Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([NH:17][CH:18]([CH2:28][OH:29])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])[CH:12]=[CH2:13].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:11]([O:14][C:15]([NH:17][CH:18]([CH:28]=[O:29])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)NC(CO)CCC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)NC(C=O)CCC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of DMSO (1.51 g, 19.3 mmol) in CH2Cl2 (25 ml) at −70° C. was added oxalyl chloride (1.34 g, 19.3 mmol). After 10 minutes at −70° C., a solution of (206a) (2.4 g, 8.8 mmol) in CH2Cl2 (10 ml) was added dropwise and the mixture stirred for 15 minutes at −70° C. Diisopropylethylamine (3.4 g, 26.3 mmol) was added and the mixture stirred at −25° C. for 15 minutes then diluting with EtOAc (50 ml) washed with a solution of sodium hydrogen sulfate 2M, concentrated to give an oil which was used immediately without purification: 1H NMR (CDCl3) δ9.5 (1H, s), 6.0-5.5 (2H, m), 5.5-5.1 (2H, m), 4.5 (2H, m), 4.2 (1H, m), 2.4-2.10 (2H, m), 2.05 (2H, m), 1.36 (9H, s).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:33])[NH:15][C:16](=[O:32])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][CH2:29][CH2:30]O)[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>ClCCl>[Br:54][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:17]2[C:16](=[O:32])[NH:15][C:14](=[O:33])[C:13]=2[C:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]4[CH:2]=2)=[CH:19]1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCCO)c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCCBr)c2ccccc12
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-[1-(4-hydroxybutyl)-1H-indol-3-yl]pyrrole-2,5-dione (0.11 g, 0.25 mmol) and triphenylphosphine (0.08 g, 0.31 mmol) in dichloromethane (3 mL) was treated with carbon tetrabromide (0.095 g, 0.286 mmol) and stirred for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 2% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.101 g (80%) of the title compound as a dark red foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21](C(C)=C)[C:20]3=[O:31])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.Cl.C(O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:31])[CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(CC(=O)c3cccc(Cl)c3)CC2)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(CC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 9 parts of 1-[3-[4-[2-(3-chlorophenyl)-2-oxoethyl]-1-piperidinyl]propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 18 parts of a concentrated hydrochloric acid, 80 parts of ethanol and 50 parts of water is stirred for 30 minutes at room temperature. The reaction mixture is evaporated and water is added to the residue. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 6.4 parts (78%) of 1 -[3-[4-[2-(3-chlorophenyl)-2-oxoethyl]-1-piperidinyl]propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 160.3° C.
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:15](=[O:16])[C@@H:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: C[C@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(c1ccccc1)N1C(=O)[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 120 °C
Yield: 21.6 %

Procedure:
To a 5 mL microwave vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N-((S)-1-phenylethyl)morpholine-3-carboxamide (PREPARATION x46, 0.394 g, 0.926 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.024 g, 0.042 mmol), and palladium(II) acetate (6.23 mg, 0.028 mmol). The vessel was evacuated, refilled with nitrogen, and sealed. Dioxane (3.9 mL) was added and the mixture was heated in a microwave to 120° C. for 3 hours. Additional catalyst was added and the reaction mixture was heated in the microwave to 120° C. for another 6 hours. The reaction mixture was then partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The dark brown crude product was purified by normal phase column chromatography (SiO2, 60 gram) eluting with a gradient of 50-100% EtOAc in hexanes over a 20 minute period. The product-containing fractions were combined and concentrated to give the title compound as a white foam (69 mg, 22%). ESI-MS m/z [M+H]+ calc'd for C17H17ClN4O2, 345.10; found 345.3.
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:30])([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:23])[C:17]([CH3:31])=[N:16]2)=[CH2:10])(C(C)(C)C)(C)C.[Br:32]N1C(=O)CCC1=O.O>C1COCC1.C(Cl)Cl>[Br:32][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:30])([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:23])[C:17]([CH3:31])=[N:16]2)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)quinoxalin-2-amine (338d), 1-bromopyrrolidine-2,5-dione (0.26 g, 1.46 mmol), and water (0.42 mL, 23.49 mmol) in THF (14.68 mL) was stirred at 0° C. for 15 min before it was warmed to RT and stir for 2 h when product was observed via lcms. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM followed by 3% 2 M NH3 in MeOH/DCM to give 2-bromo-1-(2-methyl-3-((2-methyl-4-(methylsulfonyl)butan-2-yl)amino)quinoxalin-5-yl)ethanone (338e, 306 mg, 0.71 mmol, 49% yield) as a red oil. MS (ESI, pos. ion) m/z: 428.2/430.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:32](=[O:34])[CH3:33])[CH:15]=[C:16]([N:20]2[CH2:24][C@H:23]([O:25][CH2:26][O:27][CH3:28])[C@@H:22]([O:29][CH2:30][CH3:31])[CH2:21]2)[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:35]N1C(=O)CCC1=O>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Br:35][CH2:33][C:32]([C:14]1[CH:15]=[C:16]([N:20]2[CH2:24][C@H:23]([O:25][CH2:26][O:27][CH3:28])[C@@H:22]([O:29][CH2:30][CH3:31])[CH2:21]2)[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:13]=1)=[O:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCO[C@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@@H]1OCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCO[C@H]1CN(c2cc(C(=O)CBr)cc(C(C)(C)C)c2OC)C[C@@H]1OCOC
Reaction time: 0.42 h
Yield: 101.4 %

Procedure:
Triethylamine (0.52 ml, 3.7 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.51 ml, 2.2 mmol) were added dropwise in that order to a solution of 1-{3-(tert-butyl)-5-[(3S,4S)-3-ethoxy-4-(methoxymethoxy)tetrahydro-1H-1-pyrrolyl]-4-methoxyphenyl}-1-ethanone (650 mg, 1.71 mmol) in tetrahydrofuran (7 ml) while cooling on ice, and the mixture was stirred at the same temperature for 25 minutes. N-bromosuccinimide (427 mg, 2.40 mmol) was then added and stirring was continued at the same temperature for 25 minutes. After completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (795 mg, 100%) as a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][CH2:2][C:3]2([C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]2)=[CH:24][CH:23]=1
Reactant: COC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(CNCc2ccc(OC)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Commercial available 1-tert-butyl 4-methyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (10.10 mmol, 2.75 g) and 4-methoxybenzaldehyde (15.15 mmol, 2.062 g) in anhydrous MeOH (40 mL) were stirred for 2 h at rt. After addition of sodium cyanoborohydride (20.19 mmol, 1.269 g) the reaction was stirred overnight at 45° C. The mixture was evaporated in vacuo, and solved in EtOAc and sat. aq. bicarb. After separation of the organic phase, the aq. phase was extracted with EtOAc. The combined organic phase was dried over MgSO4 and evaporated in vacuo. The crude was purified by flash chromatography (heptane/EtOAc: 10 to 100%) yielding 2.3 g oil (58%). 1H NMR (400 MHz, CDCl3, 300K): δ=1.40 (2H, s), 1.45 (9H, s), 2.07 (2H, dt, J=13.3 Hz, J=3.4 Hz), 2.66 (2H, m), 2.94 (2H, m), 3.68 (2H, s), 3.70 (3H, s), 3.76 (2H, m), 3.79 (3H, s), 6.85 (2H, d, J=8.3 Hz), 7.19 (2H, d, J=8.3 Hz). 13C NMR (100 MHz, CDCl3, 300K): δ=28.8, 31.9, 47.3, 52.3, 53.9, 55.7, 57.3, 79.8, 114.0, 129.4, 132.8, 155.2, 159.0, 176.1. MS (ES) C21H32N2O5 requires: 392. found: 393.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=O)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[F:53][C:54]([F:64])([F:63])[C:55]1[CH:60]=[CH:59][C:58]([NH:61][NH2:62])=[CH:57][CH:56]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:61]([C:58]2[CH:57]=[CH:56][C:55]([C:54]([F:63])([F:64])[F:53])=[CH:60][CH:59]=2)[N:62]=[C:25]([CH:27]2[CH2:28][CH2:29]2)[CH:24]=1)=[O:4]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CC1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-cyclopropyl-3-oxo-propionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[NH2:12][OH:13]>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH:12][OH:13])=[NH:8])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc(C#N)cn1
Reactant: NO
Solvent: CCO
Product: CN(C)c1ccc(C(=N)NO)cn1
Reaction time: 11 h

Procedure:
In a 100 ml round flask, 4.7 g (31.9 mmol) of 6dimethylamino-nicotinonitrile and 1.88 ml (31.9 mmol) of aqueous hydroxylamine (50%) are dissolved in 25 ml of ethanol. This mixture is reacted at 90° C. for 6 h. Then another 0.45 ml (8.1 mmol, 0.25 eq.) of hydroxylamine-solution is added. After 11 h at 90° C., the mixture is cooled and the solvent removed in vacuo. This yields the title compound as light yellow solid, which is used for the next step without purification. Mass spectrum: m/z (M+H)+: 181.0
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:43][N:42]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:31][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:33]4)[S:26][C:9]=3[N:10]=2)=[N:42]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reactant: Ic1n[nH]c2ccccc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: c1ccc2c(-c3nc(N4CCOCC4)c4nc(CN5CC(N6CCOCC6)C5)sc4n3)n[nH]c2c1
Yield: 19.8 %

Procedure:
A mixture of 7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidine (0.25 g, 0.37 mmol), 3-iodo-1H-indazole (0.2 g, 0.82 mmol), copper(I) 2-thiophene carboxylate (0.030 g, 0.150 mmol) and Pd(PPh3)4 (0.088 g, 0.075 mmol) in dioxane (3 mL) was subjected to microwave irradiation at 150° C. for 90 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 20:80) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 182 as an off-white solid (0.036 g, 20%). LCMS (Method G): RT=7.40 min, [M+H]+ 493.3. 1H NMR (CDCl3, 400 MHz) δ 8.58 (d, J=8.2 Hz, 1 H); 7.55 (t, J=8.2 Hz, 1 H); 7.46-7.41 (m, 1 H); 7.34-7.29 (m, 1 H); 4.48-4.33 (m, 4 H); 4.02 (s, 2 H); 3.92 (t, J=4.6 Hz, 4 H); 3.73 (t, J=4.6 Hz, 4 H); 3.70-3.66 (m, 2 H); 3.18-3.09 (m, 3 H); 2.40-2.35 (m, 4H)
Reaction SMILES: [C:1](O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([C:10]1[CH:11]=[N:12]C=[CH:14][CH:15]=1)#[N:9].OS(O)(=O)=O.[OH-].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[C:2]([C:1]1[CH:14]=[CH:15][C:10]([C:11]#[N:12])=[CH:8][N:9]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: N#Cc1cccnc1
Reactant: CC(C)(C)C(=O)O
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CC(C)(C)c1ccc(C#N)cn1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
Pivalic acid (144 mol, 5 eq) and AgNO3 (3.76 mmol, 0.13 eq) are added to a suspension of the 3-cyanopyridine (29 mmol, 1 eq) in 40 ml H2O. The mixture is stirred for 20 min after which is added 60 ml of a 10% H2SO4 solution. The reaction is stirred for a further 20 min then heated to 70° C. An aqueous solution of (NH4)2S2O8 (8.6 mmol, 1.3 eq) is added dropwise over 30 minutes and the heating is continued for 2 hours or until completion by TLC. After cooling the in ice, 2 N NaOH is added and the reaction is extracted 3 times with ethyl acetate, dried over Na2SO4, filtered and concentration. Purification is performed on silica gel with ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:23]
Reactant: CCO
Reactant: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Product: CCOc1cccc(OC)c1Cc1cc2ccccc2nc1N

Procedure:
Synthesis was performed according to EXAMPLE 3 from 2-[(2-aminoquinolin-3-yl)methyl]-3-methoxyphenol and ethanol.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([OH:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[C:44]([C:45]#[N:46])=[CH:43][C:42]2[C:37](=[CH:38][C:39]([CH3:48])=[CH:40][C:41]=2[CH3:47])[N:36]=1>C(Cl)Cl>[C:45]([C:44]1[C:35]([NH:34][CH2:33][CH2:32][NH:31][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:36][C:37]2[C:42]([CH:43]=1)=[C:41]([CH3:47])[CH:40]=[C:39]([CH3:48])[CH:38]=2)#[N:46]
Reactant: Cc1cc(C)c2cc(C#N)c(NCCN)nc2c1
Reactant: COc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NCCNc2nc3cc(C)cc(C)c3cc2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
EDC hydrochloride (0.192 g, 1 mmol), m-anisic acid (0.152 g, 1 mmol) and triethylamine (0.14 mL, 2.5 mmol) were dissolved in dry DCM (10 mL). The reaction was stirred at room temperature for 30 min. Carbonitrile 4 (0.201 g, 1 mmol) dissolved in 5 mL dry DCM was added dropwise to the solution and reaction stirred for 18 h. The reaction was diluted with DCM (50 mL) and washed with 1M NaHSO4 (aq, 2×100 mL). Organics were dried over Na2SO4, filtered and solvent was removed under reduced pressure. The crude product was then purified by flash chromatography (4:1 hexane:ethyl acetate mobile phase) to produce a light yellow solid (Compound 22) in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.13 (s, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 7.20 (d, J=7.5, 1H), 7.13 (t, J=7.8, 1H), 6.98 (s, 1H), 6.95 (d, J=8.1, 1H), 5.82 (s, 1H), 3.91 (q, J=5.3, 2H), 3.79-3.68 (m, 5H), 2.55 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.10, 159.87, 155.10, 144.27, 140.97, 136.27, 135.41, 129.42, 127.13, 124.48, 119.35, 119.23, 117.72, 116.87, 112.46, 94.30, 55.49, 43.39, 41.25, 29.92, 22.21, 18.57. IR (neat): 3380, 3357, 2957, 2925, 2217, 1605, 1583, 1535, 1258. ESI-LCMS m/z [M+H]+=375.18.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:4][NH:3]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:57]([N:59]([CH2:62][CH2:63][NH2:64])[CH2:60][CH3:61])[CH3:58]>O.CN(C)C=O>[CH2:57]([N:59]([CH2:60][CH3:61])[CH2:62][CH2:63][NH:64][C:17]([C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:7]3[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)[CH:6]=3)=[N:9][C:10]=2[CH:16]=1)=[O:19])[CH3:58]
Reactant: O=C(O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)CCNC(=O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture consisting of 50 mg of 2-(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)-1H-benzoimidazole-5-carboxylic acid, 0.065 ml of triethylamine and 1.5 ml of dimethylformamide (DMF) is stirred at room temperature for 10 minutes, mixed with 68.4 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Hatu) and stirred at room temperature for a further 30 minutes. Then 21 mg of diethylaminoethylamine are added, and the mixture is stirred at 50° C. for 3 hours. After cooling, it is diluted with 5 ml of water, and the precipitate is filtered off with suction and stirred with isopropanol at 60° C., filtered off with suction and dried in vacuo.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[N:9]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Cl)[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1>[N:9]1([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][NH:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][S:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(CCCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
344 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and in an atmosphere of nitrogen, to a solution of 0.35 ml of methyl thioglycolate in 90 ml of tetrahydrofuran, and the resulting mixute was stirred at room temperature for 30 minutes. At the end of this time, it was cooled with ice, and a solution of 2.94 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-chloropentanamide [prepared as described in step (a) above] in 30 ml of tetrahydrofuran was added dropwise to the mixture. The reaction mixture was then stirred at room temperature for 2 hours, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 2.84 g (yield 89%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[CH3:29][O-:30].[Na+].C1(C)C=CC=CC=1>O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[C:2]2[O:30][CH3:29])=[CH:7][CH:8]=1
Reactant: C[O-]
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(N(C)c2ccc(OC(C)C(=O)O)cc2)cc2ccc(Cl)cc12

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.25 g), sodium methoxide (0.63 g) and toluene was heated under reflux for 4 hrs. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic fraction was dried (MgSO4) and evaporated to give 2-{4-[N-(7-chloro-1-methoxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid.