Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: COc1cccc(B(O)O)c1
Product: COC(=O)c1c(O)c2ccc(-c3cccc(OC)c3)cc2sc1=O

Procedure:
4-Hydroxy-7-(3-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 3-methoxyphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 341.10 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]=[CH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8][CH2:7]1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8][CH2:7]1
Reactant: COC(=O)C=C[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
1.45 g (3.5 mmol) of trans-3-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-acrylic acid methyl ester in 25 mL of EtOAc were hydrogenated at normal pressure with 5% Pd/C as the catalyst to give 1.4 g (96%) of trans-3-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-propionic acid methyl ester as white solid, MS: 422 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[NH:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:4]2([NH:8][C:7](=[O:9])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3]1.[O:25]1[CH2:42][CH:26]1[CH2:27][O:28][CH2:29][CH:30]([CH2:36][O:37][CH2:38][CH:39]1[O:41][CH2:40]1)[O:31][CH2:32][CH:33]1[O:35][CH2:34]1>C(O)CCCCCCC>[OH:25][CH:26]([CH2:42][N:21]1[C:20]([CH3:23])([CH3:22])[CH2:19][C:4]2([NH:8][C:7](=[O:9])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3][C:2]1([CH3:1])[CH3:24])[CH2:27][O:28][CH2:29][CH:30]([O:31][CH2:32][CH:33]([OH:35])[CH2:34][N:21]1[C:20]([CH3:23])([CH3:22])[CH2:19][C:4]2([NH:8][C:7](=[O:9])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3][C:2]1([CH3:1])[CH3:24])[CH2:36][O:37][CH2:38][CH:39]([OH:41])[CH2:40][N:21]1[C:20]([CH3:23])([CH3:22])[CH2:19][C:4]2([NH:8][C:7](=[O:9])[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3][C:2]1([CH3:1])[CH3:24]
Reactant: C(OCC1CO1)C(COCC1CO1)OCC1CO1
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(C)NC(C)(C)C2)C1=O
Solvent: CCCCCCCCO
Product: CCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COCC(COCC(O)CN3C(C)(C)CC4(CC3(C)C)NC(=O)N(CCCCCCCC)C4=O)OCC(O)CN3C(C)(C)CC4(CC3(C)C)NC(=O)N(CCCCCCCC)C4=O)C(C)(C)C2)C1=O
Temperature: 180 °C

Procedure:
A mixture of 11.0 g of 7,7,9,9-tetramethyl-3-octyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 2.6 g of glycerol tris(2,3-epoxypropyl)ether in 10 ml of octanol was heated at 180° C. for 30 hours. After completion of the reaction, the reaction mixture was purified by column chromatography through silica gel eluted with ethyl acetate, giving the desired Compound No. 349 in the form of a colourless oil. The compound had an Rf value of 0.54 on thin-layer chromatography on silica gel when developed with a 10:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]3)=[C:19]([O:31]CC3C=CC=CC=3)[CH:18]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.[Pd]>[C:1]1([S:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]3)=[C:19]([OH:31])[CH:18]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN(c2ccc(/C=C/C3CCCN3S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1CN(c2ccc(CCC3CCCN3S(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1
Reaction time: 1 h

Procedure:
To a mixture of 5-{4-[(E)-2-(1-benzenesulfonylpyrrolidin-2-yl)-vinyl]-2-benzyloxyphenyl}-1,1-dioxo-1,2,5-thiadiazolidin-3-one (22 mg) in 4 mL ethanol/water (1:3) is added 5 mg of Degussa Pd/C and the resulting mixture is hydrogenated at 1 atm for 1 h. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by reverse phase Biotage using a gradient of 20-60% EtOH/water as eluent to furnish the title compound: LC retention time=1.10 min (Method A); (M−H)−=464.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:16].[Na+]>CO>[OH:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CO
Product: O=C(CO)c1ccc(C(F)(F)F)cc1
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-4′-trifluoromethyl acetophenone (40.0 g), sodium formate (40.0 g) and methanol (200 ml) was stirred with heating under reflux for 6 hours. There action mixture was concentrated and poured into water (500 ml). The precipitated crystals were filtered, washed with water, and air-dried to give crystals of 2-hydroxy-4′-trifluoromethyl acetophenone (24.5 g, 80%). Melting point 112-114° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[N:14]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[C:12]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:11]=1.Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>CC(O)C>[F:1][C:2]1[C:7]([CH:8]=[N:35][OH:36])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[N:14]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:13]=[C:12]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:11]=1
Reactant: CN(Cc1cc(-c2cccc(C=O)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)O
Product: CN(Cc1cc(-c2cccc(C=NO)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a solution (3 mL) of tert-butyl {[5-(2-fluoro-3-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (182 mg) in 2-propanol were added hydroxylamine hydrochloride (40 mg) and sodium acetate (47 mg). After stirring at room temperature for 3 hr, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as a pale-yellow oil (yield 150 mg, 80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:26])[F:27])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C(F)(F)F)cc2)nc(N)n1
Yield: 46 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-trifluoromethyl-phenylamine provided the title compound (46% yield). 1H NMR (DMSO-d6) δ 2.36 (s, 3H, CH3), 6.17 (s, 1H, Ar), 6.54 (s, 2H, NH2), 7.32 (d, 1H, J=8.3 Hz, Ar), 7.38 (dd, 1H, J=8.1 Hz, J—2.3 Hz, Ar), 7.43 (d, 1H, J=2.1 Hz, Ar), 7.61 (d, 2H, J=8.7 Hz, Ar), 8.00 (d, 2H, J=8.5 Hz, Ar), 9.63 (s, 1H, NH).
Reaction SMILES: CN(C=O)C.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9].[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>C(OCC)(=O)C>[Si:22]([O:6][CH2:7][C@@H:8]([OH:9])[C@@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([OH:15])[CH:16]=[O:17])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
DMF (10 mL) was placed in a 50 mL flask and cooled to 0° C. in an ice bath. 5 g of D-glucose was added, followed by 0.9 molar equiv. (6.5 mL) of tert-butylchlorodiphenylsilane. The reaction was left for 21 h at 0° C., after which it was poured into 5 mL of ethyl acetate and washed with saturated NaHCO3, brine, dried, isolated by flash column chromatography and evaporated to a yellow solid of 11 (30%). 1NMR [(300 MHz, CDCl3) 5 (ppm): 7.64 (m, 4 H), 7.32 (m, 6 H), 5.13-2.94 (m, 11 H), 1.0 (s, 9 H)], 13C NMR [(300 MHz, CDCl3) 8 (ppm): 135.5 (s, TBDPS-O), 135.45 (s, TBDPS-O), 133.3 (s, TBDPS-O), 133.2 (s, TBDPS-O), 133.0 (s, TBDPS-O), 132.9 (s, TBDPS-O), 129.6 (s, TBDPS-O), 129.5 (d, TBDPS-O), 127.6 (s, TBDPS-O), 127.55 (s, TBDPS-O), 96.6 (s, C1,β), 92.6 (s, C1,α), 77.8 to 60.7 (C2-C6), 26.7 (s, TBDPS-O, 4° C.), 19.1 (s, TBDPS-O), 19.0 (s, TBDPS-O)].
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[NH:4][CH:3]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[C:32]([N:14]2[CH2:13][CH2:12][N:11]([C:9]3[C:8]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:7][N:6]=[C:5]4[NH:4][CH:3]=[C:2]([CH3:1])[C:10]=34)[CH2:16][CH2:15]2)=[O:33])=[CH:37][CH:38]=1
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Reaction time: 5 h
Yield: 37.3 %

Procedure:
3-Methyl-5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.14 mmol, see Example 15), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0451 g, 0.151 mmol), HOBT-H2O (0.0293 g, 0.192 mmol) and EDCI (0.0341 g, 0.178 mmol) were placed in DCM (5 mL) at room temperature. DIEA (d 0.742; 0.119 mL, 0.684 mmol) was then added, and the reaction was stirred for 5 hours. The reaction was then poured into saturated Na2CO3 and extracted into DCM. The reaction was then dried, filtered, concentrated, and purified (500:5 DCM:MeOH) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.030 g, 38.1% yield).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[N:13]3[N:14]=[C:15]([N:18]=[CH:19]OCC)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[N+:1]([C:4]1[O:8][C:7]([C:9]2[N:13]3[N:14]=[C:15]([N:18]=[CH:19][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC=Nc1ccc2nnc(-c3ccc([N+](=O)[O-])o3)n2n1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(C=Nc2ccc3nnc(-c4ccc([N+](=O)[O-])o4)n3n2)CC1
Reaction time: 0.25 h

Procedure:
0.9 g. 3-(5-nitro-2-furyl)-6-(ethyoxymethyleneamino)-s-triazolo[4,3-b]pyridazine were dissolved in 20 ml. hot dioxan and mixed, while stirring, with 0.6 g. N-methyl-piperazine at 50°C. After 15 minutes, the crystals formed were filtered off with suction and recrystallized from 15 ml. of a mixture of 70% dioxan and 30 ml. dimethyl formamide. There was thus obtained 0.77 g. 3-(5-nitro-2-furyl)-6-(4-methyl-1-piperazinyl methyleneamino)-s-triazolo[4,3-b]pyridazine, which had a melting point of 247° - 248°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](O)=[O:18].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([F:13])[CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cc1F
Yield: 90.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 3-fluoro-4-methoxybenzoic acid (311 mg, 1.83 mmol), BOP—Cl (0.465 g, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide (300 mg, 90% yield) as a solid. LCMS (APCI+) m/z 381.9, 383.9 (M+H)+, Retention time=3.23 minutes (Method 2).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[NH:10])OC)=[CH:5][C:4]=1[CH3:13].CO[CH:16](OC)[CH2:17][NH2:18].Cl.OS(O)(=O)=O>CO.O.[OH-].[Na+]>[Br:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]2[NH:18][CH:17]=[CH:16][N:10]=2)=[CH:5][C:4]=1[CH3:13]
Reactant: COC(=N)c1ccc(Br)c(C)c1
Reactant: COC(CN)OC
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ncc[nH]2)ccc1Br
Reaction time: 36 h
Yield: 29.9 %

Procedure:
Methyl 4-bromo-3-methylbenzimidate hydrochloride (D87, 5.0 g; 21.9 mmol) was dissolved in methanol (30 ml) and stirred during the addition of a solution of 2-aminoacetaldehyde dimethyl acetal (2.4 ml; 21.9 mmol) in methanol (10 ml) over 30 minutes. Stirring was continued for 36 hours and evaporated in vacuo to yield an orange gum (7 g crude). This crude hydrochloride was treated with conc. H2SO4 (12 ml) at 5°, the heated at 50° for 10 minutes. The solution was cooled in ice, diluted with H2O and basified with 10% NaOH. The aqueous solution was extracted with chloroform (4 times) and the organics combined, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash silica gel chromatography eluting with 1% MeOH/CHCl3 to yield the title compound as a white solid (1.55 g; 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:39])[N:13]2[C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:38].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:39])[N:13]2[C:31]1[C:32]([Cl:38])=[CH:33][CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccc2c(-c3ccccc3Cl)nc(C3CCNCC3)cc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 mg of tert-butyl 4-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl]piperidine-1-carboxylate in 5 mL of CH2Cl2 was added 2 mL of trifluoroacetic acid. The mixture was stirred at rt for 1 h, then concentrated. The residue was dissolved in 10 mL of CH2Cl2, washed with 5 mL NaHCO3, dried (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH, followed by preparative HPLC (YMC C18 20×50 mm column; 10:90 to 100:0 v/v acetonitrile/water+0.1% TFA over 5 min; 20 mL/min) to yield the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14]C(=O)C)(=[O:3])[CH3:2].[Li+].[OH-].Cl>CO.CCOC(C)=O>[OH:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1OC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 99.5 %

Procedure:
Acetic acid 2-acetylamino-5-nitro-phenyl ester (416) (21 g, 88.2 mmol) was suspended in MeOH (185 mL) and 2M aqueous LiOH (185 mL) was added. An instantaneous reaction occurred, the solution turned red, everything dissolved and a slight exothermic reaction was felt by the warmth of the flask. TLC (Rf: 0.55 compared to Rf: 0.45 for compound 416 in EtOAc) after 10 minutes indicated complete hydrolysis. Addition of 1.0 M aqueous HCl (500 mL) caused the color to fade and a precipitate to form. Collection of the precipitate via vacuum filtration followed by rinsing with water (2×100 mL) and drying under high vacuum for 16 h gave the desired product (417) as a yellow powder. (17.2 g, 87.8 mmol, 99.5% yield). LC-MS was inconclusive. The product was used in the next step without further characterization
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])[CH2:4][CH2:3]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>C(O)C>[ClH:1].[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][N:2]2[CH2:3][CH2:4][CH:5]([CH:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:17])[CH2:6][CH2:7]2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=C1c2ccccc2CC1C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2CC1C1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A mixture of 0.46 g (0.00183 mol) of 2-(4-piperidyl)-1-indanone hydrochloride, 0.578 g (0.00251 mol) of p-nitrophenethyl bromide, 0.422 g (0.00502 mol) sodium bicarbonate and 20 mL of ethanol was stirred and refluxed for 72 hours. The ethanol was removed by evaporation, and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with water, dried over magnesium sulfate, filtered, and the ethyl acetate removed. The residue was purified by chromatography on silica gel using 2.5% methanol in chloroform as an eluant. Evaporation of the solvent gave a crystalline product that was converted to a hydrochloride salt. Recrystallization from ethanol gave 2-[1-(4-nitrophenethyl)-4-piperidyl]-1-indanone hydrochloride, mp 259°-261° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]O)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.CCN(S(F)(F)[F:37])CC.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:37])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCCCCO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCCCCF)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a suspension of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-[(6-hydroxyhexyl)oxy]phenyl}-1H-1,2,3-triazole-4-carboxamide (0.14 g) obtained in Example 183 in dichloromethane (10 ml) was added DAST (0.10 ml) at −78° C. The reaction mixture was slowly allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound as a white powder (0.02 g, 15%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:24]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1Cc2c(-c3nc(CNCc4ccccc4)no3)ncn2-c2ccccc2C1=O

Procedure:
0.93 g (3 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight with 0.51 g (3 mmol) of benzyl bromide and 0.52 g (4 mmol) of N-ethyldiisopropylamine in 10 ml of methylene chloride. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 6/1 there was obtained 3-(3-benzylaminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride (0.25 g: 17%) of m.p. 195°-198°.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[C:19]1([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:11]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)N1CCC(c2cn(-c3ccccc3)c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(-n2cc(C3CCNCC3)c3ccccc32)cc1
Yield: 69.1 %

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)-1-phenylindole (5.0 g) and 2N aqueous sodium hydroxide solution (30 ml) in ethanol (30 ml) was refluxed for 7.5 hours. Then, 2N aqueous sodium hydroxide (30 ml) was further added and the mixture was refluxed for another 5 hours. Ethanol was then distilled off and the oily residue was extracted with a mixture of chloroform and methanol (30:1 V/V). The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on alumina (500 g) and elution was carried out with a mixture of chloroform and methanol (100:1 to 5:1 V/V). The fractions containing the desired compound were combined and the solvent was distilled off under reduced pressure to give 1-phenyl-3-(4-piperidyl)indole (3.0 g). The following physical data are those of the hydrochloride.