Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25](=[O:28])[NH:26][N:27]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:33])([F:34])[F:32])[C:25](=[O:28])[N:26]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[Cl:15])[N:4]=3)[N:27]=2)=[CH:19][CH:18]=1
Reactant: Clc1ccccc1-c1nccc(CBr)n1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccnc(-c3ccccc3Cl)n2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 60 °C
Reaction time: 96 h

Procedure:
259 mg (0.18 mmol) of the compound from Example 81A (purity about 20%) were dissolved in 2 ml of acetonitrile, and 62 mg (0.21 mmol) of the compound from Example 5A and 89 mg (0.27 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 2.5 h and at RT for a further 96 h. The solid was then filtered off and rinsed with a little acetonitrile. The filtrate was concentrated under reduced pressure and directly purified chromatographically [Method 19]. This gave 31 mg of the target compound, which were subjected to a further chromatographic purification on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3, then 1:1). This gave 23 mg (22% of theory) of the target compound.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13](=[O:28])[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH2:25]Br)=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([O:12][C:13](=[O:28])[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:4]=[C:1]([CH3:2])[O:3][CH:25]=2)=[CH:22][CH:23]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)=O
Reactant: O=C(NCCOc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Product: Cc1nc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)co1
Temperature: 130 °C
Yield: 57.6 %

Procedure:
Acetamide (2.95 g, 50.0 mmol) and benzyl-[2-(4-bromoacetylphenoxy)-ethyl]-carbamate (1.20 g, 3.06 mmol) were combined in a round-bottomed flask and heated to about 130° C. for about ninety minutes. The reaction mixture was then allowed to cool to room temperature, and the resulting orange solid was partitioned between ethyl acetate and water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude solid was purified by column chromatography (silica gel; methylene chloride to 10% ethyl acetate/methylene chloride) to afford 621 mg (58% yield) of the product as a white solid. LRMS ([M+H]+)=353.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:24][CH2:23][S:22][CH2:21]1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[K+].CO>O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:24][CH2:23][S:22][CH2:21]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCSC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1(O)CCSC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A slurry of N-(t-butoxycarbonyl)-α-(3-hydroxy-2,3,4,5-tetrahydro-3-thiofuranyl)glycine, benzyl ester (2.65 g, 7.22 mmole) in 20 ml of water was treated with potassium bicarbonate (1.0 g, 7.8 mmole) followed by 15 ml of methanol. Stirring at 25° C. for 14 hours gave a homogeneous solution which was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified with 10% potassium bisulfate, saturated with sodium chloride, and extracted with ethyl acetate. Drying (sodium sulfate) and evaporation of the organic layer, and trituration of the residue with isopropyl ether gave the product as a white solid, 1.25 g, melting point 116°-118° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[NH:4][CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCCl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1(C)CNC(c2ccc(C(F)(F)F)cc2)c2ccccc21
Solvent: ClCCCl
Product: CC1(C)CN(C(=O)Nc2ccc(F)cc2)C(c2ccc(C(F)(F)F)cc2)c2ccccc21
Temperature: 80 °C

Procedure:
A 25-mL round-bottomed flask was charged with 4,4-dimethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (118 mg, 0.39 mmol), 4-fluorophenyl isocyanate (43.4 μL, 0.39 mmol) and DCE (5 mL). The reaction mixture was heated at 80° C. for 2 h and the solvent was then removed under vacuum. Purification by silica gel chromatography (20-30% EtOAc in hexanes) provided the title compound as a white solid. MS (ESI, positive ion) m/z: 443 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([NH:7][NH2:8])=[O:6].C(Cl)Cl.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=S)=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]2[O:6][C:5]([C:4]3[CH:3]=[C:2]([NH2:1])[C:11]([NH2:12])=[CH:10][CH:9]=3)=[N:7][N:8]=2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: NNC(=O)c1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nnc(Nc3ccc(C(F)(F)F)cc3)o2)cc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 30 mL vial was added 0.5 g (3.01 mmol) of 3,4-diaminobenzhydrazide, 25 mL of DCM, and 0.61 g (3.01 mmol) of 4-trifluoromethyl-phenyl isothiocyanate. Allowed to stir at r.t. for 72 h. The pink suspension was concentrated in vacuo and used directly in the next reaction. MS (m/z) 370.0 M (+1), tR=1.10, Meth 10. To 20 mL scint vial was added 1.03 g (2.61 mmol) of the crude, 10 mL of DMF, and 0.55 g (2.87 mmol) of EDCI. Allowed to stir at 60° C., for 3 h. Added water, and filtered off solid. Used directly in next reaction. MS (m/z) 336.0 M (+1), tR=1.24, Meth 10
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][NH:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:10])[N:12]([CH3:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CNN
Solvent: CCO
Product: CN(N)C(=S)Nc1ccc(F)cc1
Yield: 76.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 10.0 g (0.0653 mole) of 4-fluorophenyl isothiocyanate with 3.01 g (0.0654 mole) of methylhydrazine in 100 ml of ethanol yielded 10 g of 4-(4-fluorophenyl)-2-methyl-3-thiosemicarbazide as a solid, mp 148°-150° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)[CH:6]=[N:7][CH:8]=1.[C:21]1([O:27]C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:21][O:27][N:9]1[C:5]2[C:6](=[N:7][CH:8]=[CH:3][CH:4]=2)[C:16](=[O:17])[CH:11]=[CH:10]1
Reactant: COc1cncc(NC=C2C(=O)OC(C)(C)OC2=O)c1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COn1ccc(=O)c2ncccc21
Temperature: 245 °C

Procedure:
A two-necked RBF equipped with an air condenser was charged with 5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (18 g) and diphenyl ether (180 mL). The reaction mixture was heated at 240-250° C. for 5 min under N2 atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtain product as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:12][C:7]3[NH:8][C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
In dimethylformamide (30 ml) was dissolved 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) followed by addition of 1N-sodium hydroxide (7.5 ml). Then, under ice-cooling, a solution of 4-(4-chlorobenzoyl)benzyl bromide (2.48 g) in DMF (10 ml) was added dropwise. The mixture was then stirred at room temperature for 4 hours, at the end of which time it was poured in ice-water (250 ml). The resulting precipitate was collected by filtration, rinsed with water, and dried. The dried precipitate was purified by flash column chromatography (3-5% ethanol-containing chloroform) to provide the title compound (1.57 g). IH-NMR (DMSO-d6) 6: 2.23(3H,s), 4.50(2H,s), 6.65(1H,s), 7.60(2H,d,J=8.6Hz), 7.64(2H,d,J=8.6Hz), 7.69(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 11.42(1H,s), 11.95(1H,s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O-:13])(=O)=[O:11])=[CH2:3].[K+].S(Cl)([Cl:17])=O>CN(C)C=O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([Cl:17])(=[O:13])=[O:11])=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=C(C)c1ccccc1S(=O)(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)c1ccccc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A mixture of potassium 2-(1-methylethenyl)benzenesulfonate (7.8 g, 0.33 mmol) and 30 ml of thionyl chloride was contacted with 1.5 ml of N,N-dimethylformamide at 0°. The mixture was allowed to warm to room temperature over 45 minutes then evaporated in vacuo. Water and ether were added and the aqueous phase extracted with several portions of ether. The combined ether layers were washed with saturated sodium chloride solution, dried and evaporated under reduced pressure to yield the title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][C:31]1([CH3:38])[NH:36][CH2:35][CH2:34][NH:33][C:32]1=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:35][CH2:34][NH:33][C:32](=[O:37])[C:31]4([CH3:38])[CH3:30])[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC1(C)NCCNC1=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(=O)C3(C)C)n(C)c2n1
Reaction time: 16 h
Yield: 10.5 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (250 mg, 0.64 mmol), 3,3-dimethylpiperazin-2-one (100 mg, 0.78 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (15 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (204 mg, 0.96 mmol) was added and the mixture stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 95:5) to afford 649 as a yellow solid (34 mg, 11%). LCMS (method I): RT=3.12 min, M+H+=504. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H), 7.79 (m, 1 H), 7.30 (m, 2 H), 5.75 (bs, 1 H), 4.34 (m, 4 H), 3.94 (s, 2 H), 3.92 (s, 3 H), 3.87 (m, 4 H), 3.38 (q, J=7.4 Hz, 2 H), 3.23 (m, 2 H), 2.80 (m, 2 H), 1.54 (s, 6 H) and, 1.47 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[C:29]([NH:32][C:33]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34]1)(=[O:31])[CH3:30]>>[C:29]([NH:32][C:33]1([CH3:38])[CH2:37][CH2:36][N:35]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]=2[F:16])[CH2:34]1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Reactant: CC(=O)NC1(C)CCNC1
Product: CCOC(=O)Nc1c(F)c(N2CCC(C)(NC(C)=O)C2)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1

Procedure:
In the same manner as described in Example 2 (1), ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,7,8-trifluoro1,4-dihydro-4-oxoquinoline-3-carboxylate was allowed to react with 3-acetylamino-3-methylpyrrolidine to give ethyl 7-(3-acetylamino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl5-ethoxycarbonylamino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([NH:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([O:37]C)=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[CH3:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.O>[C:3]([O:7][C:8]([NH:10][CH:11]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([OH:37])=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=2)=[CH:17][CH:18]=1)[CH3:12])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiOH (69.0 mg, 2.86 mmol) was added to a solution of methyl 2-(2-(2-(2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A65) (320 mg, 0.573 mmol) in THF (7.5 mL) and water (2.5 mL) and the resulting mixture stirred at room temperature overnight. The resulting mixture was evaporated in vacuo then the residue was partitioned between EtOAc (15 mL) and 1 M aqueous HCl. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried with Na2SO4 and concentrated to give the title compound A66 (310 mg, 99%); LCMS-B: rt 8.30 min; m/z 545.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[O:23][CH:24]=[CH:25][C:26]=3[CH3:27])=[O:21])[CH:14]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])=[CH:45][CH:44]=1)(=[NH:42])=[O:41]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:42]=[S:40]([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:48]=2)([CH3:39])=[O:41])=[O:7])=[CH:9][C:10]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[O:23][CH:24]=[CH:25][C:26]=2[CH3:27])=[O:21])[CH:14]=1
Reactant: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cc(C(=O)O)cnc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4occc4C)c3)c2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
6-Amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid (0.1 g, 0.277 mmol) was dissolved in DMF (2.8 mL). EDCI (0.64 g, 0.332 mmol) and DMAP (3.42 mg, 0.028 mmol) were then added and the reaction mixture was stirred at 60° C. for 20 minutes. Methyl 3-(4-(S-methylsulfonimidoyl)-phenyl)propanoate (0.068 g, 0.277 mmol) was then added, and the reaction was allowed to stir for 3 hours at 60° C. The mixture was cooled to room temperature then taken up in EtOAc (10 mL) and extracted with brine (3×10 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 10% MeOH) to give the title compound (0.060 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][N:9]=[C:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([C:22](=[O:24])[CH3:23])[N:9]=[C:10]([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CC(C)=NNC(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(N=C(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 82 %

Procedure:
10.5 g of 1-p-chlorobenzoyl-2-isopropylidene hydrazine, 5.3 g of triethylamine and 100 ml of tetrahydrofuran were placed in a 200 ml round-bottom flask, and while stirring with ice-water cooling, 3.9 of acetylchloride was dropped gradually. After dropping, the mixture was heated at reflux for one hour so as to complete the reaction. The reaction mixture was cooled to room temperature and the separated salts were filtered off, and then the filtrate was concentrated to obtain yellow brown crystals, which were then recrystallized from a mixed solvent of hexane/acetone to yield 10.4 g (82%) of yellow crystalline 1-p-chlorobenzoyl-1-acetyl-2-isopropylidene hydrazine having a melting point of 73°-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Mg].[B:19](OC)([O:22]C)[O:20]C>BrCCBr.C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[C:3]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)c(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(B(O)O)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A 2 L three-necked flask equipped with thermometer, reflux condenser and mechanical stirrer was charged with 1-bromo-4-methoxy-2-(phenylmethoxy)benzene (43.0 g, 0.147 mol), anhydrous THF (600 mL) under nitrogen. Magnesium turnings (4.2 g, 0.17 mol) and 1,2-dibromoethane (0.5 mL, 6 mmol) was then added and the mixture heated to reflux. After 1.5 h, the reaction was cooled to -78° C. and B(OMe)3 (33.4 mL, 0.294 mol) added dropwise while maintaining an internal temperature below -60° C. Upon complete addition, the reaction was quenched with 5% HCl (15 mL) to pH=3.0, portioned with EtOAc (100 mL), the organic phase separated, washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo giving a pale yellow solid. The solid was triturated with hexane (90 mL), filtered and dried to afford [4-methoxy-2(phenylmethoxy)phenyl] boronic acid as a pale white solid (32 g, 85%): mp 127.0-129.0° C.; 1H NMR δ 7.8 (d, J=8.2 Hz, 1 H), 7.5-7.3 (m, 5 H), 6.6 (dd, J=8.2, 2.7 Hz, 1 H), 6.55 (d, J=2.7 Hz, 1 H), 5.65 (s, 2 H), 5.15 (s, 2 H), 3.85 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH:14]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1cccc(N)n1
Temperature: 25 °C

Procedure:
In a manner similar to that described in Preparation CD, 2-formyl-piperidine-1-carboxylic acid tert-butyl ester (360 mg, 1.69 mmol) was treated with 2,6-diaminopyridine (184 mg, 1.69 mmol) and stirred at RT to give a light brown oil. MS m/z: 307.3(M+H). Calc'd. for C16H26N4O2-306.21.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH2:9])=[CH:4][C:3]=2[O:2]1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19]>CCCCCC>[CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][NH:9][C:31]([NH:30][C:22]3[C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=[CH:24][C:23]=3[CH:27]([CH3:29])[CH3:28])=[O:32])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCC(CN)Cc1ccc2c(c1)OCO2
Solvent: CCCCCC
Product: CCCCC(CNC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 60 %

Procedure:
To 1.01 g (4.33 mmol) of 2-(3,4-methylenedioxybenzyl)hexylamine, was added 9.2 ml of a hexane solution (0.47 mmol/l) of 2,6-diisopropylphenyl isocyanate and stirred for 3 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (developed with hexane/ethyl acetate=2/1) to obtain 1.13 g of 1-(2-(3,4-methylenedioxybenzyl)hexyl)-3-(2,6-diisopropylphenyl)urea as amorphous solid (yield: 60%).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[N:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[N:20]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH:10]=[C:9]([OH:8])[CH:21]=1
Reactant: c1ccc(COc2cnc3c(c2)[nH]c2ccccc23)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1cnc2c(c1)[nH]c1ccccc12
Yield: 99.4 %

Procedure:
3-(benzyloxy)-5H-pyrido[3,2-b]indole (0.09 g, 0.328 mmol) and Palladium 10% on carbon (0.035 g, 0.033 mmol) in MeOH (Volume: 5 ml) was stirred under hydrogen for 2 hours. Filtered and concentrated to afford 5H-pyrido[3,2-b]indol-3-ol (0.06 g, 0.326 mmol, 99% yield).
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]([C@H:23]2[N:27]3[C:28](=[O:38])[C:29]([NH:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)=[N:30][C:31]([Cl:32])=[C:26]3[CH2:25][CH2:24]2)=[O:22])=[CH:15][CH:14]=1)=[NH:12])C1C=CC=CC=1.Cl.[H][H]>CO.O1CCOCC1.[Pd]>[ClH:32].[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:21]([C@H:23]2[N:27]3[C:28](=[O:38])[C:29]([NH:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)=[N:30][C:31]([Cl:32])=[C:26]3[CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:18]=1)(=[NH:10])[NH2:12]
Reactant: [H][H]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CNC(=O)[C@@H]2CCc3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N=C(N)c1ccc(CNC(=O)[C@@H]2CCc3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Yield: 165.4 %

Procedure:
To a solution of the compound obtained from Step H (50 mg) in methanol (2.0 mL) was added HCl in dioxane (4.0 M, 0.13 mL) and 10% Pd/C (20 mg). This mixture was hydrogenated with a hydrogen ballon for 1.0 h. Removal of Pd/C and solvent gave the desired product as a white solid (34 mg, 82%). 1HNMR (300 MHz, DMSO-d6) δ 9.34 (br, 2H), 9.05 (m, 3H), 7.78 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 5.02 (m 1H), 4.43–4.31 (m, 3H), 3.5 (s, br), 2.90 (m, 2H), 2.21–2.05 (m, 6H), 1.65 (m, 2H). MS m/e 415(M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11]N)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1.P(Cl)(Cl)Cl>C1C=CC=CC=1>[F:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][C:19]2[C:8]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[NH:11][C:20]=2[CH3:21])=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)c1cccc(NN)c1
Reactant: CC(=O)COc1ccc(F)cc1
Solvent: c1ccccc1
Solvent: ClP(Cl)Cl
Product: Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
To the solution of (3-methanesulfonyl-phenyl)-hydrazine (1.35 g) and 1-(4-fluoro-phenoxy)-propan-2-one (1.01 g) in benzene at RT was added equimolar amount of PCl3. The reaction mixture was stirred at RT for 1 hour and the solvent was removed in vacuo. The residue was purified by Biotage chromatography, eluted with 10–30% EtOAc/Hexane to yield 0.1 g of 3-(4-fluoro-phenoxy)-6-methanesulfonyl-2-methyl-1H-indole 401 as a light orange powder, MS: 320 ([M+H]+).