Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.FC1C=CC(CCCN[C@H]2CC[C@H:49]([C:52]3[CH:61]=CC4NC(=O)[O:58][C:54]=4[CH:53]=3)CC2)=CC=1.O1C=CC(C=O)=C1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:49][C:52]2[CH:53]=[CH:54][O:58][CH:61]=2)[C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](N(CCCc4ccc(F)cc4)Cc4ccoc4)CC3)cc2o1
Reaction time: 0.17 h

Procedure:
The free base of 6-{trans-4-[3-(4-fluorophenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one was made by the addition of K2CO3 (170 mg, 1.2 mmol) to 6-{trans-4-[3-(4-fluorophenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one hydrochloride (500 mg, 1.2 mmol) in THF (50 mL). To this suspension was added 3-furaldehyde (470 mg, 4.9 mmol) and, after 10 minutes, NaBH(OAc)3 (520 mg, 2.4 mmol) was added. After stirring the reaction mixture 3 hours, additional NaBH(OAc)3 (520 mg, 2.4 mmol) was added, and stirring continued for 14.5 hours. The solution was diluted with MeOH and brought to pH=13 with solid NaOH. The solution was then concentrated under reduced pressure. Purification by flash chromatography (silica, 90:9.5:0.5 CH2Cl2:MeOH:NH4OH), followed by formation of the HCl salt, gave 6-(trans-4-{[3-(4-fluorophenyl)-propyl]furan-3-ylmethylamino}cyclohexyl)-3H-benzoxazol-2-one (272 mg, 46%) as an off-white solid: mp 225-227° C.; IR (KBr): 2929, 1773, 1510 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.49 (s, 1H), 9.99 (br s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.27-7.24 (m, 2H), 7.18 (s, 1H), 7.14-7.10 (m, 2H), 7.02-6.98 (m, 2H), 6.75 (s, 1H), 4.30-4.18 (m, 2H), 3.33-3.29 (m, 1H), 3.20-3.12 (m, 1H), 3.01-2.93 (m, 1H), 2.67-2.53 (m, 3H), 2.22-2.15 (m, 2H), 2.07-1.88 (m, 4H), 1.78-1.66 (m, 2H), 1.62-1.49 (m, 2H); ESI-MS (m/z): 449 [M+H]+; HPLC: method A, 6.27 minutes (99.8%); Anal. Calcd for C27H29FN2O3.HCl: C, 66.87; H, 6.23; N, 5.78. Found: C, 66.54; H, 6.27; N, 5.48.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:21][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:14][CH2:13]2)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:27]
Reactant: Nc1cccnc1N1CCC(CCN2CCCCC2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1N1CCC(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35.1 %

Procedure:
To a solution of 0.029 g (0.10 mmol) of 4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine in N,N-dimethylformamide (1 mL) is added 0.017 g (0.10 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 6 hours and then purified by preparative reverse phase HPLC to provide 0.015 g (35%) of the title compound (44) as a colorless solid. [M+H]+=427.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[N:8][NH:9][C:10]([NH2:12])=[S:11])=[CH:5][N:4]=[C:3]1[N+:13]([O-:15])=[O:14]>O>[NH2:12][C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[C:3]([N+:13]([O-:15])=[O:14])=[N:4][CH:5]=2)=[N:8][N:9]=1
Reactant: Cn1c(C=NNC(N)=S)cnc1[N+](=O)[O-]
Solvent: O
Product: Cn1c(-c2nnc(N)s2)cnc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
2 Grams of 1-methyl-2-nitro-5-imidazolecarboxaldehyde thiosemicarbazone are added to a solution of 17.1 g. of FeNH4 (SO4)2. 12H2O in 35 ml. of water. The mixture is stirred at 80°-90° C. for 2 hours, and, after cooling, the solid product is collected on the filter and washed with water. The crude compound is crystallized from a mixture of methanol and dimethylformamide. Yield 0.95 g. (48%), m.p. 263°-265° C.
Reaction SMILES: [NH2:1][C:2]1[C:13]2[C@@:12]3([CH3:16])[C@H:14]([CH3:15])[C@H:8]([N:9]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:23].[C:24](OC)(OC)(OC)[CH3:25]>>[F:20][C:18]([F:21])([F:19])[C:17]([N:9]1[CH2:10][CH2:11][C@:12]2([CH3:16])[C@H:14]([CH3:15])[C@H:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]3[O:23][CH:24]([CH3:25])[NH:1][C:2]=3[C:13]=12)=[O:22]
Reactant: C[C@@H]1[C@H]2Cc3ccc(O)c(N)c3[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: COC(C)(OC)OC
Product: CC1Nc2c(ccc3c2[C@]2(C)CCN(C(=O)C(F)(F)F)[C@H](C3)[C@H]2C)O1
Temperature: 100 °C

Procedure:
1-[(2R,6R,11S)-7-Amino-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (200 mg) taken up in trimethyl orthoacetate (1 mL) is heated at 100° C. for 3 h. After cooling to ambient temperature, the mixture is concentrated and the residue is triturated with little methanol and dried to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:22])(=[O:21])[NH:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:7]=1.CO>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:22])=[O:21])[CH:16]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid methyl ester (14b) (0.35 g, 1.05 mmol) in methanol (4.3 ml) 1N NaOH solution (3.15 ml, 3.15 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution to pH˜5 of the reaction medium and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.28 g, 84%).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[NH2:24])C>C(O)(=O)C>[CH2:17]([NH:16][C:8]1[C:7]2[NH:24][C:4](=[O:3])[NH:5][C:6]=2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1N
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(C(F)(F)F)nc(NCc3ccccc3)c2[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
(3-amino-2-benzylamino-6-trifluormethyl-pyridin-4-yl)-carbamic acid ethyl ester (88 mg, 0.25 mmol) was dissolved in 5 mL of acetic acid and the reaction mixture was stirred at 80° C. overnight. The solvent was removed and the gum was partitioned in water/ethyl acetate. The organic layer was isolated, dried over MgSO4, the solvent was removed in vacuo and purified by column chromatography on silica eluting with a gradient of 1% to 5% of methanol in ethyl acetate to give 37 mg of the title compound as a colourless gum.
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4](=O)[O:3]1.[NH2:20][OH:21]>C(OCC)(=O)C>[OH:21][N:20]1[C:2](=[O:1])[C@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4]1=[O:3]
Reactant: CC(C)C(=O)O[C@H]1C(=O)OC(=O)[C@@H]1OC(=O)C(C)C
Reactant: NO
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@H]1C(=O)N(O)C(=O)[C@@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of compound (27) (5.98 g, 22 mmol) in ethyl acetate (50 mL) at 0° C. was added a 50% aqueous solution of hydroxylamine (1.75 g, 26.4 mmol). The resulting mixture was stirred at room temperature for 3 h and washed successively with aqueous citric acid solution and brine, then dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was suspended in toluene and the reaction mixture heated under reflux for 5 h, with the azeotropically liberated water being collected in a Dean-Stark apparatus. Toluene was removed in vacuo to afford the title compound (28) (6.3 g, quantitative yield). 1H-NMR (400 MHz, CDCl3): δ 1.22 (d, J=6.8 Hz, 12H), 2.69 (hept, J=6.8 Hz, 2H), 5.48 (s, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])=[CH:24][CH:23]=1>>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([N:16]2[CH2:17][CH2:18][N:19]([S:29]([CH2:28][C:25]3[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=3)(=[O:31])=[O:30])[CH2:20][CH2:21]2)[CH:4]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1N1CCNCC1
Agent: Cl
Product: O=C(O)COc1ccc(Cl)cc1N1CCN(S(=O)(=O)Cc2ccccc2)CC1

Procedure:
Prepared from the product from Example 38 step c) and benzenemethanesulfonyl chloride according to the procedure described in Example 38 step d) to give the sub-title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:41])([F:40])[C@@:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)(=[O:27])=[O:26])[CH2:21][C@@H:20]2[CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[CH:15][CH:14]=1)([OH:12])[CH3:11].FC(F)(F)C(O)=O.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CC2C=CN=CC=2)=CC=1)(O)C.FC(F)(F)C(O)=O.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CC2C=CN=CC=2)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:41][C:9]([F:8])([F:40])[C@@:10]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)(=[O:27])=[O:26])[CH2:21][C@H:20]2[CH2:33][C:34]2[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=2)=[CH:17][CH:18]=1)([OH:12])[CH3:11]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2ccncc2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2ccncc2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2ccncc2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2ccncc2)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(4-pyridinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate. 1H NMR (300 MHz, CD3OD) δ 8.61 (d, J=6.4 Hz, 2H), 7.80-7.93 (m, 3H), 7.62 (dd, J=3.8, 1.2 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.20-7.29 (m, 1H), 6.95 (d, J=8.9 Hz, 2H), 4.48 (s, 1H), 3.86 (s, 1H), 3.45-3.63 (m, 3H), 3.34-3.45 (m, 1H), 3.16 (dd, J=13.0, 5.7 Hz, 1H), 2.53-2.71 (m, 2H), 1.67 (s, 3H). m/z (ESI, +ve ion) 512.2 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.207 μM; GK-GKRP EC50 (LC MS/MS)=0.522 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:13][CH2:12][C:4]1[CH:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(C)(C)C)cc(Cl)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Cl)nc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
Dissolve 2-chloro-6-methyl-4-tert-butyl-pyridine (3.00 g, 16.33 mmol), N-bromosuccinimide (3.20 g, 17.97 mmol) and AIBN (0.03 g, 0.16 mmol) in carbon tetrachloride (60 mL) and heat to reflux. After heating for 6 hours, stir the contents overnight at ambient temperature. The contents are then concentrated to dryness and dry loaded onto a silica plug and eluted with dichloromethane to obtain the title compound (1.90 g, 7.23 mmol). MS(ES), m/z 263 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc([N+](=O)[O-])c3)c(=O)n(C3CCCC3)c12
Yield: 43.9 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(3-nitro-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-nitro-benzene (0.5 mmol) following general procedure C. LCMS: m/z 433 [M+1]+.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.Cl.CNCC>C(#N)C>[CH2:6]([N:5]([CH3:4])[C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=1)=[O:9])[CH3:7]
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: CCNC
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)C(=O)/N=c1\sc(C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (50 mg, 0.10 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (28 μL, 0.13 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added N-methylethanamine hydrochloride (11 mg, 0.11 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[N+](C1C=CC=CC=1)([O-])=O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCCl>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:26](=[O:28])[CH3:27])=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Solvent: ClCCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCc1cc(=O)oc2c(C(C)=O)c(O)cc(O)c12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a mixture of 5,7-dihydroxy-4-propyl-coumarin (2.06 g 9.36 mmol) and anhydrous AICI3 (2.53 g, 18.7 mmol) was added 1,2-dichloroethane (120 mL). The resulting suspension was heated to 75° C. with vigorous stirring. After 30 minutes of stirring, a brown slurry was obtained, then nitrobenzene was introduced into the mixture resulting in an orange colored solution. A solution of anhydrous AICI3 (2.53 g, 18.7 mmol) and acetic anhydride (0.88 mL, 9.36 mmol) in 1,2-dichloroethane (40 mL) was added dropwise over a period of 1-2 hours. After addition, the mixture was allowed to stir at 75° C. for another two hours and subsequently cooled to room temperature. The resulting mixture was poured into ice and 1N HC1. The precipitated product was filtered and then taken into ethyl acetate and the aqueous solution was extracted thoroughly with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography (1:1 hexane/ethyl acetate) yielding 5,7-dihydroxy-8-acetyl-4-propyl-coumarin (0.30 g, 12%): mp. 221-224° C.; 1H NMR (DMSO-d6) δ0.94 (t, 3H), 1.58 (sextet, 2H), 2.66 (s, 3H) 2.87 (t, 2H), 6.01 (s, 1H), 6.29 (s, 1H).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]2[C:15]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:16]=3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH2:19][C:13]2=[N:12][N:11]=1)C1C=CC=CC=1.Br.[OH-].[Na+].O>C(O)(=O)C.C(Cl)Cl>[C:20]1([C:17]2[C:16]3[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=3[N:14]3[C:10]([CH2:9][OH:8])=[N:11][N:12]=[C:13]3[CH2:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(COCc3ccccc3)n1-2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
An amount of 25 g of 1-(benzyloxymethyl)-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine is dissolved in 200 ml of glacial acetic acid; to this solution are then added 170 ml of 48% aqueous hydrobromic acid. The mixture is heated for 90 minutes at 80°, and afterwards cooled to 5°; the pH-value of the mixture is adjusted with concentrated sodium hydroxide solution to 6, whilst stirring is maintained, and water and also methylene chloride are then added. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, and concentrated by evaporation. The residue is dissolved in ethyl acetate/methanol (9:1), the solution filtered through a column of 150 g of silica gel (Merck®, particle size 0.05-0.2 mm), and the column eluted with ethyl acetate/methanol (9:1) to (7:3). The eluate is concentrated by evaporation and the residue crystallised from ethyl acetate/ether. In this manner is obtained 6-phenyl-8-chloro-4H-s-triazolo [ 4,3-a][1,4]benzodiazepine-1-methanol, M.P. 210°-211°.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])=[CH:9][C:8]=1[C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)=[O:12])=[CH:9][C:8]=1[C:27]1[CH:32]=[N:31][CH:30]=[N:29][CH:28]=1
Reactant: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(O)c(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
BBr3 1 M in DCM (3.85 mL, 3.85 mmol) was added dropwise to a stirred solution of 4-methoxy-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (100 mg, 0.257 mmol) in DCM (1.027 mL) at −70° C. and then stirred at RT for 2.5 days and under reflux for 2 days. The RM was treated with MeOH and the solvent was evaporated off under reduced pressure to give the crude product was purified by preparative HPLC (Condition 8, 50% for 0.2 min then 50% to 100% in 15 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.29 min, m/z=376.0 [M+H]+, m/z=374.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.13 (d, J=8.6 Hz, 1H) 7.36 (d, J=8.6 Hz, 2H) 7.87 (d, J=9.0 Hz, 2H) 7.93 (dd, J=8.6, 2.2 Hz, 1H) 8.09 (d, J=2.0 Hz, 1H) 9.09 (s, 2H) 9.17 (s, 1H) 10.24 (s, 1H) 10.82 (br. s, br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].ClC(OC(CC)C)=O.[CH3:21][C:22]([O:25][OH:26])([CH3:24])[CH3:23]>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][O:26][O:25][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OO
Agent: CCC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OOOC(=O)c1cccc(Cl)c1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH-electrode were added 39 g of water and 0.20 g of Arquad CB50 at 5° C. After the addition of 0.05 mole of 3-chlorobenzoic acid the pH was adjusted to 6 using a 10 wt % aqueous NaOH solution. Then, 0.05 mole of sec-butyl chloroformate was dosed within 5 min at 5° C. During this time and a post-reaction time of 165 min at 5° C. the pH was kept at a value between 6 and 9. After the post-reaction, 8.1 g of TBHP were added (0.063 mole), and using a 33 wt % aqueous NaOH solution the pH was adjusted to 13 within 5 min while keeping the temperature at 5° C. During a post-reaction time of 75 min at 5° C. the pH was maintained at 13. Then, 25 g of diethyl ether were added, and the reaction mixture was allowed to separate. After separation of the water layer, the organic layer was washed, twice with 40 g of a 15 wt % aqueous NaCl solution. The ether layer was dried over MgSO4, and the diethyl ether was removed under vacuum. As a result, 9.4 g of tert-butylperoxy 3-chlorobenzoate having a content of 95.4% were obtained in a yield of 80% based on 3-chlorobenzoic acid. The molar ratio of tert-butylperoxy 3-chlorobenzoate to tert-butylperoxy 1-methyl-1-propylcarbonate was calculated to be 97.6:2.4.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: CCCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: CCCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-propylpyridine hydrobromide*.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:34][CH2:33][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH3:24])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1CCN
Reactant: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1CCNCC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 66.4 %

Procedure:
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 2 g (0.01 mol) of 2-(2-methoxyphenyl)ethylamine were refluxed with heating together with 200 ml of DMF for 21 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5.1 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 3.05 g of the subject compound in a viscous liquid state.