Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)O)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=3)[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:10]([CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccc(Cl)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 80.6 %

Procedure:
Using [1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.46 g) synthesized in Example 19(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.25 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.41 g, 57%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[N+:11]([O-:13])=[O:12].[CH:14](I)([CH3:16])[CH3:15]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][N:7]([CH:14]([CH3:16])[CH3:15])[N:8]=[C:4]2[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1c(Cl)ccc2[nH]nnc12
Solvent: CC#N
Product: CC(C)n1nc2ccc(Cl)c([N+](=O)[O-])c2n1
Yield: 61.9 %

Procedure:
To a hot, stirred solution (50° C.) of 20.0 grams of 5-chloro-4-nitrobenzotriazole in 600 milliliters of acetonitrile is added 4.2 grams of sodium hydroxide pels and 20.0 grams of isopropyl iodide. The solution is then heated to reflux for 30 hours, filtered and the solvent removed by evaporation to yield an oil. The oil is extracted with concentrated hydrochloric acid (3×200 milliliters) and the resulting solid is collected, washed with water and air dried to yield 15.0 grams (63%) of crude 5-chloro-2-isopropyl 4-nitrobenzotriazole, m.p. 67°-70° C. The analytical sample is recrystallized from n-hexane and has a m.p. 75°-76° C.
Reaction SMILES: O[NH:2][C:3](=[NH:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15]([O:19][CH3:20])(=[O:18])[C:16]#[CH:17]>CCO>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]2[NH:14][CH:17]=[C:16]([C:15]([O:19][CH3:20])=[O:18])[N:2]=2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: N=C(Cc1ccc([N+](=O)[O-])cc1)NO
Reactant: C#CC(=O)OC
Solvent: CCO
Product: COC(=O)c1c[nH]c(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
A 250-mL round bottomed flask was charged with N-hydroxy-2-(4-nitrophenyl)acetamidine (1 g, 5 mmol, 1 eq.), methyl propiolate (500 mg, 6 mmol, 1.2 eq.) and EtOH (24 ml). The resulting mixture was stirred under reflux for 7 hrs. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was added phenyl ether (200 ml). The mixture was stirred at 190° C. for 30 minutes. After cooling to room temperature, the mixture was poured into hexane (1 L). Solid was collected and washed with hexane. The crude product thus obtained (964 mg) was purified by chromatography on silica gel using 10˜20% acetone in dichloromethane as eluent to afford the title compound as a gray solid (220 mg, 17% yield over two steps).
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:8][CH2:7]1)[CH2:3][CH2:4][OH:5].[CH:9]([C:11]1[C:19]2[C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=[N:15][C:14]=2[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:12]=1)=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH:6]1([CH:2]([NH:1][CH2:9][C:11]2[C:19]3[C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=[N:15][C:14]=3[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:12]=2)[CH2:3][CH2:4][OH:5])[CH2:8][CH2:7]1
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: NC(CCO)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccnc2c1c(CNC(CCO)C1CC1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
3-Amino-3-cyclopropylpropan-1-ol (30 mg, 0.26 mmol) was added to a solution of 1-tert-butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (39.6 mg, 0.13 mmol) in MeOH (3 mL) with AcOH (2 drops). After stirring for 90 min at rt, sodium cyanoborohydride (33 mg, 0.53 mmol) was added, and the reaction was stirred for an additional 3 h. The mixture was quenched with sat. NaHCO3 solution and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo to give 50 mg of crude 1-tert-butyl 4-methyl 3-((1-cyclopropyl-3-hydroxypropylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate as a yellow oil which was used without further purification. [M+H] found 404.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([O:12][CH2:13][CH2:14][OH:15])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]2)([O:12][CH2:13][CH2:14][O:15][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@](OCCO)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC[C@](OCCOS(C)(=O)=O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)butyl)piperidine-1-carboxylate (750 mg, 1.82 mmol) in dry CH2Cl2 (10 mL) was added Et3N (550 mg, 5.46 mmol) at −5-0° C. Then a solution of MsCl (270 mg, 2.37 mmol) in dry CH2Cl2 (5 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. Upon completion of the reaction, water (20 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers was washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methylsulfonyloxy)ethoxy)butyl)piperidine-1-carboxylate (900 mg, 99%), which was used in the next step without purification.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[OH-].[Na+].Br[C:12]1[CH:13]=[C:14]([CH:34]=[C:35]([O:37][C:38]([F:41])([F:40])[F:39])[CH:36]=1)[C:15]([N:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[O:32][CH3:33])[CH3:18])=[O:16].[CH3:42][S:43]([O-:45])=[O:44].[Na+].[NH4+].[Cl-]>CS(C)=O.[Cu]I.CCOC(C)=O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:17]([CH3:18])[C:15](=[O:16])[C:14]2[CH:34]=[C:35]([O:37][C:38]([F:41])([F:40])[F:39])[CH:36]=[C:12]([S:43]([CH3:42])(=[O:45])=[O:44])[CH:13]=2)=[C:26]([O:32][CH3:33])[CH:27]=1
Reactant: CS(=O)[O-]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Br)cc(OC(F)(F)F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(OC(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of L-proline (18.4 mg, 160 μmol) in DMSO (2 mL) was added sodium hydroxide (6.41 mg, 160 μmol) and the turbid mixture was stirred at room temperature for 30 minutes. This mixture was added to 3-bromo-N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethoxy-benzamide (0.1 g, 200 μmol) and the resulting suspension was treated with copper(I)iodide (30.5 mg, 160 μmol) and sodium methanesulfinate (164 mg, 1.6 mmol). The reaction mixture was heated to 120° C. for 19 hours. After cooling down to room temperature the reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.065 g; 65%). MS (ESI): m/z=499.09 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C@H:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:14]=2)[CH2:20][C@H:21]1[CH3:24]
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)c(F)c(F)c1
Product: C[C@@H]1Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3,4,5-trifluorophenyl)methanol and (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25](=O)[NH:26][CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:17])[CH3:18])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=3)[N:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 3.43 mmol) was dissolved in m-xylenes (18 mL) and heated at 135° C. Solid ammonium acetate (1.70 g, 22.0 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product 3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (674 mg, 1.19 mmol): LCMS-ESI+: calc'd for C25H34BrN50O5: 564.5 (M+). Found: 564.2/566.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[N:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1.O>C1COCC1>[CH3:24][C:21]1[N:20]=[N:19][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a solution of (5-methyl-3-phenyl-4-isoxazolyl)methanol (0.50 g, 2.64 mmol) in THF (8 mL) was added sodium hydride (55% dispersion in mineral oil, 0.16 g, 3.17 mmol) at 0° C. The reaction mixture was stirred for 30 min while it was allowed to warm up to room temperature. 3-Chloro-6-methylpyridazine (0.36 g, 2.77 mmol) was added and stirring was continued for 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. Concentration and purification of the residue by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (220 mg, 30%) as a yellow oil. MS: m/e=282.3 [M+H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1cccn1C
Product: CCN(Cc1cccn1C)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(1-methyl-1H-pyrrol-2-ylmethyl)-amine
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45](C4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[O:55]1[CH2:60][CH2:59][N:58]([CH2:61][CH2:62][O:63]C2C=CC(O)=CC=2)[CH2:57][CH2:56]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([O:63][CH2:62][CH2:61][N:58]4[CH2:59][CH2:60][O:55][CH2:56][CH2:57]4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: Oc1ccc(OCCN2CCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(OCCN4CCOCC4)cc3)s1)CC2

Procedure:
The title compound 88 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 88B: 1H NMR (DMSO-d6): δ 12.86 (s, 1H), 9.96 (s, 1H), 8.03 (d, J=7.98 Hz, 1H), 7.79 (d, J=7.98 Hz, 2H), 7.67 (d, J=7.36 Hz, 1H), 6.86-6.94 (m, 4H), 4.83 (s, 2H), 4.25-4.27 (m, 2H), 3.91-4.02 (m, 4H), 3.73 (t, J=5.98 Hz, 2H), 3.14-3.22 (m, 4H), 3.03 (t, J=5.98 Hz, 2H), 1.94-2.01 (m, 2H). ESI (+)/MS: 700 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Yield: 95.4 %

Procedure:
A mixture of 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was treated with a catalytic amount of 10% palladium on activated carbon (30 mg). The resulting mixture was shaken at 25° C. under 60 psi of hydrogen gas in a Parr apparatus for 24 h. At this time, the catalyst was removed by filtration through a plug of celite. The filtrate was concentrated in vacuo to afford 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (262.8 mg, 94.7%) as a pale yellow glass: EI-HRMS m/e calcd for C21H25N3O3 (M+) 367.1895, found 367.1899.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[N:8]1([C:4]2[N:3]=[C:2]([C:14]#[N:15])[CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CN(C)C=O
Reactant: Brc1ccnc(N2CCOCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccnc(N2CCOCC2)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a sealed tube a mixture of 4-(4-bromopyrimidin-2-yl)morpholine (0.40 g, 1.64 mmol), Zn(CN)2 (0.35 g, 3.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) in anhydrous DMF was degassed with argon for 10 minutes and then warmed at 120° C. After 2 hours, the mixture was cooled and diluted with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford 2-morpholin-4-yl-pyrimidine-4-carbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([N+:14]([O-])=O)=[CH:6][CH:5]=1)[CH3:2].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C.[Zn]>[NH2:14][C:7]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCOc1ccc([N+](=O)[O-])c(C(=O)OC)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(N)c(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a stirred solution of the compound prepared in Example 425 (0.200 g,) in tetrahydrofuran (4.5 mL) was added zinc dust (0.5782 g), followed by saturated aqueous ammonium chloride (4.5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water-ethyl acetate and then filtered through paper. The phases were separated, organic layer dried, concentrated in vacuo and the bright yellow oil purified by column chromatography on silica gel (1-2% methanol in dichloromethane) to provide the title compound (0.132 g) as a yellow oil having the following physical data.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[C:19]([CH2:25]Br)[CH:18]=1>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[CH2:23][C:3]1([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[CH2:25]2
Reactant: O=C1Cc2ccccc2N1
Reactant: BrCc1ccc(Br)cc1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12Cc1ccc(Br)cc1C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL) was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) drop wise, followed by the drop wise addition of tetranethylethylenediamine (0.905 mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then a solution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) was added drop wise. The reaction solution was stirred at −10 to −20° C. for 2 h and at ambient temperature for 16 h. The reaction mixture was partitioned between saturated NH4Cl (50 mL) and EtOAc (50 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][N:23]=3)=S)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>C(O)C.[Hg](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[N:35][OH:36])[C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][N:23]=3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: NO
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCN(C(=S)c2ncc(-c3ccncc3)cn2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: Cl[Hg]Cl
Solvent: CCO
Product: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCN(C(=NO)c2ncc(-c3ccncc3)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In ethanol (50 ml) was suspended 1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]thiocarbonyl]piperazine (243 mg) at room temperature, followed by the successive addition of hydroxylamine hydrochloride (338 mg), sodium acetate (399 mg) and mercury (II) chloride (132 mg). The resulting mixture was stirred at room temperature for 6 hours. The insoluble matter was filtered off through Celite filtration. The residue was purified by chromatography on a silica gel column (7% methanol—methylene chloride), whereby two fractions were obtained. They were concentrated, respectively, whereby a low-polarity compound (20 mg, colorless powder) and a high-polarity compound (20 mg, colorless powder) were obtained. Low-polarity compound:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1>[Pt]>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC2=NCCCCC2)cc1
Agent: [Pt]
Product: Clc1ccc(CC2CCCCCN2)cc1

Procedure:
Hydrogenate the thus-obtained 2-(4-chlorobenzyl)-4,5,6,7-tetrahydro-3H-azepine with platinum/active carbon/ hydrogen. Filter out the catalyst, concentrate the filtrate and distil to obtain 61.9 g (68% of theory) of the title compound with a BP of 93° at 0.1 mm of Hg.
Reaction SMILES: CC1N=CC2C(C=1)=C([N+]([O-])=O)C=CC=2.[CH3:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[N+:26]([O-])=O.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:40]=[CH:39][C:34]([CH2:35][N:36]=[C:37]=[O:38])=[CH:33][CH:32]=1>>[CH3:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[NH:26][C:37]([NH:36][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:42])[F:41])=[CH:40][CH:39]=1)=[O:38]
Reactant: Cc1cc2cccc([N+](=O)[O-])c2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Agent: Cc1cc2c([N+](=O)[O-])cccc2cn1
Product: Cc1cc2cccc(NC(=O)NCc3ccc(C(F)(F)F)cc3)c2cn1

Procedure:
A sample of 3-methyl-5-nitroisoquinoline (Description 44) enriched in the nitration byproduct 3-methyl-8-nitroisoquinoline was reduced according to Description 45 and the mixture of amines reacted with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. Isomer separation of the products gave the title compound. m/z (ES+) 360 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]4[CH2:23][C:22]5(OCC[O:24]5)[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[N:15]4[CH2:23][C:22](=[O:24])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CC1(CC2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2C1
Temperature: 25 °C

Procedure:
A solution of 3′-((3-fluorophenyl)ethynyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,8′-pyrido[2,1-b]quinazolin]-11′(9′H)-one (0.5 g, 1.3 mmol) and 4N HCl (4 mL) in THF (20 mL) was heated at reflux for 4 h. After it was cooled to room temperature, the reaction mixture was quenched with Na2CO3 solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 333 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.28-8.25 (d, J=8.19 Hz, 1H), 7.82 (s, 1H), 7.63-7.60 (dd, J=8.22, 1.50 Hz, 1H), 7.39-7.35 (m, 2H), 7.28-7.27 (m, 1H), 7.15-7.09 (m, 1H), 4.28 (s, 2H), 3.34-3.30 (t, 2H), 2.85-2.81 (t, 2H). mGluR5 PAM EC50: +++. Fold shift at 10 μM: +.