Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:26](N)=O>>[CH:23]1([CH2:22][O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:9]2[N:8]=[C:7]3[C:12](=[N:13][CH:26]=[N:6]3)[C:11](=[O:14])[N:10]=2)[CH2:24][CH2:25]1
Reactant: Nc1nc(-c2ccccc2OCC2CC2)[nH]c(=O)c1N
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: O=C1N=C(c2ccccc2OCC2CC2)N=C2N=CN=C12
Temperature: 180 °C

Procedure:
A stirred mixture of 4,5-diamino-2-(2-cyclopropylmethoxyphenyl)pyrimidin-6-one sulphate (1.48 g) and formamide (5 ml) was heated in an oil bath at 180° C. for 2 to 3 hours. The cooled mixture was filtered and the collected solid was washed with ethanol to give a crude product (1.07 g) which was recrystallised three times from ethanol to afford the title compound, 0.32 g, m.p. 259°-260° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:24])[CH2:22][OH:23])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[OH:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:24]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.3 %

Procedure:
Bromomethylbenzene (1.89 g, 7.20 mmol) was added to a mixture of methyl 3-hydroxy-5-[(2S)-1-hydroxypropan-2-yl]oxy-benzoate (1.55 g, 6.86 mmol) and potassium carbonate (1.89 g, 0.014 mol) in DMF (16 mL) and the reaction stirred at RT for 20 hours. Ethyl acetate (40 mL) was added and the mixture washed with water (40 mL), saturated sodium bicarbonate solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (1.7 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=c1[nH]c2ccccc2nc1-c1cccs1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2nc1-c1cccs1
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 3-(2-thienyl)quinoxalin-2(1 H)-one (500 mg, 2.19 mmol.) and POCl3 (6 mL) was heated to reflux at 120° C. After the material was consumed, the reaction mixture was taken up with water and ice. The solid was collected and dried in vacuo to give 2-chloro-3-(2-thienyl)quinoxaline (400 mg, 74%). 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J=4.8 Hz, 1 H), 8.00 (d, J=10.4 Hz, 1 H), 7.91 (d, J=10.4 Hz, 1 H), 7.72˜7.61 (m, 2 H), 7.52 (d, J=6.8 Hz, 1 H), 7.13 (t, J=6.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@:10]12[CH2:17][C@H:16]1[CH2:15][O:14]C(C)(C)[O:12][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][CH2:9][C@:10]1([CH2:11][OH:12])[CH2:17][C@H:16]1[CH2:15][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@@H]2C[C@]2(COCc2ccccc2)CO1
Agent: Cl
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@]1(CO)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
5.56 g (21.1mmol) of (1S, 7R)-1-benzyloxymethyl-4,4-dimethyl-3,5-dioxabicyclo[5,1,0]octane in 50 ml of tetrahydrofuran was mixed with 50 ml of 1N HCl and the mixture was stirred for 30min. at 0° C. Tetrahydrofuran was evaporated off, and the residue was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to obtain 4.08 g (18.2 mmol, 86%) of (1R,2R)-1-benzyloxymethyl-2-hydroxymethyl cyclopropane-1-methanol. Colorless oil; 1H-NMR(CDCl3) δ: 0.41 (t, J=10.8 Hz, 1H), 0.66 (dd, J=5.4, 8.7 Hz, 1H), 1.32 (m, 1H), 3.25-3.4 (m, 4H) 3.60 (dd, J=1.7, 9.6 Hz, 1H), 4.06 (m, 1H), 4.22 (d, J=7.2 Hz, 1H), 4.27 (d, J=7.2 Hz, 1H), 4.56 (s, 2H), 7.34 (m, 5H); FD MASS, m/z 223 (MH+).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].Cl>O>[CH:5]([C:4]1([CH3:8])[NH:9][C:10]([C:12]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:2][C:1]1=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1nc2ccccc2cc1C(=O)O)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(C)NC(c2nc3ccccc3cc2C(=O)O)=NC1=O

Procedure:
A solution of 2-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-3-quinolinecarboxylic acid (0.152 mol), in water (50 mL) containing sodium hydroxide (0.06 mol) is heated at 75° to 80° C. for 2 hours. The solution is cooled in an ice bath and acidified with concentrated hydrochloric acid, added in small increments. The resulting precipitate is filtered, washed with water, air dried, and recrystallized from acetone to afford the 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid, mp 239°-243.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(=O)(O)[O-].[Na+]>O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 165 °C
Yield: 91.6 %

Procedure:
A heterogeneous mixture of 2-amino-4-fluorobenzoic acid (8.7 g, 56 mmol) and formamidine acetate (29.2 g, 280 mmol) was stirred and heated at 165° C. for 2 h. The reaction mixture was suspended in H2O and the mixture was carefully basified with saturated sodium bicarbonate solution followed by stirring for 1 h. The brown solid was collected by filtration, washed with H2O and air dried to afford 8.42 g (91%) of 7-fluoroquinazolin-4(3H)-one. MS 165.0 (ES+).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:31])[C:23]4[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:26])[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCCCN1CCC(c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 78.6 %

Procedure:
To the 500 ml RB-flask was added 4-phenylpiperidine hydrochloride (5 g, 25 mmol), N-(6-bromohexyl)phthalimide (15.5 g, 50 mmol), N,N-diisopropylethylamine (21.8 ml, 125 mmol), tetrabutylammonium iodide (0.2 g), and dioxane (250 ml) at room temperature. The reaction mixture was stirred at 100° C. for 72 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography (98:2=Chloroform:2N ammonia in methanol) to afford 7.67 g of the desired product (77% yield): 1H NMR (400 MHz, CDCl3) δ 7.78-7.79 (m, 2H), 7.74-7.65 (m, 2H), 7.32-7.14 (m, 5H), 3.69 (t, 2H, J=7.35 Hz), 3.06 (d, 2H, J=11.0 Hz), 2.49 (quintet, 1H, J=7.6 Hz), 2.36 (t, 2H, J=7.6 Hz), 2.02 (t, 2H, J=12.5 Hz), 1.82 (br s, 4H), 1.69 (t, 2H, J=6.3 Hz), 1.54 (br s, 2H), 1.37 (br s, 4H); ESMS m/e: 391.3 (M+H)+; Anal. Calc. for C25H30N2O2+0.2H2O: C, 76.19; H, 7.77; N, 7.11. Found: C, 76.14; H, 7.38; N, 7.13.
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)[C@@H:28]1[N+:29]([O-:31])=[O:30])=[O:9])[CH3:12]
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCC
Reactant: O=[N+]([O-])/C=C/c1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCC)[C@@H](c2ccc([N+](=O)[O-])cc2)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq) and 1-nitro-4-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.06 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:3) in 81% yield.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH2:12][CH3:13])[C:4]=2[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl.CO>[CH2:12]([N:11]1[C:4]2[CH:3]=[C:2]([N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[F:14])[CH2:26][CH2:25]3)[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10]1)[CH3:13]
Reactant: CCn1ccc2c(=O)[nH]c(Cl)cc21
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CCn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cc21
Temperature: 140 °C
Yield: 65.3 %

Procedure:
A mixture of 6-chloro-1-ethyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (16 mg, 0.081 mmol) and 1-(2-fluorophenyl)piperazine (160 mg, 0.888 mmol) was heated at 140° C. in a sealed tube for 5 h. Flash chromatography (20/1 methylene chloride/methanol) afforded 1-ethyl-6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.28 Hz, 3H) 3.1 (d, J=4.77 Hz, 4H) 3.2 (d, J=4.77 Hz, 4H) 4.0 (q, J=7.19 Hz, 2H) 5.8 (s, 1H) 6.3 (d, J=3.01 Hz, 1H) 6.9 (d, J=3.01 Hz, 1H) 7.1-7.2 (m, 3H) 10.6 (s, 1H). LC-MS calcd. for C19H22FN4O [(M+H)+] 341, obsd. 341.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:24].C(O)C>C(OCC)C>[ClH:24].[NH:14]1[CH2:15][CH2:16][CH:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-1-piperidine-carboxylate (11.1 g, 32.7 mmol) (i.e. the product of Example 1, Step A) in 100 mL of diethyl ether was treated with a solution of 2 M hydrogen chloride in diethyl ether (166 mL, 331 mmol) at 0° C. The resulting reaction precipitate was dissolved with 100 mL of absolute ethanol and was stirred overnight at room temperature. The reaction mixture was evaporated in vacuo, re-dissolved in ethanol and evaporated again to give a solid. The resulting solid was placed under a high vacuum for several hours to give 10.38 g of the title compound as a hygroscopic white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[N-:14]=[N+:15]=[N-:16].[Li+].O>CN(C=O)C>[N:14]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[N+:15]=[N-:16]
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc([N+](=O)[O-])cc1
Yield: 96.9 %

Procedure:
A solution of 1.12 g (5.55 mmol) of 4-nitro 2-chloroethyl ether (Example 212) and lithium azide (544 mg, 11.1 mmol) in 3 mL of DMF was heated at 60° C. in an oil bath overnight under nitrogen atmosphere. The reaction was poured into water and extracted with ethyl acetate. The organics were washed with water and brine and dried over anhydrous magnesium sulfate and concentrated to give 1.12 g (97%) of the product: 1H NMR (200 MHz, CDCl3) δ8.18 (d, 2H, J=9Hz), 6.96 (d, 2H, J=9Hz), 4.21 (t, 2H, J=5Hz), 3.63 (t, 2H, J=5Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:16])=O)=[CH:4]1)[CH3:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-]>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([NH2:26])=[O:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c2ccc(OC)cc21
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C(N)=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14 mmol) is suspended in a solution of CH2Cl2 (12.5 mL) and DMF (10 μL). Oxalyl chloride (230 μL, 2.64 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (5 mL). This is then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.O>C1COCC1>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:17]1([OH:20])[CH2:18][CH2:19][C:14]2([O:21][CH2:11][CH2:12][O:13]2)[CH2:15][CH2:16]1
Reactant: c1cscn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A solution of n-butyllithium (8.1 mL of 1.6 M solution in hexane, 12.92 mmol) was added to thiazole (1.0 g, 11.75 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.84 g, 11.75 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 3 h at −78° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and chromatographed to yield 2.531 g of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol in 89% yield. MS (EI) calcd: (M+H)+=242.1; found: 242.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]([NH2:28])[C:19]1[CH:27]=[CH:26][C:25]2[O:24][CH2:23][O:22][C:21]=2[CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:28][CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[O:24][CH2:23][O:22][C:21]=3[CH:20]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc2c(c1)OCO2
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3c(c2)OCO3)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and piperonylamine in DME. ES-MS m/e (%): 336 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:21]([CH3:27])[C:22]([O:24]CC)=[O:23]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH2:27][CH2:21][C:22]([OH:24])=[O:23])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc2cc(OCc3ccccc3)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxyindole (1.15 g, 5 mmol) in N,N-dimethylformamide (40 mL) was added sodium hydride (200 mg, 5 mmol). After stirring for 30 minutes, ethyl bromopropionate (900 mg, 5.0 mmol) was added and the mixture was stirred at ambient temperature for 1 h, additional sodium hydride (100 mg, 2.5 mmol) was added. After stirring for 10 minutes, additional ethyl bromopropionate (180 mg, 1.0 mmol) was added. The mixture was stirred at ambient temperature overnight. The solvent was removed under high vacuum, the residue was dissolved in water (10 mL) and tetrahydrofuran (10 mL), NaOH (500 mg) was added and stirred for 2 h. After acidifying to pH 4–5, the mixture was extracted with methylene chloride. The methylene chloride layer was washed with brine and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (1–5% ethyl acetate in methylene chloride) to give 3-(5-benzyloxyindolyl)propanic acid as white solid. The solid was dissolved in N,N-dimethylformamide (20 mL), K2CO3(1.0 g) and iodomethane (840 mg) were added and the reaction was stirred at ambient temperature for 3 h. The mixture was concentrated under high vacuum and residue was purified by flash column chromatography (methylene chloride) to give the title compound as a colorless oil (1.10 g, 71%). 1H-NMR (400 MHz, CDCl3) δ 7.47 (d, J=7.3 Hz, 2H), 7.38 (t, J=7.3 Hz, 2H), 7.32 (d, J=7.2 Hz, 1H), 7.23 (d, J=10.2 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 6.96 (dd, J=8.8, 2.5 Hz, 1H), 6.39 (d, J=3.1 Hz, 1H), 5.10 (s, 2H), 4.41 (t, J=6.9 Hz, 2H), 3.66 (s, 3H), 2.81 (t, J=6.8 Hz, 2H).
Reaction SMILES: C(O[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([O:8][CH3:9])=[O:7])(=O)C.[CH2:18](Br)[C:19]#[CH:20].[Br-]>CN(C=O)C.CCOC(C)=O.[Zn]>[CH3:17][C:14]([CH3:15])([O:13][C:11]([NH:10][CH:5]([CH2:20][C:19]#[CH:18])[C:6]([O:8][CH3:9])=[O:7])=[O:12])[CH3:16]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: C#CCBr
Agent: [Br-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To an ice cooled suspension of the product of Example 2 (4.00 g, 16.2 mmol) and zinc dust (2.63 g, 40.5 mmol) in DMF (30 mL) under nitrogen was added slowly via syringe propargyl bromide (80% w/w in toluene) (6.02 g, 40.5 mmol). The bromide was added at such a rate as to maintain the internal temperature between 20°-25° C., then stirred at that temperature for an additional 1 hour. The reaction mixture was diluted with 100 mL of EtOAc, washed successively with 0.5N HCl (200 mL), sat'd NaHCO3 (200 mL) and sat'd NaCl and then dried (MgSO4). After filtration and concentration under reduced pressure, the residue was purified by filtration through a bed of silica gel (30% EtOAc/hexane)to give 3.59 g (97%) of product as a colorless oil after concentration under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14](=[O:16])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Cl:18])[CH:20]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Cl)c2)c(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.3 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-5-methyl-thiophene-3-carboxylic acid (1.16 g, 4.49 mmol) in dimethylformamide (50.00 ml) was treated with 3-chloro aniline (0.86 g, 6.73 mmol), DIPEA (1.74 g, 13.47 mmol) and TBTU (2.16 g, 6.73 mmol) and stirred at room temperature for 48 h. The volatiles were evaporated and the residue purified by flash chromatography (heptane/ethyl acetate), to yield [3-(3-chloro-phenylcarbamoyl)-5-methyl-thiophen-2-yl]-carbamic acid tert-butyl ester (0.45 g, 27%) as a yellow solid, MS (ISP): m/e=368.6 (M+H+)
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 28 mg (0.14 mmol) of 6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile dihydrochloride (Example 2A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 48 mg (74% of theory) of the product as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH2:33][CH2:32]2)=[CH:23][CH:24]=1
Reactant: O=C(CCCCCBr)NCc1cccnc1
Reactant: COc1ccc(-c2ccccc2N2CCNCC2)cc1
Product: COc1ccc(-c2ccccc2N2CCN(CCCCCC(=O)NCc3cccnc3)CC2)cc1

Procedure:
The title compound was prepared starting from 6-bromo-N-(3-pyridylmethyl)hexanamide and 1-[2-(4-methoxyphenyl)phenyl]piperazine following the procedure outlined for Example 21. 1H NMR (CDCl3): δ 1.35-1.42 (m, 2H), 1.53-1.63 (m, 2H), 1.68-1.78 (m, 2H), 2.28 (t, 2H, J=7.4 Hz), 2.42 (app. t, 2H), 2.65 (br s, 4H), 3.09 (br s, 4H), 3.80 (s, 3H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 6.94 (d, 2H, J=8.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.09-7.12 (m, 2H), 7.20-7.28 (m, 3H), 7.46 (d, 2H, J=8.8 Hz), 8.44 (m, 1H). GC-MS m/z 473 (M+1, 1), 472 (M+, 4), 379 (15), 282 (65), 226 (100), 210 (43), 196 (10).
Reaction SMILES: I[C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH:17][C@H:18]([CH2:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:19]([CH3:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>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(O)C>[CH3:9][N:8]([CH3:10])[C:3]1[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][C@@H:19]([CH3:30])[C@H:18]([OH:17])[CH2:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:22][CH:23]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(C)c1ncccc1I
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccnc2N(C)C)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C

Procedure:
Prepared according to the method described in Example 21b) from 3-iodo-2-dimethylaminopyridine (Example 23a), 0.253 g), ethanol (3 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (Example 21a), 0.200 g), and tetrakis(triphenylphosphine)palladium(0) (0.02 g) with heating at 90° C. for 3 hours.