Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[NH:11][C:12]4[N:13]([N:17]=[C:18]([C:20]([O:22]C)=O)[N:19]=4)[C:14](=[O:16])[CH:15]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[NH3:24]>>[NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[NH:11][C:12]4[N:13]([N:17]=[C:18]([C:20]([NH2:24])=[O:22])[N:19]=4)[C:14](=[O:16])[CH:15]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: N
Reactant: COC(=O)c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Product: NC(=O)c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Yield: 45 %

Procedure:
Methyl 5-(1H-benzo[d][1,2,3]triazol-6-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxylate (80 mg, 1.0 eq) in methanolic ammonia (8 ml) was stirred overnight at 80° C. Then the pH value of the solution was adjusted to pH 4 with HCL (3N). The solids were collected by filtration, washed with water (10 ml) and purified by prep-HPLC to afford 5-(1H-benzo[d][1,2,3]triazol-6-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxamide as a white solid (34.8 mg, 45%).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:4]([NH:6][C@H:7]([C:20]([OH:22])=[O:21])[CH2:8][CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:3].[CH:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[C:32](O)[CH:31]=1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[NH:1]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@H:2]([C:4]([NH:6][C@H:7]([C:20]([O:22][C:32]1[CH:31]=[CH:30][C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=1)=[O:21])[CH2:8][CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-L-Ala-L-Glu(OBzl)-OH (40.5 g, 0.1 mol) was dissolved in 300 ml of EtOAc and combined with 17 g (0.12 mol) of p-nitrophenol. The reaction was kept at 0° C. for 1 hour. DCC (24.7 g, 0.12 mol) was then added. The reaction was stirred for 1 hour at 0° C. and for 4 hours at room temperature. The precipitate of DCU was filtered off and the solvent was evaporated in vacuum. The residual oil was then dissolved in ether. The precipitate was filtered off and washed with ether and hexane. The yield was 35 g (64%). Rf=0.7 (CHCl3:Et-Ac:MeOH=6:3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14](O)=[O:15])[C:11]3[CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:15])[C:11]3[CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[S:19][C:10]=3[C:9]=2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution (0.05 M) of [5-(4-chlorophenyl)-6-cyclohexyl-2-(methoxycarbonyl)-4H-thieno[3,2-b]pyrrol-4-yl]acetic acid in DMF at RT was treated with morpholine (2 eq.), DIEA (1.5 eq.) and HATU (2.5 eq.). The mixture was stirred at RT for 8 h, then it was diluted with DCM and washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and dried. Evaporation of the solvent under reduced pressure gave a residue which was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 90% A isocratic for 2 min then linear to 10% A in 9 min) to afford the title compound (51%) as a solid.
Reaction SMILES: F[C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1F
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Temperature: 88 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A mixture of 5-fluoro-4-methyl-2-nitropyridine (2 g, 12.81 mmol) and 2-chloro-4-hydroxypyridine (1.66 g, 12.81 mmol) in DMF (26 mL) was sparged with Ar, treated with K2CO3 (2.66 g, 19.22 mmol), heated at 88° C. for 24 h, then at 50° C. for 2 days. The mixture was treated with water and the resulting solid collected via filtration and dried to afford 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (2.72 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1 H), 8.47 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 7.24 (d, J=2.3 Hz, 1 H), 7.12 (dd, J=5.7, 2.3 Hz, 1 H), 2.32 (s, 3 H); MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH:29][C:30](Cl)=[O:31])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH:29][C:30]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:20])[F:21])[CH:5]=3)(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[O:31])[CH:23]=1
Reactant: Nc1ccc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)cc1
Reactant: O=C(Cl)C=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C=Cc1cccnc1)Nc1ccc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 50 °C
Yield: 49.6 %

Procedure:
To a solution of 4-((3-(trifluoromethoxy)phenyl)sulfonyl)aniline (86, 0.27 mmol) in DMF (3 mL) is added 3-(pyridin-3-yl)acryloyl chloride (58 mg, 0.28 mmol) and K2CO3 (138 mg, 1 mmol). The mixture is heated at 50° C. for 2 h and the solvent is evaporated. The residue is partitioned between EtOAc (15 mL) and brine (10 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (10 mL) and the combined extracts are dried (Na2SO4) and evaporated. Purification of the residue by preparative TLC with 100:5:0.5 CH2Cl2/MeOH/NH4OH gives the titled compounds as a white solid (60 mg, 50%). (LC_MS: M+1 449.14; 1HNMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.82 (d, 1H), 8.57 (dd, 1H), 7.89-8.06 (m, 7H), 7.76 (t, 1H), 7.74 (m, 1H), 7.66 (d, 1H), 7.46 (dd, 1H), 6.91 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:7])=[O:5])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN1CCOCC1>CN(C=O)C>[CH2:39]([NH:47][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C@@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:7])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)O
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
N[1-(R)-Ethoxycarbonylethyl]-L-leucine (1.39 g, 6 mM), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.16 g, 6 mM), 1-hydroxybenzotriazole (0.93 g, 6 mM) and phenethylamine (0.7 g, 6 mM) were dissolved in DMF (50 ml) at -6°. N-Methyl-morpholine (0.62 g, 6.2 mM) was added and the reaction mixture allowed to warm to room temperature. After 12 h the solvent was removed in vacuo. The residue in EtOAc (150 ml) was washed with H2O (2×100 ml), dried and evaporated in vacuo to yield an oil which was purified by chromatography on SiO2 in EtOAc to give N[1-(R)-ethoxycarbonylethyl]-L-leucine N-phenethylamide as an oil (1.84 g). For analysis, a portion of this material was dissolved in MeOH, treated with anhydrous HCl in Et2O and evaporated in vacuo to yield the corresponding hydrochloride as a foam; (Found: C,60.28; H,8.54; N,7.35; C19H30N2O3.HCl.O.4H2O requires C,60.35; H,8.48; N,7.41%); [α]D20 =+9.4° (c=0.2, MeOH); νmax (Nujol) 3400 (br), 3100 (br), 2510 (br), 2400 (br), 1740, 1670 and 1550 cm-1 ; δ CDCl3) 0.92 and 0.95 (6H, each d, each J=7 Hz, (CH3 )2CH), 1.27 (3H, t, J=6.5 Hz, CH3CH2), 1.28 (3H,d,J=7 Hz, CH3CH), 1.3-1.7 (3H,m,CH2CH), 2.85 (2H,t,J=6 Hz,CH2CH2C6H5), 3.21 (1H,dd,J=10 Hz and 4 Hz, α-CH), 3.27 (3H,q,J=6.5 Hz, CH3CH), 3.54 (2H,q,J=7 Hz, NHCH2CH2), 4.16 and 4.18 (2H, each q, each J=6.5 Hz, OCH2CH3) and 7.25 (6H,m,C6H5 and NHCO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.25-3.29 (m, 4H), 3.73-3.76 (m, 4H), 4.15 (s, 3H), 6.59 (s, 3H), 7.30-7.49 (m, 3H), 7.74-7.77 (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=O)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][O:28][C:29]([C:31]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30]>C(Cl)Cl.CC(=O)OCC>[CH3:27][O:28][C:29]([C:31]1([NH:38][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:30]
Reactant: COC(=O)C1(N)CCCCCC1
Reactant: CC(=O)Oc1cc(C(=O)O)ccc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(Cl)c(OC(C)=O)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.4 %

Procedure:
The compound of step 1 (200 mg, 0.932 mmol) was dissolved in DCM (16 ml), DMF (12 mg) and oxalyl chloride (362 mg, 2.80 mmol) were added and the mixture was stirred at room temperature until completion of the reaction. The volatiles were evaporated in vacuo and the residue dissolved in DCM. The solution was added to a stirred mixture of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (194 mg, 0.932 mmol) in EA/saturated sodium hydrogencarbonate solution with cooling in an ice bath. Stirring continued at room temperature for 2 h. The phases were separated, aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (430 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl.O1C[CH2:37][CH2:36][CH2:35]1>O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:37][CH:36]=[CH:35][C:23]=3[CH3:29])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: Cc1ccccc1CNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.072 g, 0.15 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 3 H) 4.21 (s, 2 H) 6.92 (s, 1 H) 7.15 (m, 5 H) 7.56 (t, J=7.72 Hz, 1 H) 7.67 (d, J=8.09 Hz, 1 H) 7.79 (t, J=7.72 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.17 (d, J=5.52 Hz, 1 H) 14.22 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [P:1](Cl)(Cl)[O:2][C:3]1[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16])=[CH:5][C:4]=1[C:36]([CH3:39])([CH3:38])[CH3:37].C(=O)=O.CC(C)=O.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[OH:56].C(N(CC)CC)C>C(Cl)Cl>[C:36]([C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16])[CH:7]=[C:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:2][P:1]1[NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(OP(Cl)Cl)c(C(C)(C)C)c1
Reactant: Nc1ccccc1O
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(OP2Nc3ccccc3O2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
Into a cooled solution of 29.8 g (50 mmol) of 2,6-di-tert-butyl-4-[2-(n-octadecyloxycarbonyl)ethyl]-phenyl phosphorodichloridite in 100 ml of methylene chloride at dry ice/acetone temperature is added a solution of 5.46 g (50 mmol) of 2-aminophenol and 13.95 ml (100 mmol) of triethylamine in 25 ml of methylene chloride. After the addition is complete, the mixture is warmed to room temperature with continual stirring. After 16 hours, the reaction mixture is concentrated under reduced pressure, mixed with 50 ml of toluene and filtered to remove insoluble solids. The filtrate is reconcentrated, dissolved in hexane and treated with decolorizing charcoal. The resultant mixture is clarified and the filtrate concentrated under reduced pressure to give 27.6 g of the title compound as a white solid melting at 58°-65° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:20].Cl.[CH3:22]O>CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][CH3:22])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CO
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g (3.9 mmol) of (1-benzyloxycarbonylpiperidin-4-yl)isocyanate from Procedure 1, Step A in 10 mL of methanol was added 5 mg (cat) of DMAP. The reaction was stirred under nitrogen at rt for 24 h and then poured into water containing 2 mL of 2 N hydrochloric acid and was extracted twice with ethyl acetate. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated to give 1.4 g of the crude title compound which can be used directly in subsequent reactions.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C(OCC)C>[ClH:1].[N:12]1([CH2:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(CCCl)Cc1cccs1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cl
Product: O=C(CCN1CCCC1)Cc1cccs1

Procedure:
18.85 g (0.10 mol) of 4-chloro-1-(2-thienyl)butanone are run, over a periodof 30 min, into a solution, maintained at 100° C., of 18.5 ml (0.22 mol) of pyrrolidine in 35 ml of toluene, and the mixture is heated to reflux for 2 hours. The reaction medium is diluted with ethyl ether and the mixture is washed with water. The organic phase is extracted with 2N hydrochloric acid solution which, after alkalinisation with sodium hydroxide, is in turn extracted with ethyl ether. The organic phase is dried over dry sodium sulphate and treated with a solution of hydrogen chloride in isopropanol.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.Cl>CN(C)C=O.O>[CH3:25][N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2.5 g, 0.008 M) in dimethylformamide (DMF) (30 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.4 g, 0.009 M). The mixture was stirred at room temperature for 0.5 hours, and then methyl iodide (1.0 g, 0.008 M) was added dropwise. The reaction mixture was allowed to stir for 1 hour. The mixture was then diluted with water (50 ml), neutralized with 10% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-methyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[N:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.[NH4+:30].[OH-:31]>CCO.O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[N:24][C:25]([C:28](=[NH:30])[NH:29][OH:31])=[CH:26][CH:27]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: [NH4+]
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)nc3)c3c(c2)OC(C)(C)C3)n1
Reactant: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)nc3)c3c(c2)OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(6-cyano-pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (181) in 3 mL EtOH was added 1 mL 50% NH4OH in water. The resulting mixture was stirred at room temperature for 2 hr, concentrated in vacuo, dried under vacuum, and used as it is for the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 37.5 %

Procedure:
4,6-Dichloropyrimidine (5.89 g, 40 mmol), 5-aminoindole (6.27 g, 47 mmol) and N,N-diisopropylethylamine (20.6 ml, 0.12 mol) were dissolved in N-methylpyrrolidone (80 ml), and the reaction mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was subjected to re-extraction with ethyl acetate; and the combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; a small amount of ethyl acetate was added to the residue to crystallize; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (3.70 g, 15 mmol, 38%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:28])[CH3:27])=[N:24][CH:25]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][N:26]([CH3:28])[C:23]1[N:24]=[CH:25][C:20]([N:16]2[CH2:15][CH2:14][CH:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)=[CH:21][CH:22]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: CN(C)c1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)cn1
Temperature: 80 °C
Yield: 67 %

Procedure:
Benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (616 mg, 2.4875 mmol, 1.0 eq.), 5-bromo-2-dimethylaminopyridine (500 mg, 2.4875 mmol, 1.0 eq.) and KOBut (557 mg, 4.978 mmol, 2.0 eq.) were taken up in toluene (15 ml) and degassed with N2. BI NAP (77 mg, 0.124 mmol, 0.05 eq.) and Pd2(dba)3 (113 mg, 0.124 mmol, 0.05 eq.) were then added and the mixture was heated for 16 hours at 80° C. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, 2% MeOH in DCM). Yield: 67% (500 mg, 1.358 mmol)
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[S:14][C:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[S:11])(=O)C1C=CC=CC=1.C1COCC1.C[O-].[Na+]>CO>[CH3:29][O:28][C:18]1[C:16]2[N:17]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[S:14][C:15]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=S)NC(=O)c3ccccc3)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(N)=S)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.9 %

Procedure:
To a solution of 1-benzoyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-thiourea (1.3 g, 3.1 mmol) in methanol (20 ml)/THF (40 ml) was added NaOMe (250 mg, 4.6 mmol) and the mixture stirred for 72 h at r.t. After evaporation of the solvents water (100 ml) was added with stirring followed by acetic acid (1 ml) which caused a solid to precipitate. This solid was collected and on a glass sinter, washed with water (100 ml), followed by EtOAc (30 ml) then finally cyclohexane (30 ml). After drying the title compound was obtained as a white solid (850 mg, 87% yield), MS: m/e=316.2 (M+H+).