Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[C:5]([Cl:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]1[C:24](=O)[C:25](=[O:30])[C:26]=1[O:27]CC)[CH3:21]>C(O)C>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:25](=[O:30])[C:26](=[O:27])[C:23]=2[O:22][CH2:20][CH3:21])=[C:7]([OH:8])[C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2O)c(=O)c1=O
Temperature: 50 °C
Yield: 73.4 %

Procedure:
A mixture of 1.98 g (6.5 mmol, 1 eq) of 6-amino-3-chloro-2-(4-methylpiperazine-1-sulfonyl)phenol and 2.20 g (48.8 mmol, 2 eq) of 3.4-diethoxy-3-cyclobutene-1,2-dione in solution in 20 ml of ethanol. The reaction medium was heated at 50° C. for 16 hours. The insoluble material was filtered off, washed with ethanol and dried under vacuum at 45° C. 2.05 g of 3-[4-chloro-2-hydroxy-3-(4-methylpiperazine-1-sulfonyl)phenylamino]-4-ethoxycyclobut-3-ene-1,2-dione were obtained in the form of a yellow solid. Yield=74%.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])C1C2C(=CC=CC=2)C=CC=1.O[C:22]1[C:31]2C(=CC=CC=2)C=C[C:23]=1[CH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:17][C:6]1[C:5]2[C:18](=[CH:19][CH:20]=[CH:3][CH:4]=2)[CH:31]=[CH:22][C:23]=1[CH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccc3ccccc3c2O)cc1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Product: CCN(CC)C(=O)c1ccc(Cc2ccc3ccccc3c2Cl)cc1

Procedure:
The compound 36 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 35.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N+:26]([O-:28])=[O:27]>O>[N+:26]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:13]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[C:17]([O:19][CH3:20])=[O:18])([O-:28])=[O:27]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OC)cc2)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 65.6 %

Procedure:
To a 100 mL round-bottomed flask containing potassium hydroxide (4.7 g; 82.0 mmol) dissolved in water (20 mL) was successively added 4-methoxyphenol (10.0 g; 80.6 mmol) and methyl 4-chloro-3,5-dinitrobenzoate (20.2 g; 77.5 mmol). The flask was fitted with a reflux condenser and the reaction heated at 150° C. (oil bath) for 3 hours. After cooling to room temp, the reaction mixture was transferred to a large mortar and triturated with cold 2N NaOH (100 mL) to remove unreacted phenol. The solid was collected by filtration and air-dried to give 21.5 g of crude product. Crystallization from absolute ethanol gave 17.7 g (65.6%) of pure methyl 3,5-dinitro-4-(4-methoxyphenoxy)benzoate as light yellow needles. 300 MHz 1H NMR (CDCl3) d 3.77 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.82 (m, 4H, ArH), 8.70 (s, 2H, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([S:10][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]c(SCc3ccc(C)cc3)nc2c1
Reaction time: 24 h

Procedure:
To a mixture of 5-methoxy-2-mercaptobenzimidazole (1.673 g, 9.285 mmol) and p-xylyl bromide (1.718 g, 9.285 mmol) in DMF (33.5 mL) at 0° C., Cs2CO3 (4.53 g, 13.93 mmol) was added and the suspension was stirred for 24 h while being allow to warm from 0° C. to rt. Distilled water (150 mL) was added with vigorous stirring. The murky white suspension turned into a clearer solution with white granules. After being stirred for 20 min at rt, the mixture was filtered and the residue was rinsed with water (3×20 mL) and hexanes (3×20 mL). The crude product was >95% pure by 1H NMR analysis and was not further purified. The yield was 2.437 g, 92%. 1H NMR (500 MHz, CDCl3): δ 2.25 (s, 3H), 3.76/3.78 (app d*, 3H), 4.38/4.42 (app d*, 2H), 6.74-7.17 (m, 6H), 7.52 (d, 1H, J=7.5 Hz), 8.87 (brs, 1H); 13C NMR (125 MHz, CDCl3): δ 21.30, 37.39, 37.63, 55.89, 55.96, 94.15, 101.18, 110.39, 111.10, 112.45, 119.07, 128.98, 129.58, 133.94, 156.61. *The apparent doublets may arise from the 1,3-proton shift between the nitrogen atoms in the heterocycle.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]cc(Cl)c2c1
Product: COc1ccc2c(Cl)ncc(Cl)c2c1
Yield: 65 %

Procedure:
A solution of 4-chloro-6-methoxyisoquinolin-1(2H)-one (1.5 g, 5.90 mmol) in POCl3 (15 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (1.1 g, 65.0%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.53(s, 1H), 8.27-8.24 (d, J=12 Hz, 1H), 7.56-7.53 (d, J=12 Hz, 1H), 7.41 (s, 1H), 4.02 (s, 3H); MS: MS m/z 230.03 (M++2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C([O-])(=O)C.[NH4+:24]>>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH2:24])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1Nc1ccc(I)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: NC(=O)c1ccnc(Cl)c1Nc1ccc(I)cc1F

Procedure:
2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid and 0.5 mmol of ammonium acetate. LC/MS [8.61 min; 392 (M+1)].
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][N:11]1[C:12]2[C:8](=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21

Procedure:
In analogy to the procedure described in example 1 b], 4-(tert-butyl-dimethyl-silanyloxy)-1H-indole was reacted with bromo-acetic acid ethyl ester in the presence of cesium carbonate to give the title compound as yellow oil.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[CH3:4].[CH3:10][NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15]>CO>[CH3:1][O:2][Si:3]([CH2:6][CH2:7][CH2:8][N:11]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH3:10])([CH3:5])[CH3:4]
Reactant: CO[Si](C)(C)CCCCl
Reactant: CNCCN(C)C
Solvent: CO
Product: CO[Si](C)(C)CCCN(C)CCN(C)C

Procedure:
Under Ar, a solution of CH3OSi(CH3)2(CH2)3Cl (10.0 g, 59.3 mmol), CH3NHCH2CH2N(CH3)2 (10.0 g, 98.2 mmol) and methanol (5.0 mL) is refluxed for 22 h and then concentrated with a rotary evaporator (about 10 Torr, about 45 ° C.). The concentrate is diluted with ether (50 mL) and filtered. The solid is washed with ether (50 mL), the washings and the filtrate are combined, and the resulting solution is concentrated with a rotary evaporator (about 60 Torr, about 30 ° C.). The concentrate is filtered and the solid is washed with ether (10 mL). The washings and the filtrate are combined, and the resulting solution is concentrated with a rotary evaporator (about 60 Torr, about 30° C.). The resultant ligand, CH3OSi(CH3)2(CH2)3N(CH3)(CH2)2N(CH3)2, having the form of a light yellow liquid, is weighed (8.46 g, 36.4 mmol, 61%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:40][C@H:41]([CH2:43][CH3:44])[CH3:42])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[C@@H:41]([NH:40][C:19]1[N:18]=[C:17]2[CH2:16][NH:15][CH2:24][CH2:23][C:22]2=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH2:27][CH2:26]1)([CH2:43][CH3:44])[CH3:42].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-6-benzyl-N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (212.2 mg, 0.341 mmol) in THF (3.4 mL) was treated with Pd(OH)2 (20 wt %, 71.9 mg, 0.102 mmol). Hydrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The vent needle was removed and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 h. The reaction mixture was opened to air and filtered through a pad of Celite™, eluting with EtOAc and MeOH. The filtrate was collected and concentrated under reduced pressure to give (S)—N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine as a TFA salt (169.0 mg) as a yellow oil, which was carried forward without additional purification. ESI-MS m/z [M+H]+ 418.5.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=2)[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:37]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:3]1([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]=[CH2:37])=[CH:31][CH:30]=2)[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:18][CH2:17]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C=O)cc3)C3CCCC3)c2)CC1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(C(C(=O)Nc2cccc(CC3(C(=O)OC(C)(C)C)CC3)c2)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
39.0 mg (0.98 mmol, 60% in mineral oil) of sodium hydride were suspended in 3.0 ml of abs. THF, the mixture was cooled to 0° C. and 301.8 mg (0.84 mmol) of methyltriphenylphosphonium bromide were added. The mixture was stirred at 0° C. for 30 min, and 300 mg (0.65 mmol) of (+/−)-tert-butyl 1-(3-{[cyclopentyl(4-formylphenyl)acetyl]amino}benzyl)cyclopropanecarboxylate were then added. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was taken up in acetonitrile and filtered, and the filtrate obtained was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 219.3 mg (73.4% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Yield: 56.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.25 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to afford the title compound as a yellow solid (0.43 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC[Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].[SiH4].Cl.N1CCNC[CH2:22]1>C1(C)C(C)=CC=CC=1>[CH2:14]([O:13][Si:9]([O:16][CH2:17][CH3:18])([O:10][CH2:11][CH3:12])[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[CH3:22])[CH3:15]
Reactant: CCO[Si](CCl)(OCC)OCC
Reactant: C1CNCCN1
Agent: Cl
Agent: [SiH4]
Solvent: Cc1ccccc1C
Product: CCO[Si](OCC)(OCC)N1CCNCC1C
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
905.3 g (10.5 mol) of piperazine and 945 ml of xylene (anhydrous) as solvent are charged to a 4 liter 4-neck flask and subsequently innertized with nitrogen. The batch is heated to a temperature of 100° C., in the course of which the piperazine dissolves completely. Added dropwise at this temperature are 446.3 g (2.1 mol) of chloromethyltriethoxysilane, over the course of 1 h with thorough stirring. Following the addition of about ⅓ of the amount of silane, piperazine hydrochloride is precipitated as a salt, but the suspension remains readily stirrable until the end of the reaction. After the end of the addition, stirring is continued for a further 15 min. Subsequently the reaction mixture is heated to 110° C. and the precipitated salt is filtered off on a preheated filter.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17].[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([N:36]2[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]2)[CH:11]=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: COc1cc(CNc2cc(F)ccc2C(=O)C(F)(F)F)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)cc(OC)c1
Yield: 135.1 %

Procedure:
A solution of 1-(2-(3,5-dimethoxybenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (527 mg, 1.47 mmol), N-Boc-piperazine (296 mg, 1.62 mmol) and N,N-diisopropylethylamine (0.51 mL, 2.94 mmol) in acetonitrile was stirred at reflux for 48 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 230 mg (30%) of tert-butyl 4-(3-(3,5-dimethoxybenzylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate: 1H NMR (400 MHz, CD3OD): δ 9.32 (br t, 1H), 7.63 (dd, 1H), 6.50 (d, 2H), 6.37 (t, 1H), 6.19 (dd, 1H), 5.81 (d, 1H), 4.39 (d, 2H), 3.77 (s, 6H), 3.52-3.49 (m, 4H), 3.35-3.32 (m, 4H), 1.48 (s, 9H). MS (ESI) m/z: Calculated: 523.23; Observed: 546.3 (M++23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([NH:58][C:59]([C@@H:61]2[CH2:66][CH2:65][CH2:64][NH:63][CH2:62]2)=[O:60])[CH2:57][CH2:56]1>CN(C=O)C.C(Cl)Cl>[CH:55]1([NH:58][C:59]([C@@H:61]2[CH2:66][CH2:65][CH2:64][N:63]([C:30]([C:26]3[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])=[O:32])[CH2:62]2)=[O:60])[CH2:57][CH2:56]1
Reactant: O=C(NC1CC1)[C@@H]1CCCNC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H](C(=O)NC2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (250 mg, 0.5 mmol), HOBt (65 mg), EDAC (191 mg), (R)-piperidine-3-carboxylic acid cyclopropylamide (250 mg) and TEA (7 drops) in DMF (3 mL) was stirred at rt for overnight. The reaction was diluted with DCM, washed with water, 10% sodium carbonate, dried and concentrated. The residue was purified on a silica gel column to give 200 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C@@H:11]([C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1)[CH3:12].[H-].[Na+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:30])=[CH:4][C:3]=1[C@@H:11]([C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1)[CH3:12]
Reactant: C[C@@H](c1cc2cn[nH]c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(S)-1-(6-Fluoro-1H-indazol-5-yl)-ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 165, 23 mg, 0.065 mmol) was dissolved in DMF (0.374 mL) and cooled down to 0° C. under nitrogen conditions. NaH (3.82 mg, 0.095 mmol) was added and the RM was stirred at 0° C. for 30 min. Then methyliodide (10.84 mg, 0.076 mmol) was introduced. The RM was allowed to warm up to rt and stirred for 2.5 h, then it was quenched with water. It was extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4. The solvent was removed and the residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The acetonitrile was removed and the aqueous solution was basified with 5% NaHCO3. It was extracted twice with EtOAc and then the organics were joined and washed with brine. It was dried over Na2SO4 and the solvent was removed. The residue was triturated with pentane and the precipitate was filtered off to afford the title compound as a white solid (tR 1.0 min (conditions 2), MH+=376, 1H-NMR in DMSO-d6: 8.30 (s, 1H); 8.06 (d, 1H); 7.94 (s, 2H); 7.67 (s, 1H); 7.59 (d, 1H); 7.54 (d, 1H); 7.46 (d, 1H); 4.95 (q, 1H); 3.95 (s, 3H); 3.88 (s, 3H); 1.77 (d, 3H)).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([C:13]1[C:17]([CH2:18][CH3:19])=[CH:16][NH:15][CH:14]=1)[CH3:12].C([O-])(=O)C.[Na+].N1C=CC=C1>ClC(Cl)C.O>[CH2:11]([C:13]1[C:17]([CH2:18][CH3:19])=[CH:16][NH:15][C:14]=1[CH:3]=[O:4])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCc1c[nH]cc1CC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1cc[nH]c1
Product: CCc1c[nH]c(C=O)c1CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
Dimethylformamide (DMF) (11.2 mL, 144.5 mmol) was cooled to 10° C. in an ice bath, and the purified phosphorous oxychloride (18.5 mL, 144.5 mmol) was added over 15 minutes, while maintaining the temperature between 10 and 20° C. The ice bath was removed and the solidified complex was allowed to warm to room temperature. Dichloroethane (10 mL) was added to the solid, which was heated to 30° C. to facilitate dissolution. The mixture was stirred for 10 minutes while additional dichloroethane (23 mL) was added, and the resulting solution was cooled in an ice bath. 3,4-Diethylpyrrole (16.2 g, 131.4 mmol) was dissolved in 33 mL of dichloroethane and added dropwise over the course of 30 minutes to the cooled solution, with vigorous stirring. The ice bath was then removed, and the solution was heated to reflux and stirred at reflux for 10 minutes, after which it was cooled to room temperature. Sodium acetate (64.9 g, 790.9 mmol) dissolved in deionized water (133 mL) was added to the resulting reaction mixture while maintaining the temperature of the reaction below 30° C. The resulting two-part mixture was heated to reflux while maintaining vigorous stirring. The mixture, which had become deep brown upon addition of pyrrole, now turned dark magenta. The mixture was stirred at reflux for 15 minutes. Upon cooling to room temperature, the mixture was separated, and the combined organic layers were washed (3×) with sodium bicarbonate solution (50 mL), dried, and filtered, and the solvent was removed under reduced pressure. The resulting oil was dried overnight under vacuum to give 3,4-diethyl-2-formylpyrrole, the compound of formula (2), in 70.9% yield.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[C:26]([O:28]C)=[O:27])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[C:26]([OH:28])=[O:27])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN(C(C)=O)CC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)CC1
Temperature: 70 °C
Yield: 29.4 %

Procedure:
To a solution of methyl 5-[4-(1-acetylpiperidin-4-yl)phenyl]-6-chloro-1H-indole-3-carboxylate (120 mg, 0.30 mmol) in MeOH (4 mL) was added sodium hydroxide (1 mL, 1 M). The mixture was heated to 70° C. for 24 h. Solvent was removed under reduced pressure. The residue was acidified to pH=5 and dried in vacuum to give an oil, which was purified by preparative HPLC to give the title compound (35 mg, 30% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8](=[CH2:10])[CH2:7]1)=[O:4]>[Pd].C1COCC1>[F:43][C:2]([F:1])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:9][CH:8]([CH3:10])[CH2:7]1)=[O:4]
Reactant: C=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-methylene-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-11) (5 mg, 0.009 mmol) and palladium on carbon (10%, 10 mg) in THF (5 mL) was stirred under H2 atmosphere at room temperature for 30 minutes. The mixture was filtered through celite pad and the solvent was removed under reduced pressure. The residue was purified by preparative TLC eluting with 5% EtOAc in hexane to give 2,2,2-trifluoro-N-(3-methyl-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-12) as a white solid.