Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([O:27][C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)([CH3:26])[CH3:25]>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28]([O:27][CH:24]([CH3:25])[CH3:26])=[O:35])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2nc(-c3ccccc3)n(Cc3ccccc3)c2c1
Reactant: CC(C)OC(=O)CCCCCBr
Product: CC(C)OC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(Cc3ccccc3)c2c1

Procedure:
1-Benzyl-6-hydroxy-2-phenylbenzimidazole is alkylated according to general operating instructions 2 with 6-bromo-hexanoic acid isopropyl ester. 1-Benzyl-2-phenyl-6-[(5-(iso-propyl-oxycarbonyl)pentyl]oxy]-benzimidazole is obtained as a resin.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[C:13]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:14]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Yield: 79 %

Procedure:
To 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride described in Preparation Example 52 were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(3,5,6-trimethylpyridin-2-yl)piperazine (470 mg). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (407 mg) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (470 mg), the title compound (620 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[CH2:4][CH2:3]1>C(Cl)Cl.C(OCC)(=O)C>[O:1]=[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[CH2:4][CH2:3]1
Reactant: OC1CCc2nc3ccccc3n21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCc2nc3ccccc3n21
Reaction time: 10 h

Procedure:
A solution of 2,3-dihydro-1-hydroxy-1H-pyrrolo-[1,2-a]benzimidazole (1.0 g, 5.75 mmol)) in methylene chloride was treated with mangenese dioxide (5 g, 58 mmol) at r.t. and stirred for 10 hour. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth (Celite (trademark)). The filtrate was concentrated and purified to give the title compound. 1HNMR (CDCl3)δ 3.28 (t, 2H), 4.48 (t, 2H), 7.3-7.45 (m, 2H), 7.45-7.55 (m, 1H), 7.86-7.94 (m, 1H) ppm.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.CC([O-])(C)C.[K+].[CH2:18]([OH:22])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCO
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOc1nc(N)c2nc[nH]c2n1
Temperature: 170 °C
Yield: 70 %

Procedure:
2-chloroadenine (1) (1.53 g, 9.03 mmol) was divided among three microwave vials (10-20 mL), each containing 1-butanol (10 mL) and t-BuOK (5 mL, 1M in THF). Each vial was heated to 170° C. for 40 minutes. After reaction completion the solvent was removed by rotary evaporation and the product was purified on flash column eluting 10% methanol in ethylacetate. Evaporation of solvent gave 1.33 g (70%) of 59 as an off white solid. 1H NMR (300 MHz, DMSO) δ 0.919 (t, 3H), 1.39 (m, 2H), 1.62 (m, 2H), 4.09 (t, 2H), 6.00 (s, 2H), 7.44 (s, 1H). LCMS: m/z for C9H13N5O++H observed 208.1 at 1.34 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([OH:18])[C:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.Cl[C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:19])[C:10]=2[O:18][C:21]2[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Reactant: Cc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc(Oc2c(C3CCC3)ccc(-c3cnc(N)cn3)c2F)n1
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A suspension of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (25 mg, 0.096 mmol), 2-chloro-4-methylpyrimidine (14 mg, 0.11 mmol), and K2CO3 (27 mg, 0.19 mmol) in DMSO (2 mL) was heated at 100° Celsius for 16 hours. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give 5-{4-cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine (15 mg, 45%). MS (ESI): mass calcd. for C19H18FN5O, 351.15; m/z found, 352.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.37-8.33 (m, 1H), 8.26 (d, J=1.9, 2H), 7.81-7.75 (m, 1H), 7.26 (d, J=8.3, 1H), 7.00-6.97 (m, 1H), 3.75-3.63 (m, 1H), 2.52 (d, J=2.0, 3H), 2.27-2.09 (m, 4H), 2.04-1.92 (m, 1H), 1.87-1.76 (m, 1H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])(=O)=O)=CC=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CN(C=O)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])=[CH:31][CH:30]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNCc3ccc(Cl)cc3)O2)c(=O)[nH]c1=O

Procedure:
A solution of 396 mg of 5'-O-(p-toluenesulphonyl)-thymidine and 1.5 ml of 4-chlorobenzylamine in 2 ml of DMF was stirred at 80° C. for 2 hours. The solvent was removed by evaporation and the residue was triturated with diethyl ether. The resulting solid was recrystallized from ethanol to yield 56 mg of 5'-(4-chlorobenzylamino)-5'-deoxythymidine, mp 179°-180° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4].[C:26](#[N:29])[CH:27]=[CH2:28].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:7]2[O:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:28][CH2:27][C:26]#[N:29])=[CH:16][CH:17]=3)=[O:11])[C:8]=2[CH:19]=1)([O-:25])=[O:24]
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCC#N)cc1
Temperature: 82.5 °C

Procedure:
27.8 g of (2-butyl-5-nitro-1-benzofur-3-yl)-(4-hydroxyphenyl)methanon (VIII), 43.5 g of acrylonitrile and 3.8 g of Triton B (benzyltrimethylammonium hydroxide) are added and heated under stirring to 80-85° C. and stirred at this temperature for 48 hours. After cooling the reaction mixture to room temperature it is evaporated and the acrylonitrile is recovered for the next trial. To the residue 150 ml of dichloromethane is added and washed with 3×80 ml of sodium hydroxide of 5%. From the sodium hydroxide solution 16.2 g of starting (2-butyl-5-nitro-1-benzofur-3-yl)-(4-hydroxyphenyl)methanon is recovered.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([C:9]2[CH:10]=[C:11]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:31]=[CH:30][S:29][CH:28]=4)[CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([C:9]2[CH:10]=[C:11]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:31]=[CH:30][S:29][CH:28]=4)[CH:24]=[CH:23][C:19]=3[C:20]([O-:22])=[O:21])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na+:2]
Reactant: O=C(Nc1cc(-c2ccsc2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2ccsc2)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1
Reaction time: 0.17 h

Procedure:
A 1 mol/L aqueous solution of sodium hydroxide (0.10 mL) was added to an ethanol (4.0 mL) suspension of the obtained 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-3-yl)benzoic acid (47 mg) at room temperature, followed by stirring at the same temperature for 1 hour and 10 minutes. The solvent was evaporated under reduced pressure, and ethanol and water were added to the obtained residue. The solid substance was collected by filtration to obtain 40 mg of sodium 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-3-yl)benzoate as a white solid.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([C:9]([NH2:11])=[O:10])[C:6]([NH2:8])=[NH:7].Cl.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=O>C(O)C>[NH2:7][C:6]1[NH:8][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:14][C:5]=1[C:9]([NH2:11])=[O:10]
Reactant: N=C(N)CC(N)=O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(Br)cc2)[nH]c1N
Reaction time: 0.33 h
Yield: 8.8 %

Procedure:
Under ice-cooling, sodium ethoxide (2.1 g, 30 mmol) was added to a suspension of malonamamidine hydrochloride (4.1 g, 30 mmol) in dehydrated ethanol (50 mL), and then the mixture was stirred for 20 minutes. Moreover, 2,4′-dibromoacetophenone (4.2 g, 15 mmol) was added thereto, and the whole was stirred at room temperature for 5 hours. After the insoluble solid was filtered out, the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography to give the title reference compound (0.37 g) as a black solid (Yield 9%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[S:12][CH:13]=1)(=O)=O.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][CH2:6][N:26]3[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][CH2:8][C:9]4[N:10]=[C:11]([C:14]5[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=5)[S:12][CH:13]=4)[CH2:28][CH2:27]3)[N:10]=2)[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2nc(CCCOS(C)(=O)=O)cs2)cc(OC)c1OC
Product: COc1cc(-c2nc(CCCN3CCN(CCCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(3-Methanesulfonyloxypropyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (310 mg) and piperazine (34 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:13]([O:15]C)=[O:14])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: COC(=O)c1ccc(N2CCCC2)c(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(N2CCCC2)c(NC(=O)C(CS)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Metyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)amino]-4-(1-pyrrolidinyl)benzoate (compound of Example 14) (0.8 g) is dissolved in methanol (5 ml), and thereto is added 1N aqueous sodium hydroxide solution (5.5 ml) under nitrogen, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is acidified with hydrochloric acid and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (0.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=O.CC([O-])=O.[Na+].Cl.[OH:26][NH2:27]>CO>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=[N:27][OH:26]
Reactant: COc1c(C=O)ccc2c1ncn2C1CCCCO1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1c(C=NO)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A 1 L three-necked round bottom flask equipped with a magnetic stirrer was dried and cooled under a stream of nitrogen then charged with 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (15 g, 0.057 mol, 1.0 equiv.), NaOAc (15.67 g, 0.12 mol, 2.0 equiv.), hydroxyamine hydrochloride (8.01 g, 0.12 mol, 2.0 equiv.) and MeOH (300 mL) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was then concentrated and the residue was dissolved in EtOAc (1000 mL). The organic layer was washed with water (2×300 mL) and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde oxime (14.5 g, 93% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36].C1COCC1>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:36][CH3:35])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)ccc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)ccc3C)c(=O)n(C)c2n1
Yield: 44 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (56 mg, 0.117 mmol) and 2.0N methylamine in THF (0.71 mL, 1.421 mmol) were combined to afford 1-(3-tert-butylisoxazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (29 mg, 44% yield). 1H NMR (300 MHz, DMSO-d6), δ 1.46 (s, 9H), 2.04 (s, 3H), 2.89 (s, 3H), 3.52-3.60 (m, 3H), 5.74 (s, 1H), 7.08-7.10 (m, 1H), 7.22-7.25 (m, 1H), 7.33-7.36 (m, 2H), 7.65 (s, 1H), 7.78 (s, 1H), 7.68-7.82 (m, 1H), 8.25 (s, 1H), 8.53 (s, 1H), 8.60-8.65 (m, 1H); MS (ESI) m/z: 462.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:14][N:15]=1)=[CH:7]2.[NH2:31][CH2:32][C@@H:33]([OH:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[OH:35][C@@H:33]([CH3:34])[CH2:32][NH:31][C:17](=[O:19])[CH2:16][CH:13]1[S:12][C:11]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:3][C:2]=3[CH3:1])=[N:15][CH2:14]1
Reactant: C[C@H](O)CN
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@H](C)O)S3)[nH]c12
Reaction time: 15 h
Yield: 68 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) and (S)-(+)-1-amino-2-propanol (78 mg) in N,N-dimethylformamide (20 mL)were added 1-hydroxybenzotriazole (137 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (230 mg, yield 68%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].C([Li])CCC.[C:15](=[O:17])=[O:16].O>C1COCC1.CCCCCC>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:7]=1[CH3:8])[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: Cc1c(Br)cncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1c(Br)cncc1C(=O)O
Reaction time: 0.25 h

Procedure:
Under argon, a solution of 3,5-dibromo-4-methylpyridine (intermediate 10.1, 2.51 g, 10 mmol) in anhydrous THF (100 ml) is reacted at a temperature of −100° C. with a solution of n-butyllithium in hexane (1.6N, 6.5 ml). The reaction mixture is stirred for 15 min and then dry ice is added. The temperature is kept for 15 min at −85° C., for 1 h 30 min at −78° C. and for 2 h at room temperature. Water is added. The solvents are evaporated under vacuum and the residue is purified, eluting on diol grafted silica with MeOH.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[NH4+]>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][N:12]2[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 47 %

Procedure:
NaH (4.5 mmol, 1.5 equiv.) was suspended in DMF (5 ml), and 6-nitro-indole (3 mmol, 1 equiv.), dissolved in DMF (5 ml), was added at 0° C. The mixture was stirred for 30 min. Then tert-butyl bromoacetate (3.6 mmol, 1.2 equiv.) was added and the mixture was stirred for 15 h at 25° C. The reaction mixture was hydrolysed with ammonium chloride and extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 20 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 47%
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[C:17](/[CH:19]=[C:20]4/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/4)[CH:16]=[CH:15][N:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:29][C:30]([NH2:32])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:25]=[C:23]1[N:22]([CH2:29][C:30]([NH2:32])=[O:31])[C:21](=[O:26])/[C:20](=[CH:19]/[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:27])=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)[N:18]=2)/[S:24]1
Reactant: Cc1ccc(N2CCN(c3nccc(/C=C4\SC(=O)NC4=O)n3)CC2)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(c3nccc(/C=C4\SC(=O)N(CC(N)=O)C4=O)n3)CC2)cc1
Temperature: 55 °C
Yield: 34.8 %

Procedure:
To 10 mg of (Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was added 4 mg of 2-bromoacetamide, 4 mg of potassium carbonate, and 0.5 mL of DMF. The reaction mixture was heated to 55° C. for 4 h, concentrated under reduced pressure, and purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient using trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide (Z)-2-(2,4-dioxo-5-((2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidin-3-yl)acetamide (4 mg, 11.5 mg theoretical, 35%). LC-MS m/z: 439 (M+1).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][NH:14][C:15]1[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=1.[Cl-].[Cl-].[Ca+2]>>[CH3:13][N:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:21][C:6]1=[O:7]
Reactant: CNc1cccnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Ca+2]
Agent: [Cl-]
Product: Cn1c(=O)[nH]c2ncccc21
Yield: 79.7 %

Procedure:
CDI (2.251 g) was added to a solution of N3-methylpyridine-2,3-diamine (1.14 g) in THF(dry) (50 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) over weekend. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.1 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:6]=2[O:7][CH:8]=1.[C-:18]#[N:19].[Na+]>O1CCCC1.O>[CH3:2][C:3]1[C:4](=[O:17])[C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:6]=2[O:7][C:8]=1[C:18]#[N:19]
Reactant: O=c1c(CCl)coc2c1COc1ccccc1-2
Reactant: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C#N)oc2c(c1=O)COc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A solution of 3-chloromethyl-4H,5H-[1]benzopyrano[4,3-b]pyran-4-one (2.65 g, 10.65 mmoles, described in Example 5) in tetrahydrofuran (130 ml) is combined with a solution of sodium cyanide (5.3 g) in water (27 ml). The mixture is stirred overnight at room temperature and poured into water. The solution is extracted with chloroform. The chloroform extract is dried and evaporated. The residue is chromatographed on silica gel using ethyl acetate-benzene (1:19), the eluates are evaporated, and the residue is crystallized from chloroform-diethyl ether to give the title compound (0.767 g), mp 179°-181° C.; nmr (CDCl3) δ 2.25(s, 3H), 5.2(s, 2H), and 6.8-7.7(m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>>[CH2:22]([NH:29][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(NCc3ccccc3)ncc21
Temperature: 140 °C
Yield: 53.7 %

Procedure:
To 2-Chloro-9-cyclopentyl-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (50 mg, 0.162 mmol) in nbutanol (2 ml), was added benzylamine (71 μl, 0.648 mmol) and diisopropylethylamine (113 μl, 0.648 mmol). The reaction mixture was heated to 140° C. in a microwave for 90 minutes. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound (33 mg) as an off-white powder. NMR DMSO D6 1.10 (6H, s), 1.46-1.58 (4H, m), 1.60-1.74 (4H, m), 3.13 (3H, s), 3.42 (2H, s), 4.52 (2H, d), 4.95-5.04 (1H, m), 7.24-7.30 (1H, m), 7.31-7.39 (4H, m), 7.83 (1H, s), 8.64 (1H, br s); HPLC rt(min): 10.36; MS (ES+) 380, (ES−) 378.