (0.5 mL) and allyl isocyanate (0.025 mL, 0.28 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.5, 161.1 (dd), 158.0, 157.9 (dd), 151.2, 141.0, 138.8, 136.6, 136.1, 135.0, 132.7, 132.2, 128.9, 127.5 (dd), 126.0 (dd), 122.6, 121.0, 116.6, 115.7, 112.9, 112.7 (dd), 105.8 (dd), 43.2, 19.7
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C1COCC1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a 12-L, three-neck, round-bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel and thermocouple was charged 4-bromo-3-fluoroaniline (800.0 g, 4.21 mol, Matrix lot #Q13H), THF (6.4 L, 8 vol), and solid sodium bicarbonate (530.5 g, 6.32 mol, 1.5 eq). The addition funnel was charged with benzyl chloroformate (861.9 g, 5.05 mol, 1.2 eq), which was added dropwise to the reactor over 70 minutes. The temperature of the reaction was maintained below 20° C. with an ice water bath. The batch was aged 1 hour at room temperature at which point HPLC analysis indicated that the reaction was complete. The reaction mixture was transferred to a 22-L flask and the mixture was diluted with water (6.4 L, 8 vol). The two-phase mixture was warmed to 50° C. and held at temperature for 16 hours to quench the excess benzyl chloroformate. The mixture was transferred hot to a separatory funnel to remove the lower aqueous phase. A rag layer was observed which was taken with the aqueous layer. The THF layer was filtered through Whatman #1 filter paper to remove some particulates, and the mixture was transferred back to a 22-L flask equipped for distillation. Heptane was added in portions and distilled to remove the THF. (Note that it is best to distill some of the THF out first before adding the first amount of heptane.) A total of 26.5 L of heptane was added, and the total distillate collected was 25 L. At this point, the pot temperature had reached 97.7° C. and the distillate coming over contained 0.9% THF by 1H NMR analysis. The mixture was cooled to room temperature and the thick white slurry was filtered. The filter cake was washed with heptane (4 L). The product was dried in a vacuum oven at 40° C. to give 1257.0 g of intermediate 5 (92% yield). The HPLC assay was 98.3% (AUC).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:16][CH2:15][C@H:14]([CH2:17][N:18]4[CH2:23][CH:22]=[C:21]([C:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[NH:26][CH:25]=5)[CH2:20][CH2:19]4)[O:13][C:9]3=2)[N:4]=1)[CH3:2].Cl.[H][H]>[Pd].CO>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:16][CH2:15][CH:14]([CH2:17][N:18]4[CH2:19][CH2:20][CH:21]([C:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[NH:26][CH:25]=5)[CH2:22][CH2:23]4)[O:13][C:9]3=2)[N:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1ccc2c3c(ccc2n1)OC[C@H](CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc2c3c(ccc2n1)OCC(CN1CCC(c2c[nH]c4ccccc24)CC1)O3
Yield: 75.3 %

Procedure:
To a mixture of 0.25 g (0.59 mmole) of (2S)-8-ethyl-2-[(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline and 0.2 g of 10% palladium on carbon in 100 mL of methanol was added 0.2 mL of concentrated HCl. The mixture was treated with 60 psi of hydrogen in a Parr apparatus for 15 hours. It was then filtered through celite and concentrated to an oil in vacuum. Ethyl acetate (300 mL) was added and the mixture was washed with 300 mL portions of saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. Column chromatography on silica gel with 0-2% methanol/chloroform as eluant gave 0.19 g of the title compound as the free base. Recrystallization from ethanol with the addition of 0.052 g of fumaric acid gave 0.15 g of the (S)-enantiomer of the title compound as an off-white fumarate (m.p. 169-172° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([CH:27]=1)[NH2:26])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:25]2[CH:27]=[C:21]([CH:18]([CH3:19])[CH3:20])[CH:22]=[CH:23][C:24]=2[CH3:28])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: Cc1ccc(C(C)C)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(C)C)cc1Nc1nc(Cl)nc2c1CCC2c1ccccc1
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (500 mg, 1.886 mmol) in NMP (Volume: 7543 μl) was added 5-isopropyl-2-methylaniline (281 mg, 1.886 mmol) and DIPEA (329 μl, 1.886 mmol). The resulting mixture was brought to 120° C. and stirred for 2 h. The mixture was then diluted with EtOAc (25 mL), washed with water(2×10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (Silica, Thomson 40 g, 0-35% EtOAc/Hexanes) gave 2-chloro-N-(5-isopropyl-2-methylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (81421-078-01) (220 mg, 0.582 mmol, 30.9% yield). LC-MS (M+H)+=378.1. 1H NMR (500 MHz, MeOD) δ ppm 7.30-7.41 (3 H, m), 7.19-7.26 (3 H, m), 7.16 (2 H, d, J=7.93 Hz), 7.11 (1 H, d, J=7.63 Hz), 4.27 (1 H, t, J=7.63 Hz), 2.91 (1 H, ddd, J=13.89, 6.87, 6.71 Hz), 2.77-2.86 (1 H, m), 2.61-2.76 (2 H, m), 2.24 (3 H, s), 2.03-2.13 (1 H, m), 1.27 (5 H, dd, J=7.02, 1.53 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][C:6]1[C:13]([CH2:19][CH2:20][OH:21])([CH2:17][CH3:18])[O:14][CH2:15][CH2:16][C:5]2=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClCCl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([C:13]1([CH2:19][CH2:20][OH:21])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:16][CH2:15][O:14]1)=[CH:3][C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:10][C:9]=3[CH2:11][CH3:12])[CH3:18]
Reactant: CCc1cc(Br)cc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CCc1cc(-c2ccccc2)cc2c3c([nH]c12)C(CC)(CCO)OCC3
Temperature: 90 °C
Yield: 19.9 %

Procedure:
To a solution of 2-(6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (3.8 g, 10.8 mmol) in ethylene glycol dimethyl ether (50 mL) was added potassium phosphate (6.37 g, 30 mmol), phenylboronic acid (1.83 g, 15 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane. The reaction mixture was heated at 90° C. (oil bath) overnight. It was quenched with water and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50% ethyl acetate/hexane, followed by Sephadex LH-20, 50% chloroform/hexane) to give the title compound (0.75 g, 20% yield). 1H NMR (CDCl3) δ 7.77 (s, 1H), 7.66 (d, 1H), 7.63 (m, 1H), 7.56 (d, 1H), 7.44 (m, 3H), 7.32 (m, 1H), 4.06 (m, 2H), 3.72 (m, 3H), 2.91 (m, 3H), 2.81 (dt, 1H), 2.65 (dd, 1H), 2.20 (m, 1H), 2.07 (m, 2H), 1.40 (t, 3H), 0.95 (t, 3H). ES-MS (m/z) 348 [M−1]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][N:11]([CH3:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCNCC2)c2[nH]ncc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2[nH]ncc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of (±)-7-(1-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)ethyl)-5-methyl-1H-indazole (24 mg, 0.065 mmol) and sodium cyanoborohydride (20.5 mg, 0.327 mmol) in acetonitrile (1.5 mL) at 0° C. was added formalin (0.053 mL). The reaction was treated with 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added. The ice bath was removed and stirring continued for another 2 h. The reaction was diluted with diethyl ether and washed with 1 M sodium hydroxide. The ethereal was concentrated and purified by column chromatography (10% 2 M ammonia in MeOH/CH2Cl2) to give 12.5 mg (50.2%) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 9.67 (bs, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.23-7.27 (m, 2H), 7.03-7.07 (m, 2H), 6.83 (s, 1H), 4.47 (q, J=10 Hz, 1H), 3.35 (d, J=10 Hz, 1H), 3.25 (d, J=10 Hz, 1H), 2.55-2.65 (m, 2H), 2.38 (s, 3H), 2.25-2.29 (m, 1H), 2.21(s, 3H), 1.9-2.2 (m, 5H), 1.40 (d, J=5.0 Hz, 3H); 13C-NMR (CDCl3, 126 MHz) δ 161.49 (d, J=980 Hz), 135.7, 133.9, 130.0, 128.8, 125.8, 125.7, 124.4, 118.9, 115.5, 115.3, 78.9, 51.9, 51.8, 50.9, 46.2, 32.7, 32.4, 22.4, 21.3; Mass spec.: 382.4 (MH)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)#[N:2].[CH3:13][C:14]([OH:16])=[O:15]>[Pd]>[C:14]([OH:16])(=[O:15])[CH3:13].[C:14]([OH:16])(=[O:15])[CH3:13].[NH2:2][CH2:1][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: N#CCc1nc2ccccc2[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Product: NCCc1nc2ccccc2[nH]1
Reaction time: 6 h
Yield: 95 %

Procedure:
A mixture containing 2-cyanomethylbenzimidazole (2.0 g, 12.7 mmol), 10% Pd/C (1.0 g), and AcOH (40 mL) was hydrogenated at 42 psi for 6 h in a Parr apparatus. The reaction mixture was filtered through a bed of Celite® and concentrated to give the title compound (3.4 g, 95%): 1H NMR (250 MHz, CDCl3) δ 7.04-28.13 (m, 7H), 3.17-3.39 (m, 4H); MS (ES) m/e 162.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[OH:12])C.FC(F)(F)S([O-])(=O)=O>>[CH3:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[OH:12]
Reactant: CCc1cccc([N+](=O)[O-])c1O
Agent: O=S(=O)([O-])C(F)(F)F
Product: Cc1cccc([N+](=O)[O-])c1O

Procedure:
The title compound was prepared in the same manner as indicated for the synthesis of 2-ethyl-6-nitrophenol and was converted to the corresponding trifluoromethane sulfonate according to the procedure described in Example 26.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@@H:23]([O:26][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.92 g, 2.0 mmol) in 10 ml of CH2Cl2 is added at 0° C. methanesulfonyl chloride (0.31 mL, 4.0 mmol) followed by triethylamine (0.56 ml, 4.0 mmol). The reaction mixture is stirred at room temperature for 24 h and treated with water. The aqueous layer is extracted 2 times with CH2Cl2. The organic layer is dried with sodium sulfate, filtered and concentrated under reduced pressure to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([OH:20])=O)=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]([OH:32])[CH2:29][NH:30][CH3:31])[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][NH:11][C:10]=1[C:18]([N:30]([CH2:29][CH:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=1)[OH:32])[CH3:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1[nH]nc(C(=O)O)c1OCc1ccccc1
Reactant: CNCC(O)c1cccc(Br)c1
Product: COC(=O)c1n[nH]c(C(=O)N(C)CC(O)c2cccc(Br)c2)c1OCc1ccccc1

Procedure:
The title compound was prepared from methyl 4-benzyloxy-3-carboxy-1H-pyrazole-5-carboxylate (prepared as in Example 31, Step 1) using a procedure similar to that described in Example 31, Step 2, except that 1-(3-bromophenyl)-2-(methylamino)ethanol (prepared as described in Tsushima, S., et al., EP 278621 and Cudahy, M. M., et al., WO 2003059911) was used in place of (1R)-2-(methylamino)-1-phenylethanol. ES MS (M+2)=490.
Reaction SMILES: Br.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SCC1C=CC=CC=1)=[NH:8].[CH3:17][N:18]([CH3:32])[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][S:24][C:23]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:22]1=2>CCO>[CH3:17][N:18]([CH3:32])[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][S:24][C:23]2[CH:27]=[C:28]([NH:31][C:7]([C:3]3[O:2][CH:6]=[CH:5][CH:4]=3)=[NH:8])[CH:29]=[CH:30][C:22]1=2
Reactant: CN(C)CCN1CCSc2cc(N)ccc21
Reactant: N=C(SCc1ccccc1)c1ccco1
Agent: Br
Solvent: CCO
Product: CN(C)CCN1CCSc2cc(NC(=N)c3ccco3)ccc21
Reaction time: 48 h
Yield: 89.3 %

Procedure:
Benzyl furan-2-carbimidothioate hydrobromide (1.139 g, 3.82 mmol) was added to a mixture of 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.829 g, 3.49 mmol) in EtOH (20 mL). The mixture was stirred for 2 days under argon atmosphere. The solution was quenched with saturated sodium bicarbonate (50 mL). The solution was transferred to a separatory funnel, diluted with water (50 mL), and extracted with CH2Cl2 (50 mL). The aqueous phase was washed with CH2Cl2 (50 mL). The combined organic fractions were washed with brine (50 mL) and dried (Na2SO4). The crude material was subjected to flash chromatography on silica gel (2.5-5% (2M NH3 in MeOH):CH2Cl2). The collected fractions gave compound 19 as a brown oil (1.03 g, 90%). 1H NMR (CDCl3) δ 7.46 (s, 1H), 7.03 (brs, 1H), 6.73-6.68 (m, 3H), 6.50 (brs, 1H), 5.03 (brs, 2H), 3.62-3.59 (m, 2H), 3.40 (t, J=7.2 Hz, 2H), 3.05-3.02 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.29 (s, 6H); ESI-MS (m/z, %): 333, 331 (MH+, 91), 260, 262 (100).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)[N:6]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].[Na+].[I-].O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:22][O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([N:7]1[C:8]([CH3:10])=[CH:9][C:5]([O:4][CH2:3][CH2:2][NH:26][CH2:25][CH2:23][OH:24])=[N:6]1)[CH:20]=[CH:19]2
Reactant: NCCO
Reactant: COc1ccc2cc(-n3nc(OCCCl)cc3C)ccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-n3nc(OCCNCCO)cc3C)ccc2c1
Temperature: 110 °C
Yield: 41.1 %

Procedure:
A mixture of 3-(2-chloroethoxy)-5-methyl-1-(6-methoxynaphthalen-2-yl)-1H-pyrazol (0.15 g, 0.47 mmol), ethanolamine (0.115 g, 1.89 mmol) and catalytic amount of NaI in N-methylpyrrolidone (NMP) (30 ml) was heated to 110° C., in a nitrogen atmosphere, during 20 hrs. Next, it was cooled, and water and ethyl acetate was added to the residue. The organic phase was washed with water several times, dried over Na2SO4, filtered and evaporated, thereby leaving a residue of 66 mg of 2-(2-(1-(6-Methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethylamino)etanol. The aqueous phase was extracted with dichloromethane, dried over Na2SO4, filtered and evaporated leaving a crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate/methanol, from 8/2 until 0/10) thereby obtaining additional 40 mg of desired compound. A total weight of 104 mg (yield: 65%) of 2-(2-(1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethylamino)etanol in the form of a colourless oil was obtained.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCOCC1>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][N:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(S(N)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 1-ethanesulfonylpiperazine (1.0 g) in dioxane (10 ml) was added sulfamide (0.51 g). The reaction was then heated at 100° C. for 24 h. The reaction was allowed to cool before being concentrated in vacuo. The residue was stirred in Et2O for 4 h and the mixture filtered to give the product as a white solid. Yield: 1.3 g.
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[C:3](Cl)=[O:4].[CH2:13]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1)[CH:14]=[CH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([N:17]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1)[C:3](=[O:4])[CH:2]([Cl:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[CH:14]=[CH:15][CH3:16]
Reactant: CC=CCNc1ccc(Cl)c(C(C)C)c1
Reactant: O=C(Cl)C(Cl)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCN(C(=O)C(Cl)c1cccc(F)c1)c1ccc(Cl)c(C(C)C)c1
Reaction time: 0.33 h

Procedure:
2.6 g of 2-chloro-2-(3-fluorophenyl)acetyl chloride were gradually added dropwise to 2.2 g of N-(2-butenyl)-N-(4-chloro-3-isopropylphenyl)amine and 2.0 g of anhydrous potassium carbonate in 40 ml of N,N-dimethylformamide with stirring at 20°-30° C. After the stirring was additionally continued for 20 minutes, potassium carbonate was removed by filtration, and extraction was then carried out with toluene. After drying over anhydrous sodium sulfate, the reaction solution was concentrated by means of an evaporator to quantitatively obtain the desired oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9](Cl)[CH:8]=1)=[O:5].[CH:21]1([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([NH:26][C:24]([CH:21]2[CH2:23][CH2:22]2)=[O:25])[CH:8]=1)=[O:5]
Reactant: NC(=O)C1CC1
Reactant: O=C(Nc1cc(Cl)ncc1F)c1c(Cl)cc(Cl)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1cc(NC(=O)C2CC2)ncc1F)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Yield: 9.3 %

Procedure:
To a microwave tube was added 2,4,6-trichloro-N-(2-chloro-5-fluoropyridin-4-yl)benzamide (71 mg, 0.20 mmol), cyclopropanecarboxamide (42.8 mg, 0.50 mmol), Pd2(dba)3 (18 mg, 0.020 mmol), XantPhos (14 mg, 0.025 mmol), Cs2CO3 (197 mg, 0.60 mmol) and dioxane (1.5 mL). The mixture was degassed with N2 for 2 min. The resulting mixture was irradiated in a microwave reactor at 140° C. for 35 min and then cooled to room temperature. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product (7.5 mg, yield: 9.2%). 1H NMR (DMSO-d6, 400 MHz): δ 11.08 (s, 1H), 10.83 (d, 1H), 9.00 (s, 1H), 8.32 (s, 1H), 7.82 (s, 2H), 1.98 (d, J=4.6 Hz, 1H), 0.82 (t, J=6.1 Hz, 4H). LCMS (ESI) m/z: 402.0 [M+H+].
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[S:5][C:4]([C:14]([O:16][CH3:17])=[O:15])=[C:3]([O:18][CH3:19])[C:2]=1[C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: COC(=O)c1sc(-c2ccccc2Cl)c(Br)c1OC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OC
Reaction time: 8 h
Yield: 57.5 %

Procedure:
7.84 g of compound of step A, 4.10 g of 4-chlorophenylboronic acid and 21.68 ml of a 2M solution of sodium carbonate are added to 60 ml of toluene. Argon is bubbled through for 30 min, before adding 1.25 g of Tetrakis. Heating is carried out at 110° C. overnight. After a return to ambient temperature, 60 ml of distilled water are added and the mixture is extracted with 60 ml of ethyl acetate, and the organic phase is dried and evaporated. The product obtained is purified by silica chromatography (eluent: heptane/ethyl acetate (80/20; v/v)). 4.90 g of the expected compound are obtained.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:19]2[C:18]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=3[CH:12]=[N:11][C:10]=2[NH:9][N:8]=1.CO.[ClH:30]>O1CCOCC1>[C:1]1([CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:19]2[C:18]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[CH:12]=[N:11][C:10]=2[NH:9][N:8]=1.[ClH:30].[C:1]1([CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:19]2[C:18]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[CH:12]=[N:11][C:10]=2[NH:9][N:8]=1
Reactant: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCNC3
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To the crude tert-butyl 1-o-tolyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate obtained from step 1 was added anhydrous methanol (2 mL) followed by a 4N solution of HCl gas in 1,4-dioxane (0.175 mL). The reaction mixture was shaken at 55° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude desired product, 1-o-tolyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine hydrochloride salt, which was used in the next step without any further purification.