Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]([CH3:17])([C:14](O)=O)[C:11](O)=O>O>[CH3:9][C:10]([C:14]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)([C:17]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:11]
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: Nc1ccccc1S
Solvent: O
Product: CC(C)(c1nc2ccccc2s1)c1nc2ccccc2s1
Reaction time: 3 h

Procedure:
To a flask were added 50 g polyphosphoric acid. After heating to 70 C under nitrogen, a mixture of 3.13 g 2-aminothiophenol and 1.65 g dimethylmalonic acid was added. The reaction mixture was heated to 150 C for 2 hours, then 165 C for 3 hours. After cooling to 80 C, the mixture was poured into 100 ml water. The slurry was cooled to 5 C, filtered and the solid was washed with water. The solid was added to a mixture of 20 ml ethanol and 210 ml water at 50 C and basified with aqueous ammonium hydroxide. After cooling to 10 C, the solid was filtered and washed with water. The solid was dissolved in 50 ml hot ethanol, hot filtered and 5 ml water was added and the solution was cooled to 5 C. Following filtration, the white solid was washed with 75% ethanol and dried.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C:12](=O)[CH:11]2[O:15][CH:10]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C.[Cl-].[NH4+]>CO>[Si:1]([O:8][CH:9]1[CH2:10][C:11](=[O:15])[C:12]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C2OC21
Reactant: OCCCCS
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCO)C(=O)C1
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
2.80 g (12.2 mmoles) of 4(R)-t-butyldimethylsilyloxy-2,3-epoxycyclopentanone and 1.30 g (12.2 mmoles) of 4-mercaptobutan-1-ol were dissolved in 12 ml of methanol, and with stirring 1.87 ml (13.5 mmoles) of triethylamine was added. The stirring was continued for 30 minutes. Ten milliliters of a saturated aqueous solution of ammonium chloride was added, and the mixture was concentrated. The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting oily product was chromatographed on a silica gel column using hexane/ethyl acetate (8/1) as an eluent to give 3.12 g (81%) of 4(RS)-t-butyldimethylsilyloxy-2-(4-hydroxybutylthio)-2-cyclopentenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=1
Reactant: COc1nc(S(C)(=O)=O)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1nc(S(C)(=O)=O)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2-methoxy-6-(methylsulfonyl)-3-nitropyridine (Preparation 83, 290 mg, 1.249 mmol) in EtOAc/EtOH (1:1, 10 mL) was added palladium on charcoal (10%, 100 mg). The flask was charged with hydrogen and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo to give the title compound (245 mg, 97%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:29][NH:30][CH2:31][CH3:32]>>[CH2:31]([N:30]([CH3:29])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:32]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C20H23FN6O2, 398.2
Reaction SMILES: CO[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6].C[O-].[Na+].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>>[NH2:6][C:5]1[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COC=C(C#N)c1ccccc1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1scc(-c2ccccc2)c1N
Temperature: 65 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
3-Methoxy-2-phenylacrylonitrile (17.9 g, 112.5 mmol) was dissolved in NaOMe (5 M in MeOH, 31.5 ml, 157.5 mmol), and then methyl thioglycolate (16 ml, 180.0 mmol) was added thereto. The mixture was heated with stirring at 65° C. for 24 hr. After the completion of the reaction was confirmed by thin layer chromatography (TLC), the reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was washed with distilled water and extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was distilled under reduced pressure, and the concentrate was purified by silica gel column chromatography (EtOAc:Hex=1:5) to give 5.1 g (21.9 mmol, 26% yield in three steps) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:24]([O:26]C(C1C=CN(C2C=CC(OC)=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:18]=[CH:19][C:20]([O:26][CH3:24])=[CH:21][CH:22]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccccc1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)c1C
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1

Procedure:
Prepared similarly according to a reaction sequence in Example 3 steps (a), (b), and (c) for the synthesis of 2,3-dibromo-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 1-(4-Methoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 469 (M+H)+.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][CH2:4][N:5]1[C:14](=[O:15])[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[C:6]1=[O:7].[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>C(O)CCC>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:16][CH:2]([OH:1])[CH2:3][CH2:4][N:5]3[C:14](=[O:15])[CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[C:6]3=[O:7])[CH2:26][CH2:25]2)=[O:23])=[CH:30][CH:31]=1
Reactant: O=C1C2CCCCC2C(=O)N1CCC1CO1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCCCO
Product: O=C(c1ccc(F)cc1)C1CCN(CC(O)CCN2C(=O)C3CCCCC3C2=O)CC1
Yield: 39.8 %

Procedure:
A mixture of N-(3,4-epoxybutyl)cyclohexane-1,2-dicarboximide (3 g), 4-(4-fluorobenzoyl)piperidine (3.23 g) and n-butanol (62 ml) was refluxed for 6 hours, followed by evaporation of n-butanol under reduced pressure. The residue was purified by silica gel column chromatography to give the objective compound (2.3 g). Yield, 38.2%. M.P., 121°-122° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[C:19]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])[CH:18]=[C:17]([CH2:33]Br)[N:16]=1)=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([CH2:33][N:1]2[CH2:9][CH2:8][N:7]([CH2:33][C:17]3[CH:18]=[C:19]([C:21]4[C:22]([O:31][CH3:32])=[CH:23][C:24]([O:29][CH3:30])=[CH:25][C:26]=4[O:27][CH3:28])[CH:20]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[N:16]=3)[CH2:6][CH2:5][N:4]([CH2:33][C:17]3[N:16]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH:20]=[C:19]([C:21]4[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=4[O:31][CH3:32])[CH:18]=3)[CH2:3][CH2:2]2)[CH:18]=[C:19]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1)=[O:14])[CH3:11]
Reactant: C1CNCCNCCN1
Reactant: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CBr)n1
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CN2CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CC2)n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
1,4,7-triazacyclononane (31.5 mg) and compound 14 (0.3 g, 0.76 mmol) were dissolved in dry acetonitrile (20 mL) Potassium carbonate (0.17 g) was added and the mixture was refluxed overnight. The mixture was allowed to cool to room temperature, filtered and concentrated. Purification on silica gel (eluent CH2Cl2:EtOH: HOAc; 80:20:1, v/v/v) yielded the title compound (0.17 g, 62%). ESI-MS: [M+H]+ 1117.5 calc. for C60H73N6O15+ 1117.5
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2c3ccccc3CNc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of 5,11-dihydro-10H-dibenz [b,e][1,4]diazepine 1.9 g of 4-[(2-methylbenzoyl) amino]benzoyl chloride, 4 ml of triethylamine and 0.2 g of 4-(dimethylamino)pyridine in 60 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is poured into ice water and the separated organic layer washed with 50 ml each of water, 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and the solvent removed to give a residue. The residue is chromatographed on a silica gel column using 1:4 ethyl acetatehexane to give 1.8 g of the desired product as a solid, m.p. 68°-71° C.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[S:19]([NH2:22])(=[O:21])=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)ccc1NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1S(N)(=O)=O
Yield: 94.2 %

Procedure:
A solution of 2-benzylamino-5-trifluoromethylbenzenesulfonamide (7.3 g) in methanol (80 mL) was supplemented with 10% Pd/C (0.73 g) and submitted to hydrogen under pressure (4 bars) during 90 min. at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized in methanol-water to give the title compound (yield: 5 g); m.p. 142-143° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:11][NH:10][CH2:9][C:4]32[O:8][CH2:7][CH2:6][O:5]3)[CH2:2]1.Br[CH2:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][C:3]2([CH2:1][CH2:2]2)[C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:9]1
Reactant: OCCCBr
Reactant: C1COC2(CNCC23CC3)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CC2(CC2)C2(C1)OCCO2

Procedure:
The compound (B) (100 mg) was mixed with 3-Bromopropanol (120 mg) and K2CO3 (120 mg) in Acetonitrile. The reaction was refluxed overnight and filtered; the filtrate was evaporated and purified on silica gel column to give the titled product. Mass: (M+1), 214
Reaction SMILES: OC1C=C2C(=CC=1)N(C)C=C2C[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21].C[O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[CH2:42][CH2:43]N(C)C(C)CCCCCC(NC1C=CC(OC)=CC=1)=O>>[OH:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[CH2:42][CH2:43][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21]
Reactant: COc1ccc(NC(=O)CCCCCC(C)N(C)CCc2c[nH]c3ccc(OC)cc23)cc1
Reactant: COc1ccc(NC(=O)CCCCCNCCc2cn(C)c3ccc(O)cc23)cc1
Product: COc1ccc(NC(=O)CCCCCNCCCc2c[nH]c3ccc(O)cc23)cc1

Procedure:
6-[[2-(5-hydroxy-1-methyl-indol-3-yl)ethyl]amino]-N-(4-methoxyphenyl)-hexanamide, 7-[[2-(5-methoxy-1H-indol-3-yl)ethyl]methylamino]-N-(4-methoxyphenyl)-octanamide,
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([NH2:13])=[N:12][C:7]2=[CH:6][CH:5]=1.[N:15]1([C:20](N2C=CN=C2)=[S:21])[CH:19]=[CH:18][N:17]=[CH:16]1>C(#N)C>[F:14][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([NH:13][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:21])=[N:12][C:7]2=[CH:6][CH:5]=1
Reactant: Nc1nc2ccc(OC(F)F)nc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: FC(F)Oc1ccc2nc(NC(=S)n3ccnc3)sc2n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (310 mg, 1.43 mmol) and di(1H-imidazol-1-yl)methanethione (311 mg, 1.75 mmol) were dissolved in acetonitrile (5 mL) and heated to 70° C. in a sealed vial for 10 hours. The vial was then stored in the freezer for 16 hours. The solids were collected by filtration and washed with acetonitrile to afford N-(5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-1H-imidazole-1-carbothioamide (296 mg, 0.72 mmol, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (d, J=4.77 Hz, 1 H), 8.06 (d, J=8.53 Hz, 1 H), 8.01 (s, 1H), 7.72 (s, 1 H), 7.54 (s, 1 H), 6.94-7.13 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]3)=[CH:4][C:3]=2[CH3:21])=[N:24][CH:25]=1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1N
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1Nc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
tert-butyl (RS)-2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (60 mg), 2,5-dibromopyridine (48.6 mg, CAS 624-28-2) and cesium carbonate (100 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.12 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.37 mg) were then added. The reaction mixture was then capped and stirred at 80° C. for 1 hour. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-(5-bromopyridin-2-ylamino)-3-methylphenyl)morpholine-4-carboxylate (40 mg, 44%) as a colourless amorphous solid. MS (ISP): 450.2 ([{81Br}M+H]+), 448.1 ([{79Br}M+H]+), 394.3 ([{81Br}M+H—C4H8]+), 392.1 ([{79Br}M+H—C4H8]+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][C@H:26]([CH2:31][OH:32])[C:27]([O:29][CH3:30])=[O:28]>>[OH:32][CH2:31][C@@H:26]([N:25]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 70 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (10 g, 0.05 mol), methanol (200 mL, 5 mol), triethylamine (18 mL, 0.13 mol) and (R)-methyl 2-amino-3-hydroxypropanoate hydrochloride (9.8 g, 0.063 mol) where by the reaction became homogeneous. The reaction was then heated at 70° C. overnight. The solvent was removed and the residue purified by flash chromatography (120 g silica gel, 0-10% MeOH/DCM) to obtain the product as a yellow solid. MS m/z=293.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 110 °C

Procedure:
To a solution of 6-bromo-2-chloroquinoline of Step A (1.25 g, 5.15 mmol) in N,N-dimethylformamide (35 mL) is added piperazine (4.43 g, 51.4 mmol) and the mixture is heated at 110° C. under nitrogen for 3 hours. After cooling, it is diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[O:25][CH3:26])[CH:6]=1)C=C.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:7]2[CH:6]=[C:5]([NH2:4])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[O:28][CH3:27])[CH:13]=3)[N:8]=2)=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: COc1ccccc1CN
Reactant: C=CCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(Cl)cc12
Product: COc1ccccc1CNc1ccc2nc(NCc3ccc(F)cc3OC)cc(N)c2c1

Procedure:
The title compound, MS: m/e=433.2 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine and 2-methoxybenzylamine
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[N:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Reactant: COC(OC)N(C)C
Product: Cc1ccnc(-c2sc(N=CN(C)C)nc2C)c1

Procedure:
A solution of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)thiazole (300 mg) in N,N-dimethylformamide dimethyl acetal (1.5 ml) was stirred at ambient temperature for 14 hours and evaporated under reduced pressure. The residue was triturated with 2-propanol (1 ml) and diisopropyl ether, and the solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N,N-dimethyl-N′-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-formamidine (268 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([O:24]CC)=[O:23])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37]CC)=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl>C(O)C>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([OH:24])=[O:23])[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]=1[C:35]([OH:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-n2c(C(=O)O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)O)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A mixture of diethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (1) (2.8 g, 5.29 mmol), 2M NaOH (aq.) (26.4 mL, 52.9 mmol), in ethanol (12 mL) and THF (20 mL) was stirred at 60° C. for 72 h. After cooling to RT, the mixture was acidified with 6M HCl (aq.) and the resulting precipitate was collected by filtration, washed with water (5 mL), and Et2O (5 mL) to afford 4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylic acid (2) (1.94 g, 67%) as an off-white solid: m/z 474 (M+H)+ (ES+); 472 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 2H), 7.46-7.40 (m, 4H), 7.39-7.29 (m, 6H), 7.16-7.07 (m, 2H), 6.92-6.84 (m, 2H), 5.07 (s, 4H), 3.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(OC(=O)C)C.C(O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cccc(F)c1C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(N)cccc1F
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Dissolve 2-Amino-6-fluoro-benzoic acid (3.00 g, 19.3 mmol) in ethylacetate (59 mL) and ethanol (59 mL) and add (trimethylsilyl) diazomethane (19.3 mL, 38.68 mmol, 2M in hexane) at room temperature and stir the solution for 1 h 30 min. Remove the solvent under reduced pressure to afford the title compound (3.26 g, quantitative). MS (ES+): 170 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=2)[N:10]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:9]=1)(C)(C)C.O.C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][NH:50][CH:51]=2)O1>CC#N.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>[C:28]([N:10]1[C:11]([C:13]2[S:14][C:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:26]=[C:25]([C:47]5[CH:48]=[N:49][NH:50][CH:51]=5)[CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=2)=[N:12][C:8]([NH2:7])=[N:9]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)(C)C)n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-tert-butyl-1H-[1,2,4]triazol-3-yl]-carbamic acid tert-butyl ester (0.94 g, 1.8 mmol) was dissolved in MeCN (20 mL) and H2O (20 mL) and added potassium acetate (601 mg, 6.12 mmol). The reaction flask was degassed by bubbling N2 for 5 min. Charged with 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (456 mg, 2.53 mmol) and then tetrakis(triphenylphosphine)palladium(0) (280 mg, 0.24 mmol). The reaction was subjected to microwave irradiation at 140° C. for 20 min. The reaction was cooled to r.t., filtered through a plug of Celite and diluted with water. Extracted three times with EtOAc and the combined organic portions were dried over MgSO4, filtered and concentrated. The crude residue was taken up in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). Stirred at room temperature for 1 h and concentrated in vacuo. The resultant residue was taken up in a minimal amount of DMF/DMSO (1:1) and purified by rp-HPLC to provide 58 mg (10% yield) of 122. LC/MS(ESI+): m/z 408 (M+H). 1H NMR (400 MHz, DMSO) δ 12.96 (bs, 1H), 8.31 (m, 2H), 7.99 (bs, 1H), 7.50-7.39 (m, 2H), 7.34 (d, J=1.5, 2H), 5.47 (s, 2H), 4.47-4.24 (m, 4H), 3.39 (dd, J=15.8, 10.7, 4H), 1.78 (s, J=18.7, 9H).