Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:25]4[N:21]([CH3:20])[C:22](=[O:27])[NH:23][C:24]4=[O:26])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(=O)NC1=O
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1C(=O)NC(=O)C1=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Temperature: 70 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (20 mg, 0.074 mmol) in 0.5 mL EtOH was added 1-methylimidazolidine-2,4-dione (8.4 mg, 0.074 mmol) and piperidine (7.5 μL, 0.074 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-1-methylimidazolidine-2,4-dione. LCMS (M+1=369)
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.Cl.C(Cl)Cl>C(#N)C>[CH:10]12[N:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[CH:13]([CH2:12][CH2:11]1)[CH2:14][NH:8][CH2:9]2
Reactant: N#Cc1ccc(NCCCN2C3CCC2CN(Cc2ccccc2)C3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(NCCCN2C3CCC2CNC3)cc1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a cold solution of 4-{[3-(3-benzyl-3,8-diazabicyclo[3.2.1]oct-8-yl)propyl]amino}benzonitrile (6.26 g, 17.4 mmol; from step (c) above) in acetonitrile (100 mL) was added 12 M HCl (5.8 mL). The reaction mixture was stirred for 15 minutes, concentrated in vacuo and dried under high vacuum overnight. The resulting hydrochloride salt was added to a suspension of 10% Pd/C (800 mg) in methanol (250 mL). The reaction was then stirred under hydrogen (1 atmosphere of pressure) for 50 min. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The resulting residue was partitioned with saturated NaHCO3 (100 mL) and CH2Cl2 (200 mL). The organic layer was dried (Na2SO4), filtered and concentrated ill vacuo to give the crude product. Flash chromatography on silica gel eluting with a gradient of CH2Cl2:CMA (4:1 to 2:1) gave 2.02 g (43%) of the title compound.
Reaction SMILES: [Na].C([NH:4][C:5]([NH:10]C)=[N:6][CH2:7][CH2:8][SH:9])#N.Cl.[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19]Cl>C(O)C>[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:9][CH2:8][CH2:7][NH:6][C:5]([NH2:10])=[NH:4]
Reactant: CNC(=NCCS)NC#N
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=N)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (1.43 g) was added, with stirring under nitrogen, to dry ethanol (100 ml). After the sodium had dissolved a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (4.90 g) in dry ethanol (50 ml) was added and the mixture was stirred at room temperature for one hour. 5-Methyl-4-chloromethylimidazole hydrochloride (5.18 g) was added in batches over a period of one hour at room temperature. The mixture was then stirred at room temperature, for a further hour and heated at reflux temperature for 1/2 hour. After cooling the mixture was filtered and the filtrate was evaporated to a glassy solid (8.8 g). This crude product was chromatographed on silica gel with acetonitrile as eluant and the solid product obtained (3.60 g) was recrystallised from acetonitrile to give N-cyano-N'-methyl-"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p.=140°-142° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([O:22][CH:23]([CH3:25])[CH3:24])=[C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]4=[C:15]([O:30][CH:31]([F:33])[F:32])[C:14]=3[C:13]2=[O:34])=[CH:8][CH:7]=1)C.C(O)(=O)C.Cl>O>[F:33][CH:31]([F:32])[O:30][C:15]1[C:14]2[C:13](=[O:34])[N:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:35])=[O:3])=[CH:7][CH:8]=3)[C:20](=[O:21])[C:19]=2[C:18]([O:22][CH:23]([CH3:25])[CH3:24])=[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=12
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OC(F)F)c4ccccc4c3OC(C)C)C2=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1c2c(c(OC(F)F)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2=O
Temperature: 25 °C
Yield: 9 %

Procedure:
Ethyl(4-{4-[(difluoromethyl)oxy]-9-[(1-methylethyl)oxy]-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.14 g, 0.289 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (8 ml) for 1 hour. The reaction was cooled to room temperature. On addition of water, the resulting white solid was collected by filtration and washed with water. This was dried in the vacuum oven to give the title compound (0.120 g, 0.026 mmol). LC/MS: Rt=3.36, [MH]+ 456.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:8]([C:7]1[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1-n1cccn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (942 mg, 5.94 mmol), pyrazole (967 mg, 14.2 mmol) and powdered potassium carbonate (2 g) in DMF (10 mL) was stirred vigorously at room temperature for 4 days. The mixture was diluted with water, causing precipitation of a solid, which was filtered and dried, affording 670 mg (63%) of 3-nitro-2-(pyrazol-1-yl)pyridine. 1 H NMR (CDCl3) δ 6.51 (m, 1), 7.37 (dd, 1 J=5, 8), 7.76 (m, 1) 8.03 (dd, 1, J=2, 8), 8.40 (m, 1), 8.60 (dd, 1, J=2, 5).
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Cl:8].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[Cl:8][C:4]1[N:3]([O:2][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: On1ccnc1Cl
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Product: CN(C(=O)On1ccnc1Cl)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (77%, oil).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:44]>CCO>[NH2:44][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)[C@@H](CS(=O)(=O)c3ccccc3)C2)cn1
Temperature: 110 °C
Reaction time: 5 h
Yield: 22.9 %

Procedure:
A 2-mL vial was charged with 2-(4-((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.026 g, 0.039 mmol) and ammonium hydroxide (30 wt %, 0.50 mL, 3.9 mmol) and EtOH (0.5 mL). The vial was sealed and the reaction mixture was stirred at 110° C. for 5 h. The reaction mixture was concentrated and purified by column chromatography (10 g of silica, 0-5% (2 M NH3 in MeOH) in DCM) to afford 2-(4-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.0057 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:17](OCC)[CH2:18][Cl:19])C.Cl>C(O)C>[Cl:19][CH2:18][CH:17]1[C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:12][O:13]1
Reactant: COc1ccc(CCO)cc1OC
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(CCl)OCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
A mixture of 3,4-dimethoxybenzeneethanol and 62.8 g of chloroacetaldehyde diethylacetal in 1 l of absolute ethanol saturated with anhydrous hydrochloric acid, was stirred at ambient temperature for 24 h. The solvent was evaporated and 88.4 g (88.8%) of 1-chloromethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran was obtained by distillation.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Sn](CCCC)(CCCC)[CH:20]1[CH2:25][CH2:24][CH:23]=[CH:22][O:21]1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([C:24]2[CH2:23][CH2:22][O:21][CH2:20][CH:25]=2)[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CCC=CO1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Clc1nc(C2=CCOCC2)nc(N2CCOCC2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
In a three necked flask under nitrogen equipped was dissolved 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (610 mg, 2.6 mmol), tributyldihydropyranylstannane (1.45 g, 3.89 mmol, 1.5 eq), and (Ph3P)2PdCl2 (150 mg, 0.21 mmol, 0.1 eq) in anhydrous dioxan (5 ml). The reaction mixture was heated under stirring to 90° C. for 16 hrs. For purification silica gel (10 g) was added to the mixture and the solvent was removed to let the product adsorbed on the silica gel. The silica gel plug was placed on a column and the mixture was flash chromatographed with hexane:ethyl acetate (10:1) to give after removal solvent the product as off white solid (345 mg=47% yield); MS (ESI) m/z 281.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:18])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:33])[N:21]=1.CN1CCCC1=O>Cl.[OH-].[Na+]>[NH2:33][C:22]1[N:21]=[C:20]([NH:18][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[C:15]3[NH2:17])[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:23]=1
Reactant: Nc1ccc2nc(-c3ccccc3)cc(N)c2c1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Nc1nc(Nc2ccc3nc(-c4ccccc4)cc(N)c3c2)cc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 92 %

Procedure:
2-Phenyl-quinoline-4,6-diamine, 0.5 grams (2.12 mmole) and 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine, 0.83 grams (4.25 mmole) were weighed directly into a reaction flask and 10 mL of dry N-methyl-2-pyrolidinone and 2 drops of concentrated hydrochloric acid was then added to the flask. The mixture was heated at 100° C. overnight under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with aqueous sodium hydroxide whereupon a dark brown solid precipitated. The solid was collected and dried under vacuum to yield 0.365 grams of N6-[2-amino-6-(4-fluorophenyl)pyrimidin-4-yl]-2-phenylquinoline-4,6-diamine (92% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.C(OC([NH:24][C@@H:25]([CH2:29][O:30][CH3:31])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:26]([C@@H:25]([NH2:24])[CH2:29][O:30][CH3:31])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1[CH3:16]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC[C@H](N)c1nc2ccc(F)c(C)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A mixture of 4-fluoro-3-methyl-N2-phenylbenzene-1,2-diamine (560 mg, 2.59 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (624 mg, 2.85 mmol), HOAt (388 mg, 2.85 mmol), 4-methylmorpholine (626 μL, 5.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (547 mg, 2.85 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in 4N HCl in dioxane (5 mL) and the mixture heated at 70° C. for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound (545 mg, 70%). LCMS (Method C): RT 3.95 min [M+H]+ 300.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[I:19]I.O>C1COCC1>[I:19][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2
Reactant: II
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(I)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 1.00 g (4.22 mmol, Aldrich) of 6-bromo-2-methoxynaphthalene in 10 ml of dry THF at -78° was added dropwise 4.5 ml (1.4M in pentane, 6.3 mmol, Aldrich) of t-butyllithium solution over 10 minutes. The reaction mixture was stirred at -78° for 30 minutes then at 0° for 15 minutes. The resulting yellow solution was re-cooled to -78° then 1.20 g (4.72 mmol, Aldrich) of iodine was added in one portion. The reaction mixture was warmed to room temperature, stirred for 1 hour then added to 50 ml of H2O and extracted with 50 ml of ethyl acetate. The organic extract was washed with an additional 50 ml of H2O, dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was recrystallized (EtOAc/petroleum ether) to afford 805 mg (67%) of title compound as pale yellow flakes, m.p. 142°-143°.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]=2[C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]1=2.[NH2:30][CH2:31][CH2:32][N:33]([CH3:42])[CH2:34][CH2:35][CH2:36][N:37]([CH2:39][CH2:40][NH2:41])[CH3:38]>>[CH3:38][N:37]([CH2:36][CH2:35][CH2:34][N:33]([CH3:42])[CH2:32][CH2:31][NH:30][C:13]1[C:14]2[C:2](=[O:1])[C:3]3[CH:4]=[CH:5][N:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1)[CH2:39][CH2:40][NH:41][C:13]1[C:14]2[C:2](=[O:1])[C:3]3[CH:4]=[CH:5][N:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1
Reactant: CN(CCN)CCCN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3ccccc3c3c2C(=O)c2ccncc2-3)cc1
Product: CN(CCCN(C)CCNc1nc2ccccc2c2c1C(=O)c1ccncc1-2)CCNc1nc2ccccc2c2c1C(=O)c1ccncc1-2

Procedure:
In a similar manner to Example 4, this compound was obtained starting from toluene-4-sulfonic acid 7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (the compound of Reference Example 6c-1) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[N:20][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: Fc1ccc2cnn(C3CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc(N3CCC(n4ncc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
6-Fluoro-1-(piperidin-4-yl)-1H-indazole (260 mg, 1.19 mmol), 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (230 mg, 1.19 mmol) and DIEA (269 uL) in DMSO (4 ml) under Ar were heated in a microwave reactor at 200° C. for 1 hour. After removal of most of the DMSO in vacuo, water (10 mL) was added and the aqueous layer extracted several times with CHCl3 (50 mL). The organic layer was washed with brine, dried (MgSO4), decolorized with NORITE, filtered and the solvent removed in vacuo. The resulting residue was purified via ISCO column chromatography (Amine “Redisep” 14 gram column eluded 0-100% EtOAc/hexane over 20 column volumes), then re-crystallized from DCM with heptanes to yield 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-1H-indazole.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](=[O:17])[CH3:16])=[CH:14][C:9]=2[N:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH:3]([CH3:5])[CH3:4].[Br:26]Br.C(OCC)C>C(O)(=O)C>[ClH:1].[Br:26][CH2:16][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:8][C:9]=2[CH:14]=1)=[O:17]
Reactant: COc1cccc(-c2nc3cc(C(C)=O)ccc3n2CC(C)C)c1
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cccc(-c2nc3cc(C(=O)CBr)ccc3n2CC(C)C)c1
Yield: 63.2 %

Procedure:
To a solution of 32.7 g (91.3 mM) of 1-[1-isobutyl-2-(3-methoxy phenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride in 330 ml of acetic acid are added dropwise 4.7 ml (91.4 mM) of bromine. 100 ml of diethyl ether are then added and the crystalline product is filtered off. It is washed with diethyl ether and dried under vacuum to give 35 g of 2-bromo-1-[1-isobutyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride.
Reaction SMILES: C(C1N=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH:18][C:19]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)=[O:20])[S:17][C:8]=3[C:7]=2N=1)(C)(C)C.Cl.[F:27][C:28]([F:36])([F:35])[C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[NH:31]>>[F:27][C:28]([F:36])([F:35])[C:29]([C:30]1[N:32]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH:18][C:19]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)=[O:20])[S:17][C:8]=3[C:7]=2[N:31]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(C(=N)N)C(F)(F)F
Reactant: CC(C)(C)c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2
Agent: Cl
Product: CC(C)(c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2)C(F)(F)F

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate A but in Stage A.3 3,3,3-trifluoro-2,2-dimethyl-propionamidine hydrochloride (Stage 44.2) was used instead of tert-butylamidine hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=[CH:3]1.[H-].[Na+].FS([C:18](C(O)=O)([F:20])[F:19])(=O)=O.O>CC#N>[F:19][CH:18]([F:20])[O:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1cccc(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc(OC(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 6-oxo-1,6-dihydropyridine-2-carboxylate (3.074 g; 20.07 mmol) in anh. MeCN (310 ml) was treated portionwise with NaH (60% dispersion in mineral oil; 2.167 g; 54.19 mmol), and stirring at rt, under nitrogen, was continued for 30 min. FSO2CF2CO2H (6.077 g; 34.12 mmol) was then added dropwise, and the resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 30 min. Water (25 ml) was slowly added, and MeCN was removed under reduced pressure. Water (150 ml) and AcOEt (150 ml) were added, and the separated aq. layer was further extracted with AcOEt (2×100 ml). The mixed organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded methyl 6-(difluoromethoxy)picolinate as a yellow solid. LC-MS (conditions D): tR=0.89 min.; no ionisation.
Reaction SMILES: [OH:1][N:2]1[C:11]2[C:6](=[C:7]3[S:14][C:13](=[O:15])[NH:12][C:8]3=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([OH:19])=[O:18])=[CH:3]1.[OH-].[K+].O.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([O:1][N:2]1[C:11]2[C:6](=[C:7]3[S:14][C:13](=[O:15])[N:12]([CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:8]3=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([OH:19])=[O:18])=[CH:3]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cn(O)c2ccc3[nH]c(=O)sc3c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(OCc2ccccc2)c2ccc3c(sc(=O)n3Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To a mixture of 1.0 g of 2,3,6,9-tetrahydro-6-hydroxy-2,9-dioxothiazolo[5,4-f]quinoline-8-carboxylic acid, 0.96 g of an 85% -- potassium hydroxide aqueous solution, 20 ml of water and 7 ml of methanol was added dropwise 2.77 g of benzyl bromide and the mixture was stirred for 44 hours at room temperature.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[C:10]([CH3:20])=[N:9]1.[OH-].[Na+].O.Cl>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]([CH3:20])=[N:9]1
Reactant: COC(=O)CCc1c(C)nn(-c2ccccc2O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nn(-c2ccccc2O)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 26.4 %

Procedure:
29.9 mg of methyl 3-(1-(2-hydroxyphenyl)-3,5-dimethyl-1Hpyrazol-4-yl)propanoate was dissolved in 0.6 ml of methanol, and to the mixture was added 0.29 ml of 1N-sodium hydroxide and stirred at room temperature for 3.5 hours. To the reaction mixture was added 20 ml of water, neutralized with 1N-hydrochloric acid, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 7.5 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]2[CH:37]2[CH2:39][CH2:38]2)=[CH:29][C:28]=1[F:44]>>[CH:37]1([N:34]2[C:35]3[C:30](=[CH:29][C:28]([F:44])=[C:27]([N:11]4[CH2:12][CH2:13][N:8]([C:7]5[CH:6]=[CH:5][C:4]([N:14]6[CH2:18][C@H:17]([CH2:19][NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[O:16][C:15]6=[O:25])=[CH:3][C:2]=5[F:1])[CH2:9][CH2:10]4)[N:36]=3)[C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33]2)[CH2:38][CH2:39]1
Reactant: CS(=O)(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: CS(=O)(=O)NC[C@H]1CN(c2ccc(N3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
This compound was synthesized in analogy to the procedure described in Example 10 using 0.082 g N-[(5R)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-methansulfonamide (0.22 mmol) and 0.067 g 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (0.22 mmol).