Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:23])([CH3:22])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[C:54]#[N:55].CCOCC>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:22])([CH3:23])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:50][C:51]3[CH:58]=[CH:57][CH:56]=[C:53]([C:54]#[N:55])[CH:52]=3)=[CH:40][CH:41]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a stirred mixture of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[[(4-aminophenyl)sulfonyl](isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (40 mg, 0.07 mmol) and cesium carbonate (22 mg, 0.07 mmol) in 1.5 mL of N,N-dimethylformamide was added 3-bromomethylbenzonitrile (13 mg, 0.07 mmol). The mixture was stirred at room temperature for 12 hours followed by dilution with 25 mL of ether. The ether was extracted with water (5×15 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (8.5:1.5) as eluent to provide 41 mg (85%) of the title compound. 1H-NMR (DMSO-d6): δ 0.80-0.86 (6H,dd), 1.37 (3H,s), 1.48,1.55 (3H,s)*, 1.75 (2H,m), 1.94 (1H,m), 2.58-2.78 (6H,m), 2.92-3.09 (2H,m), 3.15-3.21 (1H,m), 3.61 (2H,m), 3.81 (1H,m), 4.14 (1H,m), 4.74 (1H,q), 5.17 (2H,s), 5.53,5.57 (1H,d)*, 5.99 (2H,s,b), 6.58 (2H,d), 6.95 (2H,d), 7.11,7.14 (2H,d)*, 7.22,7.28 (2H,d)*, 7.60 (1H,t), 7.80 (2H,m,b), 7.91 (1H,s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.CN(CCN(C)C)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=[O:37])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]([OH:37])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of 4-bromoanisole (5.00 g, 26.70 mmol) in THF (100 mL) at −78° C. was added n-BuLi (1.9M in hexanes, 14 mL, 26.7 mmol). After the solution was stirred at −78° C. for 45 minutes, TMEDA (4.03 mL, 26.7 mmol) was added followed by a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (4.76 g, 22.3 mmol) in THF (20 mL), and the mixture was stirred at −78° C. for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and after work-up and purification gave 4-[hydroxy-(4-methoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (3.40 g, 47%) as a white foam.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[CH3:11])=[C:5](I)[CH:4]=1)=[O:2].CN(C)C(N(C)C)=N.[CH2:22]([OH:25])C#C>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.[Cu]I>[OH:25][CH2:22][C:10]1[NH:9][C:6]2[C:7]([CH:11]=1)=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a degassed solution of N-(4-formyl-2-iodo-phenyl)-acetamide (0.760 g, 2.63 mmol) in anhydrous DMF (20 mL) were added bis(triphenylphosphine)palladium(II) dichloride (90 mg, 0.13 mmol), copper (I) iodide (0.03 g, 0.13 mmol), 1,1,3,3-tetramethyl guanidine (1.51 g, 13.1 mmol), and propargyl alcohol (0.210 g, 3.68 mmol). The reaction mixture was stirred at room temperature for 2 hours and then at 80° C. for 24 hours under nitrogen. Solvent was evaporated under reduced pressure. Water (100 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic phase was backwashed with water (2×100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Solvent was evaporated and crude compound was purified by the Simpliflash system (60% ethyl acetate in hexanes as eluent) to give 2-hydroxymethyl-1H-indole-5-carbaldehyde as a pale yellow solid. Yield: 0.10 g (22%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24](Cl)=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>ClCCl>[CH2:30]([N:32]([CH2:33][CH3:34])[C:24]([CH:19]1[C:18]2[C:17]3[C:12](=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=3[O:27][CH3:28])[N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:25])[CH3:31]
Reactant: CCNCC
Reactant: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1c(OC)ccc(Cl)c1n2CCOCc1ccccc1
Temperature: 0 °C
Yield: 69.2 %

Procedure:
9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (8) (1.6 g, 3.7 mmol) was then dissolved in dichloromethane (50 mL), cooled to 0° C., stirred and diethylamine (810 mg, 11.0 mmol, 1.1 mL) was added dropwise. The reaction was allowed to warm to room temperature over a period of 18 h. The reaction mixture was then washed with 10% aqueous potassium carbonate (50 mL), separated, dried over magnesium sulfate and concentrated in vacuo to a gum. The crude material was crystallized from diethyl ether to afford 1.2 g (71%) of 9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (9) as a white crystalline solid. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 13.0, 14.5, 19.8, 22.2, 27.9, 36.4, 40.4, 41.9, 43.8, 55.0, 70.8, 73.3, 100.2, 108.5, 108.6, 119.9, 122.5, 127.4, 127.5, 128.3, 131.5, 137.8, 138.2, 152.4, and 174.5.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:21](=[O:22])[CH2:20][S:19][C:18]3=[O:23])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:24](=O)[CH2:25][CH2:26][CH3:27].N1CCCCC1>C(O)C>[CH:24](=[C:20]1[S:19][C:18](=[O:23])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][S:10]([C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])[C:21]1=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: O=C1CSC(=O)N1CCCCS(=O)(=O)c1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCS(=O)(=O)c2cccc3nccn23)C1=O

Procedure:
To a solution of 0.22 g (0.62 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylsulfonyl)butyl]thiazolidine-2,4-dione and 0.10 ml (1.1 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.01 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 0.269 g (quant., yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>Cl>[ClH:15].[CH2:1]([N:8]([CH2:9][CH2:10][Cl:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)Cc1ccccc1
Agent: Cl
Product: CN(CCCl)Cc1ccccc1
Reaction time: 2 h
Yield: 133.2 %

Procedure:
Combine hydrogen chloride (50 mL; 4M in dioxane), N-benzyl-N-methylethanolamine (61.12 mmol; 10 g), thionyl chloride (73.30 mmol; 5.34 mL) and heat to 90° C. Stir for 2 h, evaporate and crush the solids under ether, sonicate 15 min, filter, wash with ether, dry under vacuum to provide the title compound (10.75 g; 80%). MS (ES): m/z=184 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:6]2[O:5][CH:4]([CH2:3][N:2]([CH3:1])[C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC1Cc2cccc(-c3ccccc3C)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cccc2c1OC(CN(C)C(=O)OCc1ccccc1)C2
Yield: 64.3 %

Procedure:
Treatment of (±)-[(N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.67 g, 32.64 mmol) with diisopropylethylamine (0.512 g, 3.97 mmol) and benzyl chloroformate (0.605 g, 3.17 mmol) generally according to the procedure described for Intermediate 12 provided 0.790 g (77%) of (±)-benzyl {[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[Cl:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N>CC(O)C.CO>[Cl:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=3)[C:22]([NH:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[O:23])[CH:5]=[CH:4][N:3]=2)[CH:44]=1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CC(C)O
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(Cl)c(N4CCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 80 °C
Yield: 38 %

Procedure:
In a 10 mL vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.200 g, 0.395 mmol), 5-chloro-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (0.165 g, 0.474 mmol) were taken up in iPrOH (3 mL) and pyridinium p-toluenesulfonate (0.238 g, 0.949 mmol) was added. The vial was sealed and heated to 80° C. overnight. When reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, absorbed onto silica gel and flash chromatographed. Fractions containing the desired product were concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.12 g, 0.15 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.38 (dd, J=4.4, 1.1 Hz, 1H), 8.53 (s, 1H), 8.25 (d, J=5.3 Hz, 1H), 8.02 (d, J=0.4 Hz, 1H), 7.87 (s, 1H), 7.63-7.79 (m, 2H), 7.28-7.50 (m, 2H), 7.10-7.28 (m, 3H), 6.97 (t, J=6.9 Hz, 1H), 6.82 (s, 1H), 6.60 (d, J=5.2 Hz, 1H), 4.23 (q, J=6.7 Hz, 2H), 3.83 (s, 3H), 3.27-3.34 (m, 2H), 3.03 (s, 3H), 2.93-3.01 (m, 4H), 2.75 (t, J=6.6 Hz, 2H), 2.51-2.64 (m, 4H), 1.40 (t, J=6.8 Hz, 3H). MS (M+H, ES+) 817.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9].[Br:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: CNC(=O)CCNCCOC
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)CCN(CCOC)c1nc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
3-(2-methoxyethylamino)-N-methyl-propanamide (Intermediate 111; 608 mg, 3.79 mmol) 5-Bromo-2,4-dichloropyrimidine (Aldrich; 950 mg, 4.17 mmol), Triethylamine (555 μL, 3.98 mmol), and DCM (5 mL) were combined and stirred over the weekend at room temperature.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[Cl:20][C:21]1[C:25]([CH2:26][CH3:27])=[N:24][N:23]([CH3:28])[C:22]=1[C:29](O)=[O:30].C(=O)([O-])O.[Na+]>O>[Cl:20][C:21]1[C:25]([CH2:26][CH3:27])=[N:24][N:23]([CH3:28])[C:22]=1[C:29]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])=[O:30]
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: CCc1nn(C)c(C(=O)O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C)c(C(=O)OCCCCC(C)=C(F)F)c1Cl
Temperature: 100 °C
Reaction time: 7 h
Yield: 73.7 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.45 g (2.4 mmol) of 4-chloro-5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 7 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.52 g (yield: 74%) of 6,6-difluoro-5-methyl-5-hexenyl 4-chloro-5-ethyl-2-methyl-2H-pyrazole-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH:16]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[C:15](=O)[C:14]2[C:13]([C:24](OCC)=[O:25])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[NH:8][C:9]2[C:14]3[C:15](=[N:30][NH:31][C:24](=[O:25])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:16]1[C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1nccn1C)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1nccn1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
A mixture of ethyl 2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (3 mL) was stirred at room temperature for 3.5 h. Evaporated the solvent and methanol (1 mL) was added, filtered and washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (45 mg, yield 41%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.46 (s, 3H), 3.49 (s, 3H), 4.78-4.81 (d, J=12.0 Hz, 1H), 5.08-5.11 (d, J=12.0 Hz, 1H), 6.69 (s, 1H), 6.76-6.79 (m, 3H), 6.99-7.02 (d, J=7.6 Hz, 1H), 7.42-7.49 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:39])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[CH3:39]
Reactant: Cc1ccc(N)cc1O
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (44 mg, 0.357 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 56% yield (0.084 g, 0.1655 mmol).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.O>[CH2:16]([O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.13 g, 53.41 mmol) was added portionwise to an ice-cooled solution of (S)-(−)-N-boc-3-pyrrolidinol (10 g, 53.41 mmol) in tetrahydrofuran (100 mL) and the mixture was stirred at 0° C. for 1 hour. Benzyl bromide (6.4 mL, 53.41 mmol) and tetrahydrofuran (50 mL) were added and the mixture was stirred for 6 hours allowing the temperature to rise to 25° C. The reaction mixture was then slowly diluted with water (50 mL), concentrated in vacuo and the aqueous residue was extracted with ethyl acetate (3×70 mL). The combined organic solution was washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to give an orange oil. This oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 66:33, to afford the title compound as a colourless oil in 74% yield, 10.93 g.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][C:25]=2[CH:36]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:26][C:25]=3[CH:36]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2o1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3oc(C(=O)OC(C)(C)C)cc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.000 g, 3.336 mmol), tert-butyl 5-amino-1-benzofuran-2-carboxylate (0.778 g, 3.336 mmol) and TEA (0.340 ml, 2.471 mmol) in MeCN (5 ml) was heated in a microwave reactor at 160° C. for 1.5 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[O:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:23]2[CH:24]=[CH:25][O:21][N:22]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccon1
Product: O=C(Nc1ccon1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and isoxazol-3-amine (43 mg, 0.51 mmol). The title compound was obtained as a brown solid (20.0 mg, 11% yield). 1H NMR (400 MHz, d6-DMSO) δ: 11.90 (1H, s), 9.03 (2H, s), 8.86 (1H, m), 6.89 (1H, s). MS m/z: 415.18, 417.16 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([F:18])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1.Cl>O1CCCC1>[CH2:1]([O:5][C:6]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:9]([C:10]([NH:48][S:45]([CH:42]2[CH2:44][CH2:43]2)(=[O:47])=[O:46])=[O:12])=[C:8]([F:18])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(F)c(C(=O)O)cc1C1CC1
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCOc1cc(F)c(C(=O)NS(=O)(=O)C2CC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To a stirred solution of 4-butoxy-5-cyclopropyl-2-fluorobenzoic acid (0.039 g, 0.15 mmol) in tetrahydrofuran (1 mL) and under an atmosphere of nitrogen was added carbonyldiimidazole (0.030 g, 0.18 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled down to room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.02 mL, 0.02 mmol) was added followed by cyclopropanesulfonamide (0.024 g, 0.20 mmol) and the stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% gradient ethyl acetate in hexanes) to afford the title compound (0.011 g, 20%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.82-8.57 (m, 1H), 7.57 (d, J=9.24 Hz, 1H), 6.58 (d, J=14.42 Hz, 1H), 4.04 (t, J=6.30, 6.30 Hz, 2H), 3.16-3.05 (m, 1H), 2.18-1.74 (m, 3H), 0.72-0.61 (m, 2H), 1.71-0.84 (m, 13H), 0.74-0.60 (m, 2H); MS (ES+) m/z 356.1 (M+1); MS (ES−) m/z 354.2 (M−1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1)[CH3:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O)[CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:6]2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCc1cnc(NC2CCNCC2)nc1
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3ncc(CC)cn3)CC2)ccc1OC
Temperature: 55 °C
Yield: 38 %

Procedure:
To a solution of (5-ethyl-pyrimidin-2-yl)-piperidin-4-yl-amine (30.9 mg, 0.15 mmol, 1.0 equiv; intermediate C1) and 3-ethoxy-4-methoxy-benzaldehyde (32.4 mg, 0.18 mmol, 1.2 equiv; commercially available) in ethanol (2 mL) was added acetic acid (27.0 mg, 0.45 mmol, 3.0 equiv) and the mixture stirred at 55° C. After 1 h sodium cyano borohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 21.0 mg (38%) of the title compound. MS (ESI): 371.5 [M+H]+.