Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:28]=3)[C:23](O)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.C(Cl)CCl.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:39]1([NH:42][C:23](=[O:24])[C:22]2[CH:26]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:28]=[C:20]([NH:19][C:6]3[C:5]4[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[C:7]=3[CH3:18])[CH:21]=2)[CH2:41][CH2:40]1
Reactant: NC1CC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)NC2CC2)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure U by stirring 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoic acid (0.030 g, 0.065 mmol), DMAP (0.016 g, 0.131 mmol), EDC (0.025 g, 0.131 mmol), cyclopropylamine (6.46 μL, 0.092 mmol), and DCM (0.6 mL) at 23° C. for 1 hour. Purification by reverse-phase HPLC afforded N-cyclopropyl-3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68-8.71 (1H, m), 8.61 (1H, s), 8.24 (1H, d, J=4.3 Hz), 8.08 (1H, dd, J=9.3, 6.2 Hz), 7.99 (1H, dd, J=7.6, 1.8 Hz), 7.85-7.89 (1H, m), 7.74 (1H, dd, J=10.4, 2.7 Hz), 7.45-7.51 (2H, m), 6.82-6.84 (1H, m), 6.59-6.61 (1H, m), 6.44 (1H, t, J=2.2 Hz), 3.68-3.74 (4H, m), 3.04-3.09 (4H, m), 2.76 (1H, m), 2.18 (3H, s), 0.60-0.69 (2H, m), 0.51 (2H, dd, J=4.2, 2.2 Hz). Mass Spectrum (ESI) m/e=498.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([S:7][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=2)=[N:4][N:3]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Cc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title compound was prepared according to Example 1 by using 5-methyl-1,3,4-thiadiazole-2-thiol (264 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 6 hr.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:12]=2[C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O>C1COCC1.CO.[OH-].[Na+]>[C:1]1([S:7]([NH:10][C:11]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:12]=2[C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of methyl 4-(2-phenylsulfonylamino-5-chlorobenzoyl-amino)benzoate (122 mg; prepared in Example 1.) in THF-MeOH (4 ml+2 ml), 2N NaOH aqueous solution (0.5 ml) was added at room temperature. The mixture was stirred overnight. To the reaction mixture, 2N HCl (0.6 ml) and water were added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified by recrystallization from the mixture of AcOEt-hexane to give the title compound (80 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1.CO[CH:27](OC)[N:28](C)C.Cl.NO>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:23][N:28]=[CH:27][C:15]=2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:10][CH:9]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CCSCc1ccc(C(=O)CC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: NO
Product: COC(=O)CCSCc1ccc(-c2oncc2C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To tert-butyl 3-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)-3-oxopropionate (472 mg, 1.34 mmol) was added N,N-dimethylformamide dimethylacetal (5 ml), and the mixture was stirred at 100° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethanol (10 ml). Hydroxylamine hydrochloride (280 mg, 4.03 mmol) was added, and the mixture was stirred at 70° C. for 2 hours. The solvent was evaporated under reduced pressure and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (330 mg, 65%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.O[CH2:13][C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Br.O>[N:16]1[CH:15]=[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=3[N:3]=2)[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: OCc1cnc2ccccn12
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2[nH]c(SCc3cnc4ccccn34)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 903 mg (5.5 mmole) of 2-mercapto-5-methylbenzimidazole and 805 mg (5.4 mmole) of 3-hydroxymethylimidazo[1,2-a]pyridine (prepared as in Example 1) was dissolved in 10 ml of 48% aqueous hydrobromic acid and 10 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and made alkaline with potassium carbonate. The oil that separated was extracted into dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil that crystallized on standing. The solid was collected by filtration, washed with diethyl ether, and air dried to yield the title compound as 610 mg of analytically pure solid. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]#[N:13]>CCO.Cl.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:11][C:12]#[N:13])[CH:4]=1
Reactant: N#CCc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCc1cc(N)ccc1Cl
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a suspended solution of (2-Chloro-5-nitro-phenyl)-acetonitrile (4.0 g, 20.0 mmol) in EtOH (10 mL) is added a solution of Sn(II)Cl2 (15.36 g, 81.0 mmol) in concentrated HCl (14 mL) at 75° C. After the mixture is stirred for 30 minutes at 75° C., the mixture is diluted with EtOAc and neutralized with K2CO3 until a pH of 8 is achieved. The organic layer is washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product, which is purified by recrystallization with CH2Cl2/EtOAc/Hexane to give the title intermediate as a solid (3.04 g, 89.7%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](Cl)=[C:4](Cl)[C:5]([F:8])([F:7])[F:6].[OH-].[Na+].[H][H]>O1CCCC1.[Pd]>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: [H][H]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: FC(F)(F)CCC(F)(F)F
Yield: 48.2 %

Procedure:
To 1,1,1,4,4,4-hexafluoro-2,3-dichloro-2-butene (23.5 g, 0.1 mole) in 50 ml tetrahydrofuran were added sodium hydroxide (8.5 g) and as catalyst 5% by weight palladium on carbon (3 g). This mixture was hydrogenated with hydrogen at temperatures of 20 to 40° C. under pressures of 20 to 40 bar. The reaction mixture was worked up as in Example B, producing 8.0 g (75% of theory) of 1,1,1,4,4,4-hexafluorobutane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 92.6 %

Procedure:
Sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (154 mg, 0.50 mmol), 2-chloro-3-nitropyridine (79 mg, 0.50 mmol) and DMSO (2.5 mL) were combined and the resulting solution stirred at ambient temperature for 19 hours. The solution was partitioned between EtOAc (25 mL) and water (25 mL) and the organic layer was subsequently washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to afford semi-pure 2-{[6-(4-fluorophenyl)naphthalen-2-yl]sulfonyl}-3-nitropyridine as a yellow solid (189 mg) which was used directly in the following step. 1H NMR (500 MHz, d6-DMSO): δ 8.85 (1H, dd, J=1.3, 4.6 Hz), 8.75-8.73 (1H, m), 8.63 (1H, dd, J=1.3, 8.1 Hz), 8.38 (2H, t, J=7.7 Hz), 8.25 (1H, d, J=8.8 Hz), 8.06 (1H, dd, J=1.7, 8.6 Hz), 7.98-7.92 (4H, m), 7.39 (2H, t, J=8.8 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:36]=[CH:35][S:34][CH:33]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][NH:30][C:26]2[CH:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)c4)n[nH]c3n2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of {4-[3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (120 mg, 0.185 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another two hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give N-(3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine as solid. (Yield 75 mg, 84%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH3:4].I[CH2:22][CH2:23]CC.O>O1CCCC1>[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH2:4][CH2:22][CH3:23]
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a suspension of sodium hydride (60-72% in mineral oil, 38 mg, 0.94 mmol) in tetrahydrofuran (2 ml) was added a suspension of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 100 mg, 0.469 mmol) in tetrahydrofuran (5 ml) at 0° C. After 30 min, 1-iodobutane (0.11 ml, 0.94 mmol) was added. The mixture was stirred at room temperature for 3 h and at 70° C. for 4 h. After cooling to room temperature, water (30 ml) was added and extracted with ethyl acetate (50 ml×2). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The obtained solid was washed with hexane to give 67 mg (53%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[N:7]=[CH:8][C:9]([C:11]3[C:12]4[N:13]([N:17]=[C:18]([NH2:20])[N:19]=4)[CH:14]=[CH:15][N:16]=3)=[CH:10][C:2]=12.Cl[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>C(O)(C)(C)C>[O:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:9]5[CH:8]=[N:7][C:3]6=[N:4][CH:5]=[CH:6][N:1]=[C:2]6[CH:10]=5)=[N:16][CH:15]=[CH:14][N:13]4[N:17]=3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: Nc1nc2c(-c3cnc4nccnc4c3)nccn2n1
Reactant: Clc1ccc(N2CCOCC2)cc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Product: c1cn2nc(Nc3ccc(N4CCOCC4)cc3)nc2c(-c2cnc3nccnc3c2)n1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
8-Pyrido[2,3-b]pyrazin-7-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine, 4-(4-chloro-phenyl)-morpholine (1.1 eq.), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl]2-(2-aminoethyl)phenyl)Pd(II) (0.25 eq), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl; BrettPhos (0.25 eq.) are combined and suspended in t-butanol. The suspension is purged with N2 and lithium bis(trimethylsilyl)amide, (3 eq; 20% (ca 1.06M) solution in THF/ethylbenzene) is added. The vessel is sealed under N2 and heated to 65° C. for 2 h and then to 110° C. for 2 h. The mixture is filtered and concentrated. Purification via prep. HPLC gives the title compound.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH3:14][N+:15]([CH3:17])=C.[I-].[C-]#N.[K+]>C(#N)C.C(OCC)(=O)C>[C:9]([CH2:8][C:7]1[C:6]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=[CH:2][C:17]=2[NH:15][CH:14]=1)#[N:1]
Reactant: C=[N+](C)C
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2[nH]cc(CC#N)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl indole-4-carboxylate (1.1 g 6.2 mmol) and Eschenmoser's salt [N,N-dimethylmethyleneammonium iodide] (1.3 g, 7 mmol) in acetonitrile (15 ml) is refluxed for 3 hours. The reaction mixture is concentrated, redisolved in dichloromethane (400 ml) and washed with 1M sodium hydroxide (200 ml) and water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated. The resulting methyl 3-(dimethylaminomethyl)indole-4-carboxylate (1.2 g) is methylated with methyl iodide (0.7 ml) in a mixture of dichoromethane (25 ml) and ether (13 ml). The reaction mixture is concentrated, the product dissolved in DMSO (7 ml) and treated with potassium cyanide (700 mg, 10 mmol). After stirring at r.t. overnight the reaction mixture is diluted with ethyl acetate (200 ml) and washed with three portions of water (100 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 2:3 to give methyl 3-(cyanomethyl)indole-4-carboxylate as a dark oil. Hydrogenation in acetic acid over platinum oxide gives the desired intermediate as an orange solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:18]([NH:21][C@@H:22]([CH2:28][NH2:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[Cl:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.C1COCC1>CC(=O)OCC>[Cl:30][C:31]1[N:32]=[CH:33][N:34]=[C:35]([NH:29][CH2:28][C@H:22]([NH:21][S:18]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)(=[O:20])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:36]=1[N+:37]([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CCOC(=O)[C@H](CN)NS(=O)(=O)c1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CNc1ncnc(Cl)c1[N+](=O)[O-])NS(=O)(=O)c1cccc2ccccc12
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
2.96 g (29.3 mmol) of triethylamine were added dropwise at −10° C. in the course of 5 minutes to 5.0 g (13.9 mmol) of ethyl (2S)-2-(naphthalene-1-sulfonylamino)-3-aminopropionate (EP 1070707 (EP 99114372.8)) and 2.84 g (14.6 mmol) of 4,6-dichloro-5-nitropyrimidine, dissolved in 140 ml of abs. THF. The mixture was stirred at −5° C. for 15 minutes and then at room temperature for 12 h. The reaction mixture was taken up in EA and extracted with a saturated aqueous NaCl solution, the organic phase was dried over MgSO4 and filtered, and the solvent was distilled off in vacuo. For purification, the residue was chromatographed over silica gel (EA/heptane 3:7). Yield: 6.38 g.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[ClH:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[S:29][C:28]([C:31]([NH:33][C@@H:34]3[CH:39]4[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]4)[CH2:35]3)=[O:32])=[CH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C1COCC1>CN(C=O)C>[ClH:12].[N:36]12[CH2:37][CH2:38][CH:39]([CH2:40][CH2:41]1)[C@@H:34]([NH:33][C:31]([C:28]1[S:29][C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][NH:14][C:10]([NH:9][CH3:8])=[O:11])=[CH:23][CH:24]=[CH:25][C:26]=3[CH:27]=1)=[O:32])[CH2:35]2
Reactant: NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reaction time: 18 h

Procedure:
51.0 μl (0.37 mmol) of triethylamine and 43.5 ld (0.73 mmol) of methyl isocyanate are added to a suspension of 85 mg (0.18 mmol) of 7-[2-(aminomethyl)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 73) in 1 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, the reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 65.5 mg (74% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCCOCc1ccc(C(=O)O)c(F)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCOCc1ccc(C(=O)Cl)c(F)c1

Procedure:
2-Fluoro-4-(propoxymethyl)benzoic acid (1.5 g, 7.1 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 2-fluoro-4-(propoxymethyl)benzoyl chloride.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[CH:4]1.C1([OH:21])C=CC=CC=1>C(OCC)C>[ClH:1].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13](=[NH:14])[OH:21])=[CH:4]1
Reactant: Cn1cc(CC#N)c2ccccc21
Reactant: Oc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: Cn1cc(CC(=N)O)c2ccccc21
Reaction time: 96 h
Yield: 30 %

Procedure:
Hydrogen chloride was bubbled through a solution of 3 g (176 mmol) of 1-methylindole-3-acetonitrile and 8.28 g (88 mmol) of phenol in 70 ml of dry diethyl ether for 2 hours and the resulting solution was left to stand for 4 days. The solvent was removed under reduced pressure. The residual gum was triturated with diethyl ether to give 1.4 g (30%) of 1-methyl3-indoleacetimidate hydrochloride in the form of a purple solid of melting point 119° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccc(C)nc1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(C)nc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.3 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.37 g, 0.007 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (4.30 g, 0.033 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (2.00 g, 0.007 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (410 mg, 15%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1>>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCCCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 62.9 %

Procedure:
In a manner similar to that described in Example 3, heptanoyl chloride (0.051 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.048 g of 4-[4-(heptanoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+306.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1.C(OC([N:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[CH:39]=[C:38]([NH:40][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:1])([F:27])[F:26])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH:37]=[N:36]1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: O=C(O)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cn[nH]c1)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure for 126, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-amino-pyrazole-1-carboxylic acid tert-butyl ester. The intermediate carboxylic acid tert-butyl ester was dissolved in DCM (5 mL) and treated with TFA (2 mL) before the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue triturated in water to give 127 as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1 H); 8.51 (d, J=2.2 Hz, 1 H); 8.23 (s, 1 H); 7.96 (dd, J=8.5, 2.2 Hz, 1 H); 7.84 (s, 2 H); 7.39 (d, J=8.5 Hz, 1 H); 7.02 (s, 1 H); 5.77 (q, J=8.7 Hz, 2 H); 4.59 (t, J=5.8 Hz, 2 H). 3 Protons obscured by water peak. LCMS: RT=9.11 min, M+H+=445