Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:35][CH2:36][C:37](Br)=[O:38]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:35][CH2:36][C:37]([O:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)=[O:9])=[C:19]2[OH:20])=[O:38]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CBr)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110 (0.23 g), Et3N (0.090 mL), and catalytic DMAP (5-10 mol %) in 20 mL DMF is cooled to 0° C. Bromoacetyl bromide (0.050 mL) is added in one portion. The reaction is stirred at 0° C. for 20 minutes, then at room temperature for 1.5 h. Once the reaction was complete, it is partitioned between CH2Cl2 and H2O. The aqueous layer is extracted 3× with CH2Cl2. The organics are combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a liquid which subsequently crystallizes to an off-white solid when it is dried on the vacuum pump overnight. The solid is triturated in CH2Cl2 /hexanes, filtered, and dried to give the desired product (0.27 g, 0.53 mmol, 91%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12]N(C)C)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[C-]#N.[Na+].[CH3:21][N:22](C=O)C>CCOC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][C:21]#[N:22])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: CN(C)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 60 %

Procedure:
6-Trifluoromethyl-N,N-dimethyl-1H-indole-3-methanamine (1.2 g, 4.95 mmol) and NaCN (0.72 g, 14.86 mmol, 3.0 eq.) were combined with DMF (10 mL) and EtOAc (2 mL). The mixture was heated to reflux for 6 hours, then cooled to rt. The product was extracted with EtOAc and the organic layer was washed with water and dried (MgSO4). The solvent was removed in vacuo to give 0.66 g (60%) of the title compound after column chromatography (Hex:EtOAc 1:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[C:4]([O:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.[C:20]([C:22]1[N:26]([CH3:27])[C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([C:22]1[N:26]([CH3:27])[C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[C:4]([O:15][C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: CCCNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 28.9 %

Procedure:
According to general procedure B, 4-bromo-N-propyl-2-(trifluoromethoxy)benzenesulfonamide (217 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propyl-2-(trifluoromethoxy)benzenesulfonamide (66 mg, 29%) was provided after purification. MS (ESI) m/z 387. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Mg].BrC(Br)C.BrC1C=CC(C[C:12]2([O:18][C:19]3([CH2:25][C:26]4[CH:31]=[CH:30][C:29](Br)=[CH:28]C=4)CCCCO3)[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=CC=1.[CH3:35][C:36]1([CH3:49])[CH2:40][O:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2OC)=[N:37]1.[Cl-].[NH4+]>O1CCCC1>[CH3:49][C:36]1([CH3:35])[CH2:40][O:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:30]2[CH:31]=[CH:26][C:25]([CH2:19][O:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:28][CH:29]=2)=[N:37]1
Reactant: Brc1ccc(CC2(OC3(Cc4ccc(Br)cc4)CCCCO3)CCCCO2)cc1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2-c2ccc(COC3CCCCO3)cc2)=N1
Yield: 53 %

Procedure:
Tetrahydrofuran (15 ml) was added to 1.2 g (49.4 mmol) of flaky magnesium, followed by the addition of a small amount of dibromoethane under stirring. After the confirmation of bubbling, a solution of 11.0 g (40.6 mmol) of 4-bromobenzyl-tetrahydropyranyl ether in tetrahydrofuran (15 ml) was dropwise added thereto. After the confirmation of the dissolution of the magnesium, the resulting mixture was further stirred at room temperature for one hour. Then, a solution of 7.0 g (34.1 mmol) of 4,4-dimethyl-2-(2'-methoxyphenyl)oxazoline in tetrahydrofuran (5 ml) was dropwise added thereto, followed by stirring for 12 hours. The reaction liquid was poured into a saturated aqueous solution of ammonium chloride, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 6.61 g of the title compound as an oil (yield 53%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.O[NH:42][C:43]([C:45]1[C:46]2[CH:47]=[CH:48][NH:49][C:50]=2[CH:51]=[CH:52][CH:53]=1)=[NH:44]>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:18][N:44]=[C:43]([C:45]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:46]=4[CH:47]=[CH:48][NH:49]5)[N:42]=3)[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: N=C(NO)c1cccc2[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: FC(F)(F)c1sc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
4-Phenyl-5-(trifluoromethyl)-2-thiophenecarboxylic acid (310 mg), HOBT (170 mg) and EDCI.HCl (242 mg) were dissolved in DMF (3 ml) and stirred at room temperature for 20 mins. D9 (200 mg) was dissolved in DMF (3 ml) and added to the above solution and stirring continued at room temperature for two hours. The reaction mixture was then heated to 90° C., cooled to RT, stood overnight, re-heated to 80° C. and stirred for 3 hours, cooled to room temperature and evaporated to dryness. The residue was re-dissolved in H2O and extracted with EtOAc (×3) and the combined organic extracts evaporated to dryness. The residue was purified by flash silica chromatography, eluting with a 25-75% mixture of diethyl ether in hexane to give the title compound (265 mg) as a brown solid. A sample of this compound (100 mg) was purified by MDAP to give the title compound (62 mg) as an off white solid. δH (CDCl3, 400 MHz): 7.33-7.36 (2H, m), 7.41-7.42 (1H, m), 7.46-7.52 (5H, m), 7.61 (1H, d), 7.94 (1H, s), 8.06 (1H, d), 8.46 (1H, br s). MS (ES): C21H12F3N3OS requires 411; found 412 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:31]=[CH:30][C:20]([CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1)#[N:2].[ClH:32]>>[ClH:32].[NH2:22][CH2:21][C:20]1[CH:30]=[CH:31][C:17]([C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[C:1]#[N:2])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2c(C#N)ccc3[nH]c(=O)c4sccc4c23)cc1
Agent: Cl
Product: N#Cc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CN)cc1
Yield: 74 %

Procedure:
Following General Procedure D-3, tert-butyl 4-(8-cyano-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (10 mg, 0.023 mmol) was reacted with 4 N HCl (3 mL) to afford the desired product (7.4 mg, 74%) as a dark brown solid: 1H NMR (500 MHz, CD3OD) δ 7.89 (d, J=8.6 Hz, 1H), 7.74 (t, J=9.5 Hz, 2H), 7.65 (dd, J=14.4, 7.0 Hz, 2H), 7.55-7.53 (m, 2H), 6.08 (d, J=5.4 Hz, 1H), 4.32 (s, 2H); ESI MS m/z 330 [C19H13N3OS−H]−; HPLC 98.3% (AUC), tR=9.36 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5])[CH3:2].S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([Cl:18])=[O:10])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)Oc1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Oc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
5.9 g (28 mmol) of 2-(ethoxycarbonyloxy)benzoic acid are dissolved in 30 ml of toluene with a few drops of pyridine. 2.15 ml (29 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. The residue is precipitated from pentane. The solid is filtered off and then dried. 5.2 g of 2-(ethoxycarbonyloxy)benzoyl chloride are obtained in the form of a white solid with a yield of 80%.
Reaction SMILES: [OH-].[Na+].CO.[Cl:5][C:6]1[N:11]=[CH:10][C:9]2[C@@:12]3([C:23]4([CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]4)[N:22]4[C@@H:17]([C:18](=[O:43])[O:19][C@@H](C5C=CC=CC=5)[C@H]4C4C=CC=CC=4)[C@@H:16]3[C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=3[F:51])[C:13](=[O:15])[NH:14][C:8]=2[CH:7]=1.[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(OCC)C>[Cl:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]3([C@@H:16]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=4[F:51])[C@H:17]([C:18]([OH:43])=[O:19])[NH:22][C:23]43[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]4)[C:13](=[O:15])[NH:14][C:8]=2[CH:7]=1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ncc21
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2cc(Cl)ncc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
1N sodium hydroxide solution (1.8 ml) was added to a methanol (10 ml) solution of the compound (1.00 g, 1.49 mmol) obtained in Step 1 of Example 108 and the resulting mixture was stirred at 70° C. for 5 hours. 65% Aqueous methanol (15 ml) solution of cerium (IV) diammonium nitrate (3.2 g, 5.96 mmol) was added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. Subsequently, the reaction mixture was rendered weakly acidic (pH 4 to 5) by addition of 1N sodium hydroxide solution and then concentrated under reduced pressure. After extraction with ethyl acetate, the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and filtered and then the solvent in the filtrate was evaporated under reduced pressure. The residue obtained was solidified by addition of diethyl ether to give 480 mg (65%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)[C:3]([F:6])([F:5])[F:4].[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.C(O)C>CN(C)P(N(C)C)(N(C)C)=O.C(O)C.O>[F:1][C:2]([F:23])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCCCCCCC(F)(F)C(F)(F)F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCC(F)(F)C(F)(F)F)cc1

Procedure:
A solution of 18.1 g. of 11-(pentafluoroethyl)-1-(methanesulfonyloxy)undecane and 19.8 g. of ethyl p-aminobenzoate in hexamethylphosphoramide is heated at 120° C. for 20 hours. After cooling, the reaction mixture is diluted with ethanol:water (1:1) (30 ml.) and chilled. More ethanol is added, the mixture is filtered and the solid residue is recrystallized from ethanol to yield the product as a white solid.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:40]=[O:41])[CH:33]=[CH:32][CH:31]=1>ClCCl>[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:40]([C:6]2[N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:4]=[N:3][CH:2]=2)[OH:41])[CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1cccc2cccnc12
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-iodo-1-tritylimidazole (commercially available) 5.2 g, 11.94 mmol) in dichloromethane (80 mL) at −10° C. was treated with ethyl magnesium bromide (3.98 mL, 11.94 mmol, 3M in ether) and allowed to react for 45 m. A solution of quinoline-8-carbaldehyde, (Intermediate 11) (1.5 g, 9.55 mmol) in dichloromethane was added via syringe at −10° C. and stirred for 16 h at room temperature. The mixture was quenched with water (50 mL) and a sat. solution of ammonium chloride (50 mL) and subjected to an aqueous work-up. The residue was purified by chromatography on silica gel with 3% NH3-MeOH: CH2Cl2 to give to give quinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 12) as a solid, (3.7 g 82.7%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH2:18][CH3:19])=[O:9])=[O:2]
Reactant: CCO
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C=O)ccc1O

Procedure:
5-Formylsalicylic acid (3.0 g, 17 mmol), conc. sulfuric acid (1 mL) and absolute ethanol (100 mL) were heated at reflux for 3.5 days with stirring under N2. The reaction was cooled, then carefully quenched by adding saturated sodium bicarbonate (40 mL). Solvent was removed in vacuo, and the resulting mixture was acidified with 1M HCl (50 mL), then extracted with EtOAc. The organic phase was extracted with water, then brine, and dried (MgSO4). Removal of solvent and chromatography on silica gel, eluting with 0% to 25% EtOAc in hexanes gave a colorless crystalline solid (2.3 g), mp 67°-69° C. after solvent removal. 1 H-NMR(300 MHz, CDCl3): 11.49 (s, 1H), 9.90 (s, 1H), 8.40 (d, 1H, J=2 Hz), 8.00 (dd, 1H, J=8,2 Hz), 7.11 (d, 1H, J=8 Hz), 4.48 (q, 2H, J=7 Hz), 1.46 (t, 3H, J=7 Hz). IR(KBr): cm-1 3186, 1684.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>CC#N>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[O:13][C:11]1[CH:10]=[CH:9][C:8]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][O:6][C:7]=2[CH:12]=1
Reactant: Clc1nc2ccccc2s1
Reactant: OCCc1coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-benzofuran-6-ol (0.42 g, 2.4 mmol) in MeCN (10 mL) was added Cs2CO3 (0.77 g, 2.4 mmol) and 2-chlorobenzthiazole (0.29 mL, 2.4 mmol) and the reaction mixture was stirred (rt, 15 h) and then heated (60° C., 2 h). The reaction mixture was cooled (rt) and partitioned with EtOAc and brine (50 mL each). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-100%) to provide the title compound as an amber oil (0.37 g, 50%). MS (ESI): mass calcd. for C17H13NO3S, 311.4; m/z found, 312.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.73 (d, J=8.0, 1H), 7.67 (d, J=8.0, 1H), 6.61 (d, J=8.5, 1H), 7.58 (br s, 1H), 7.53 (d, J=2.0, 1H), 7.41-7.37 (m, 1H), 7.29-7.26 (m, 2H), 3.97-3.93 (m, 2H), 3.96 (t, J=6.5, 2H), the hydroxyl proton was not detected.
Reaction SMILES: [CH3:1][NH:2][NH2:3].CN(C)C=O.[C:9]([N:11]=[C:12](SC)[NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)#[N:10]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:19]=2)=[N:11][C:9]([NH2:10])=[N:3]1
Reactant: CSC(=NC#N)NCCCOc1cccc(CN2CCCC2)c1
Reactant: CNN
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCC2)c1

Procedure:
Methyl hydrazine (6.9 g) and dry dimethylformamide (10.95 g) were heated at reflux in toluene for 1 hr. N'-Cyano-N-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]carbamimidothioic acid, methyl ester (10 g) was then adde and the mixture heated at reflux for 5 hr. Evaporation of the solvent gave the title compound as a yellow oil which was converted to the fumarate salt in ethanol. The title compound was regenerated as the free base with aqueous sodium carbonate, and extracted into ethyl acetate. Evaporation of the solvent and trituration of the residue with light petroleum (b.p. 60°-80°) gave the title compound as a white solid (3.4 g) m.p. 95°-95.5°. TLC silica; methanol:0.88 ammonia (80:1) single spot Rf 0.5.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Cl[C:20]1[CH:21]=[C:22]2[CH2:30][CH2:29][O:28][C:27](=[O:31])[C:23]2=[C:24]([CH3:26])[N:25]=1.[F-].[K+]>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.C1(C)C=CC=CC=1>[CH3:26][C:24]1[N:25]=[C:20]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH:21]=[C:22]2[CH2:30][CH2:29][O:28][C:27](=[O:31])[C:23]=12
Reactant: Cc1nc(Cl)cc2c1C(=O)OCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cccs2)cc2c1C(=O)OCC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
2-(tributylstannyl)thiophene (940 mg, 2.52 mmol) was dropwisely added to a toluene solution of 6-chloro-8-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.26 mmol) and Pd(PPh3)4 (146 mg, 0.13 mmol), and then stirred overnight at 100° C. The solution was cooled down to room temperature, added with 15 mL of 0.4M KF solution and then extracted with methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. A silica gel column chromatography (33% EtOAC/Hexanes) was performed on the resulting residue and obtained 298 mg (96%) of 8-methyl-6-(thiophene-2-yl)-3,4-dihydro-pyrano[3,4-c]pyridine-1-on in yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([O-])(O)=O.[Na+].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(O)C>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1NCCCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a mixture of 4-chloro-3-nitropyridine (8 g) and NaHCO3 (4.2 g) in ethanol (200 cm3) at room temperature was added over 3 minutes 4-aminobutanol (4.5 g). The mixture was stirred at room temperature for 11/4 hours and the solvent was then removed under vacuum. The residue was suspended in saturated aqueous NaHCO3 solution (50 ml) and extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated. The residue was then recrystallised from ethyl acetate to afford the title compound, (6.5 g, 62%), as yellow crystals, m.p. 80-82°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[CH:20]([NH2:22])[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[CH:20]([NH:22][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cncn23)CC1
Solvent: CCO
Product: CC(=O)N1CCN(c2c(C(C)Nc3ncnc4[nH]cnc34)cc(Cl)c3cncn23)CC1
Temperature: 110 °C
Yield: 43.5 %

Procedure:
A mixture of 1-[5-(4-acetylpiperazin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6-yl]ethanamine (11.2 mg, 0.035 mmol), 6-bromo-9H-purine (14 mg, 0.070 mmol) and IV, N-diisopropylethylamine (18 μL, 0.10 mmol) in ethanol (0.93 mL) was heated to 110° C. overnight. Purification by preparative LCMS (pH 10) gave the desired compound (6.7 mg, 44%). LCMS calculated for C20H23ClN9O (M+H)+: m/z=440.2. found: 439.9. 1H NMR (300 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.17 (m, 3H), 7.42 (s, 1H), 7.37 (s, 1H), 5.90 (s, 1H), 3.80 (m, 2H), 3.65 (m, 2H), 3.50 (m, 1H), 3.40 (m, 2H), 3.20 (m, 2H), 2.09 (s, 3H), 1.52, (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[N:8]/[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([N+:40]#[C-:41])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:40]=[CH:41][N:8]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:25][CH:24]=1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(/N=C/c2ccncn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 4-{[(1E)-pyrimidin-4-ylmethylene]amino}piperidine-1-carboxylate (C13) (57.66 g, 198.6 mmol), 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2) (38.30 g, 132.4 mmol) and potassium carbonate (36.59 g, 264.8 mmol) in DMF (575 mL) was stirred for 18 hours. The reaction was filtered, and the solids were washed with ethyl acetate and discarded. The combined filtrates were diluted with ethyl acetate (1 L) and washed with water (2×1 L), and the combined aqueous layers were extracted with ethyl acetate (500 mL). Concentration of the combined organic layers in vacuo provided a solid, which was heated at reflux with tert-butyl methyl ether (400 mL), then cooled to room temperature and granulated for 1 hour. The solid was collected by filtration and washed with additional tert-butyl methyl ether; this filtrate was concentrated under reduced pressure and treated in the same way, using 75 mL of tert-butyl methyl ether, to obtain a second crop. The combined solids provided the product as a white solid. Yield: 41.70 g, 98.47 mmol, 74%. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.81-1.92 (m, 2H), 2.16 (br d, J=12 Hz, 2H), 2.77-2.85 (m, 2H), 4.30 (br s, 2H), 4.90 (tt, J=12.0, 3.8 Hz, 1H), 7.04 (dd, J=8.7, 8.7 Hz, 2H), 7.17 (dd, J=5.3, 1.4 Hz, 1H), 7.41 (dd, J=8.9, 5.4 Hz, 2H), 7.79 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 9.29 (d, J=1.5 Hz, 1H).