Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>N1C=CC=CC=1>[OH:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2c(O)cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
2-Amino-3-nitrophenol (308 mg) was dissolved in 10 ml of pyridine, then 341 mg of 4-methoxybenzoyl chloride was added at 0° C. and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated in vacuo, 20 ml of chloroform was added to the resulting residue and the mixture was again concentrated in vacuo. This operation was further repeated three times, and the residue from which the pyridine had been removed was purified by silica gel column chromatography using chloroform as an eluting solvent to give 428 mg of 2′-hydroxy-4-methoxy-6′-nitrobenzanilide.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([OH:31])=O)=[CH:26][C:20]=4[S:19](=[O:33])(=[O:32])[N:18]=3)[C:7]2=[O:34])[CH2:3][CH2:2]1.Cl.C[N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]=C=NCC.ON1C2C=CC=CC=2N=N1.C(OC(=O)NC1CCNC1)(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:41][CH:40]1[CH2:39][CH2:38][N:37]([C:29](=[O:31])[CH2:28][O:27][C:25]2[CH:24]=[CH:23][C:21]3[NH:22][C:17]([C:8]4[C:7](=[O:34])[N:6]([NH:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:15]5[C:10]([C:9]=4[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=5)=[N:18][S:19](=[O:32])(=[O:33])[C:20]=3[CH:26]=2)[CH2:46]1
Reactant: O=C(O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CCN=C=NCCCN(C)C
Agent: CC(C)(C)OC(=O)NC1CCNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1CCN(C(=O)COc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4ccccc4n(NCC4CC4)c2=O)N3)C1
Reaction time: 24 h
Yield: 54.3 %

Procedure:
The product of Example 384B (24 mg, 0,05 mmole), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol) and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester(19 mg, 0.1 mmol). The mixture was stirred for 1 day. The solution was poured into ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate, water, and brine, dried with magnesium sulfate, filtered and concentrated. The residue was triturated with methanol/water and filtered. The solid was treated with hydrochloric acid (1 M in dioxane, 2 mL) and stirred overnight, filtered and washed with ethyl acetate/hexane (1:1) to give title compound (15 mg, 51%). 1H NMR (500 MHz, BENZENE-d6) δ 0.16 (m, 2 H) 0.43 (m, 2 H) 1.01 (m, 1 H) 2.14 (m, 2 H) 2.29 (m, 1 H) 2.89 (d, J=6.84 Hz, 2 H) 3.36 (m, 2 H) 3.81 (m, 2 H) 4.88 (m, 2 H) 7.42 (m, 3 H) 7.61 (m, 1 H) 7.88 (m, 1 H) 8.09 (d, J=8.30 Hz, 1 H) 8.17 (d, J=8.30 Hz, 1 H) 8.28 (s, 3 H) 13.99 (s, 1 H). MS (ESI−) m/z 551 (M−H)−.
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][C:12]([O:14]CC)=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-])=O>C(O)C.[C].[Pd]>[CH2:4]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][C:12](=[O:14])[NH:1]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CC2(CCCCC2)CN1
Yield: 0.9 %

Procedure:
190 g (0 82 mole) Ethyl 1-nitromethyl-1-cyclohexaneacetate in 3168 mL ethanol are hydrogenated for 4 hours at 125° C. in the presence of 62.9 g 10% palladium-carbon. At the end of the take up of hydrogen, the catalyst is filtered off and the colorless solution obtained is distilled to dryness in a vacuum. 116.2 g 2-Aza-spiro[4,5]decan-3-one in the form of a colorless crystallizate are obtained; yield 91.6% of theory. Content 97.1% (GC); m.p. 88° to 90° C.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22](Br)=[N:23][CH:24]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[S:1]1[C:5]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[CH:24][N:23]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc2sc(-c3ccc(Cn4ccnc4)cn3)cc2c1

Procedure:
Synthesized using benzo[b]thiophen-2-ylboronic acid (149 mg, 0.84 mmol) and 1a (100 mg, 0.42 mmol) according to Method C. Yellow solid. Yield: 46 mg, 0.16 mmol, 38%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.17 (s, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.35-7.38 (m, 2H), 7.46 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (brs, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.80-7.83 (m 1H), 7.84 (d, J=0.6 Hz, 1H), 7.86-7.88 (m, 1H), 8.52 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 119.0, 119.7, 121.7, 122.6, 124.2, 123.6, 125.3, 130.4, 130.6, 135.6, 137.3, 140.3, 140.8, 143.8, 148.5, 152.8; MS (ESI): m/z=292.04 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]([CH2:26][CH2:27][C:28](=[NH:31])[NH:29][OH:30])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][CH2:27][C:28]2[N:31]=[C:35]([OH:37])[O:30][N:29]=2)[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[O:9])=[CH:32][CH:33]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCC(=N)NO)Cc2ccc(Cl)cc2)c1
Solvent: C1COCCO1
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCc2noc(O)n2)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-[2-(N-hydroxycarbamimidoyl)-ethyl]-amide (1 eq.) in dioxane was added triphosgene (1.7 eq.) under nitrogen. The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The layers were separated, the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc/DCM/MeOH: 50/50/0/0 to 50/50/90/10) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-[2-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][C:11]#[N:12]>>[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([O:7][CH2:10][C:11]#[N:12])[CH:1]=1
Reactant: Cc1cccc(O)c1
Reactant: N#CCBr
Product: Cc1cccc(OCC#N)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 36, using the m-cresol instead of the p-cresol and the bromoacetonitrile instead of the methyl bromoacetate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:20]([N:23]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:20]([N:23]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)Cc1ccc(C=O)cc1
Reactant: Cn1ccnc1CN(CCCCN)Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)Cc1ccc(CNCCCCN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (349 mg) obtained in Example 117-4 was dissolved in methanol (7.0 ml). Then, the solution was added with the compound (323 mg) obtained in Example 117-1 and trimethyl orthoformate (0.340 ml) and stirred at room temperature for 2 hours, followed by cooling to 0° C. The solution was added with sodium borohydride (75.5 mg) and stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with an aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform) and treated with hydrochloric acid, thereby obtaining hydrochloride (89.8 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[O:17]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[O:17][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=S(=O)(OC1CCCCC1)C(F)(F)F
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: Clc1ccc(C=C(OC2CCCCC2)n2cncn2)c(Cl)c1

Procedure:
Analogously to Example 1a,b, after reacting 1-(2,4-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone with cyclohexyl triflate there was obtained 1-[2-(2,4-dichloro-phenyl)-1-cyclohexyloxy-vinyl]-1H-[1,2,4]triazole as a white solid with m.p. 84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]=[O:22])=[N:6][CH:7]=1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.10 g, 0.30 mmol) in 5.5 ml of DCM was added pyridine (0.24 ml, 2.97 mmol), followed by Dess-Martin periodinane (0.166 g, 0.39 mmol). The reaction was allowed to proceed at rt for 2 h and quenched by the adding of 1M aq. sodium thiosulfate (5 ml) and satd. NaHCO3 (5 ml). After stirring vigorously, the reaction was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated to yield 105 mg of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carbaldehyde. The aldehyde was used without further purification. LCMS [M+H]+=335.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([C:8](N(OC)C)=[O:9])=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1ncc(Br)cc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ncc(Br)cc1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of crude 5-bromo-3-fluoro-N-methoxy-N-methylpyridine-2-carboxamide (27.94 g, 106.2 mmol) in THF (350 mL) at −78° C. was added lithium aluminum hydride (1M in THF, 45.67 mL, 45.67 mmol) dropwise. The reaction was stirred at −78° C. for 2 hours, then H2O (100 mL) and brine (100 mL) were added. The mixture was warmed to RT and partially concentrated in vacuo, diluted with ethyl acetate and filtered through celite. The aqueous layer was extracted 4× with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was filtered through a silica gel plug with 10% ethyl acetate in hexanes to provide 5-bromo-3-fluoropyridine-2-carbaldehyde that gave proton NMR spectra consistent with theory.
Reaction SMILES: [C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[C@@H:11]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C1COCC1.[ClH:60]>CCOCC>[ClH:60].[C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:39][CH2:40][S:41](=[O:44])(=[O:45])[CH2:42][CH2:43]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[C@@H:11]([NH2:16])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 2(S)-tert-Butoxycarbonylamino-4-methyl-pentanoic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12e) (0.35 g, 0.52 mmol), anisole (0.5 mL) and THF (10 mL), is added hydrogen chloride (4 M in dioxane, 4 mL, 15.7 mmol) in a dropwise manner. The mixture is stirred at RT overnight. Ether is then added dropwise to the mixture while stirring. Under reduced pressure, the mixture is concentrated to one-third of its original volume. Ether is again added, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether and ethyl acetate, and dried under vacuum to give the title compound in 39% yield (0.12 g). 1H NMR (400 MHz, CD3OD): δ 7.52 (dd, 1H), 7.37 (t, 1H), 7.26 (dd, 1H), 6.02 (ABq, 2H), 4.88 (m, 1H), 4.20 (m, 3H), 4.10 (dd, 1H), 3.83 (m, 1H), 3.35 (m, 2H), 3.23 (tt, 1H), 3.12 (m, 2H), 2.54 (s, 3H), 2.35 (m, 2H), 2.17 (m, 2H), 1.85 (m, 2H), 1.72 (m, 1H), 1.02 (d, 3H), 1.01 (d, 3H). MS-APCI (m/z+): 341, 385, 572.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][CH3:19])=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccccc1N
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccccc2OC)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-methoxy-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) 88.74 (s, 1H), 8.24 (br, 1H), 7.69 (d, 1H), 7.12-6.92 (5H), 6.70 (br, 1H), 3.97 (t, 2H), 3.87 (s, 3H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 350.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)CCC1>[CH2:23]([NH:30][C:7]1[CH:6]=[C:5]2[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]3[C:4]2=[CH:3][C:2]([Cl:1])=[C:19]2[C:14]=3[N:15]=[CH:16][CH:17]=[CH:18]2)=[CH:9][CH:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(NCc3ccccc3)ccc21
Yield: 43.4 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (400 mg, 1.19 mmol), benzyl amine (510 mg, 4.7 mmol) and NMP (2 ml) gave title compound (218 mg, 42%) after purification by column chromatography using DCM/MeOH (95:5) as the eluent.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[S:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>CC(C)=O>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:13][C:1](=[O:3])[CH3:2])=[S:12])=[CH:9][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(N)=S)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COc1ccc(C(=S)NC(C)=O)cc1
Yield: 72.2 %

Procedure:
A solution of acetyl chloride (4.69 g, 59.8 mmol) in acetone (20 mL) was added dropwise to a solution of 4-methoxythiobenzamide (5.00 g, 29.9 mmol) and pyridine (4.76 g, 60.1 mmol) in acetone (30 mL). The reaction mixture was heated to reflux for 30 min then poured onto ice water. The resulting precipitate was isolated via filtration and dried under vacuum overnight to provide a light yellow/orange solid (4.52 g, 72%). 1H NMR (400 MHz, CDCl3) δ2.56 (s, 3H), 3.87 (s, 3H), 6.89 (dd, J=6.9, 2.0 Hz, 2H), (dd, J=6.9, 2.0 Hz, 2H).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=3)[C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:45][CH2:46]OS(C)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:52]=[N+:53]=[N-:54].[Na+].CN(C=O)C>O>[N:52]([CH2:46][CH2:45][C:15]1[N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]2[C:17]([C:16]=1[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=3)[C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)=[N+:53]=[N-:54]
Reactant: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCOS(C)(=O)=O)n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCN=[N+]=[N-])n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Temperature: 60 °C
Yield: 99 %

Procedure:
Methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together under N2 and heated to 60° C. After 1 hour the reaction was cooled and water was added. Extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Removed solvent to obtain methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (light-yellow solid) in 99% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.S(Cl)([Cl:14])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Reaction time: 1 h
Yield: 82 %

Procedure:
N,N′-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux. After 1 hour, the solution was cooled and the solvent was evaporated. The mixture was co-evaporated with toluene to give a dark solid. Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.S(Cl)([Cl:29])=O>CN(C=O)C>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([Cl:29])=[O:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(c2ccc(-c3nc4ccc(C(=O)O)cc4s3)cn2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3nc4ccc(C(=O)Cl)cc4s3)cn2)CC1
Temperature: 70 °C

Procedure:
2-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazole-6-carboxylic acid hydrochloride acid (46 mg, 0.12 mmol) was added to thionyl chloride (3 mL), followed by 3 drops DMF, before heating at 70° C. o.n. The solvent was thereafter evaporated in vacuo and once with toluene to give crude 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazole-6-carbonyl chloride. Ammonium hydroxide (cone., 3 mL) was added dropwise to this crude product and the mixture was thereafter stirred for 1 h at r.t. The r.m. was extracted twice with DCM, dried (Na2SO4), and evaporated in vacuo. The obtained residue was purified by prep. HPLC to give the title compound (7 mg) as a light yellow solid. 1H NNR δ 8.81 (d, 1 H) 8.58 (s, 1 H) 8.16 (dd, 1 H) 8.07 (br. s., 1 H) 7.99 (s, 2 H) 7.45 (br. s., 1 H) 7.00 (d, 1 H) 3.61-3.71 (m, 4 H) 2.37-2.46 (m, 4 H) 2.23 (s, 3 H) 1.89 (s, 3 H); MS m/z (M+H) 354.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:19][C:20]1[C:21](Cl)=[N:22][CH:23]=[C:24]([CH:35]=1)[C:25]([N:27]([CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH3:28])=[O:26]>>[Cl:19][C:20]1[C:21]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[N:22][CH:23]=[C:24]([CH:35]=1)[C:25]([N:27]([CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH3:28])=[O:26]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CN(C)CCCN(C)C(=O)c1cnc(Cl)c(Cl)c1
Product: CN(C)CCCN(C)C(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol and 5,6-dichloro-N-[3-(dimethylamino)propyl]-N-methylnicotinamide, and in the same manner as in Example 65 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (58 mg) was obtained as a yellow amorphous solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3]C1.C(=O)(O)[O-].[Na+].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](Cl)[C:24]2[N:29]=[C:28]([O:30][CH3:31])[C:27]([Cl:32])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].O>C(#N)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:24]2[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([O:30][CH3:31])[N:29]=2)[NH:7][CH:1]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1nc(C(Cl)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(C(NC2CCCC2)c2ccc(C(C)(C)C)cc2)ccc1Cl

Procedure:
Cyclohexylamine (0.30 mL) and sodium bicarbonate (259 mg) were sequentially added to a solution of 6-[(4-tert-butylphenyl)(chloro)methyl]-3-chloro-2-methoxypyridine (200 mg) in acetonitrile (4 mL) at room temperature, and then the mixture was heated under reflux for six hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:50→1:10) to give N-[(4-tert-butylphenyl)(5-chloro-6-methoxypyridin-2-yl)methyl]cyclopentanamine as a pale yellow amorphous (201 mg, 87%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([OH:29])=[O:28].CO.Cl>C[O-].[Na+].O>[OH:30][C@@H:26]([CH2:25][CH2:24][NH:23][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:27]([OH:29])=[O:28]
Reactant: NCC[C@H](O)C(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCC[C@H](O)C(=O)O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 91.2 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and (S)-(−)-4-amino-2-hydroxybutyric acid (122 mg, 1.02 mmol) in 0.5 N NaOMe in MeOH solution (1.4 mL, 0.7 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (100 mL), acidified by 1 N HCl aqueous solution to pH=3-4 and extracted with EtOAc. Organic layer was washed with brine, dried over Mg2SO4, filtered and concentrated to provide the title compound (120 mg, 0.31 mmol) in 92.4% yield. LC-MS ESI−: 381.05 (M−1)−.