Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=1)([CH3:9])[CH3:8].CI>CC(C)=O>[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][CH3:1])=[O:17])[CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccn(CC(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)Cn1ccc(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
Potassium carbonate (298 mg, 2.15 mmol) was added to a solution of 2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 1.07 mmol) in acetone at 0° C. and the reaction was stirred at 0° C. for 15 min. Methyl iodide (0.13 mL, 2.15 mmol) was added at 0° C. and the mixture refluxed for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina by using 1-2% ethyl acetate in petroleum ether as eluent afforded methyl 2-(3-Isopropylpyrrol-1-yl)acetate (135 mg, 69%) as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[OH:11][C:12]([CH3:27])([CH3:26])[CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:14][CH2:13][C:12]([CH3:27])([OH:11])[CH3:26])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(C)c1OCCC(C)(C)O
Temperature: 80 °C
Yield: 70 %

Procedure:
4-Bromo-2,6-dimethylphenol (2.00 g, 9.95 mmol), toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (Intermediate 10, 2.83 g, 10.9 mmol) and potassium carbonate (1.01 g, 10.9 mmol) are combined in N,N-dimethylformamide (50 mL) and heated at 80° C. for 24 hours. The mixture is cooled, poured into water and extracted with diethyl ether. The organic phase is dried and the solvent removed. The residue is purified by flash chromatography (0-50% ethyl acetate in cyclohexane) to give the title compound (Yield 2.00 g). GC (METHOD 1): tR=11.26 min; Mass spectrum (EI+): m/z=286/288 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:26]=[C:12]2[C:13]([NH:17][C:18]3[CH:23]=[C:22](C)[N:21]=[C:20](C)[N:19]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1.[Cl:27]C1C2=CN(C3C(Cl)=CC=CC=3Cl)N=C2C=CN=1.NC1C=C(Cl)N=CN=1>>[Cl:27][C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:13]2[C:12]3=[CH:26][N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:10]=[C:11]3[CH:16]=[CH:15][N:14]=2)[CH:23]=1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(C)n1
Agent: Nc1cc(Cl)ncn1
Product: Clc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 57 %

Procedure:
Following the procedure described above for [2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]-(2,6-dimethylpyrimidin-4-yl)amine, 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine and 4-amino-6-chloropyrimidine were reacted to afford the title compound as a yellow solid (244 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (br s, 1H), 9.15 (s, 1H), 8.76 (s, 1H), 8.70 (s, 1H), 8.04 (d, J=6.4 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.71 (t, J=8.1 Hz, 1H), 7.30 (d, J=6.4 Hz, 1H). LCMS (Method D): RT=2.40 min, m/z: 391 [M+H+].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH3:18])[C:3]=1[CH3:19].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]2[CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:4]([CH3:18])[C:3]=1[CH3:19]
Reactant: Cc1c(I)ccc(N=C2NC3(CCCC3)CS2)c1C
Reactant: BrC1CCCC1
Product: Cc1c(I)ccc(N=C2SCC3(CCCC3)N2C2CCCC2)c1C

Procedure:
4-Iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2,3-dimethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][OH:10].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][O:10][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: Cc1cccc(Cl)c1CO
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2Cl)c1
Reaction time: 4 h

Procedure:
A solution of (2-chloro-6-methylphenyl)methanol (Step A, 3 g, 19.1 mmol) and diisopropyl azodicarboxylate (DIAD, 4.13 ml, 21 mmol) in THF (20 ml) was added drop wise to a solution of ethyl 2-(3-hydroxyphenyl)acetate (3.79 g, 21 mmol) and triphenylphosphine (5.48 g, 21 mmol) in THF (30 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 4 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 2:1) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:27]S(O)(=O)=O>C(Cl)Cl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:27])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)O
Reactant: O=C(O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Yield: 71 %

Procedure:
A solution of 70.0 g (0.22 mol) of 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylic acid (Example 1), 35.2 g (1.1 mol) of methanol, 350 mL of methylene dichloride, and 0.5 mL of methanesulfonic acid was heated under reflux for 21 h. The reaction mixture was cooled, washed with water, dried over sodium sulfate, concentrated in vacuo, and crystallized from ethyl acetate:hexane to give 51.8 g (71%) of methyl 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylate in two crops: m.p. 175°-177° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7](P(OC)(OC)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[O:31][CH:30]=[N:29][C:28]=1[CH:32]=O)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([C:7]([NH:8][C:9](=[O:10])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:32][C:28]1[N:29]=[CH:30][O:31][C:27]=1[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ocnc1C=O
Reactant: COP(=O)(OC)C(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=Cc1ncoc1C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 47.2 %

Procedure:
To a solution of N-(tert-Butoxycarbonyl)-α-dimethylphosphonoglycine-tert-butyl ester (11.8 g, 34.68 mmol) and 5-tert-butyloxazole-4-carboxaldehyde (6.9 g, 45.08 mmol) in DMF (50 mL) was added Cs2CO3 (12.4 g, 38.15 mmol) under an argon atmosphere at room temperature. The reaction mixture was stirred for 14 h at room temperature. After removal of solvent in vacuo, the residue was dissolved in AcOEt, successively washed with 10% citric acid, 5% NaHCO3 and saturated NaCl for three times, dried over Na2SO4, and concentrated in vacuo. The residual oil was purified by a silica gel column chromatography to yield 6.0 g (47%) of title compound as a white solid: mp 170-172° C.; 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 6.55 (s, 1H), 1.54 (s, 9H), 1.49 (s, 9H), 1.38 (s, 9H); HRMS (EI): m/z 366.2159 (M+) (calcd for C19H30N2O5: 366.2154).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.C(=O)([O-])O.[Na+].O.[Br:20][CH:21]([CH2:25][CH2:26][CH2:27][Br:28])[C:22](Cl)=[O:23]>C(OCC)(=O)C>[Br:20][CH:21]([CH2:25][CH2:26][CH2:27][Br:28])[C:22]([NH:2][C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)=[O:23]
Reactant: Nc1cc2c(cc1O)CCCC2
Reactant: O=C(Cl)C(Br)CCCBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2c(cc1O)CCCC2)C(Br)CCCBr
Reaction time: 0.5 h

Procedure:
To a mixture of 3-amino-5,6,7,8-tetrahydro-2-naphthol hydrobromide (1.70 g), sodium hydrogencarbonate (1.46 g), ethyl acetate (15 ml) and water (10 ml) was added under ice-cooling while stirring a solution of 2,5-dibromovaleryl chloride (1.94 g) in ethyl acetate (6 ml). The whole mixture was stirred for further 30 minutes. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer was washed with an aqueous saline. solution, then dried (MgSO4), followed by distilling off the solvent to obtain 3-(2,5-dibromovaleryl)amino-5,6,7,8-tetrahydro-2-naphthol. This compound was dissolved in dimethylformamide (20 ml). To the solution was added powdery potassium carbonate (1.2 g), and the mixture was stirred at room temperature for 1.5 hour. To the resultant was added water, and precipitated crystals were collected by filtration, washed with water and dried, followed by recrystallization from ethyl acetate to obtain 1.53 g (67.8%) of 2-(3-bromopropyl)-6,7,8,9-tetrahydro-2H-naphtho [2,3 -b][1,4]oxazin-3(4H)-one as crystals, m.p. 139°-140° C. This compound was found to be identical with the product obtained in Reference Example 7.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9].O.[NH2:39][NH2:40].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CO.O>[F:36][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH3:21])[NH:40][N:39]=2)[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Reactant: NN
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CO
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(c2cc(C)[nH]n2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a mixture of N-(3,5-Bis-trifluoromethyl-benzyl)-N-[8-chloro-1-(3-oxo-butyryl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (0.13 mmol, 72 mg), hydrazine hydrate (1.3 mmol, 40.0 μL) in MeOH (2 mL) was added P4O10 (0.5 g) at room temperature. The resulting suspension was stirred vigorously at 70° C. for 12 h. After completion, the mixture was diluted with water (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated to dryness. Flash chromatography (EtOAc-Hexane as eluent 1:1) afforded the title compound as viscous foam; Rf 0.28 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 545 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
To a stirred solution of tert-butyl 4-(2-hydroxyphenyl)-piperazine 20 (1 g, 0.0035 mol.) and cesium carbonate (2.34 g, 0.0071 mol.) in 5 mL of DMF anhydrous was added a solution of ethyl 4-bromobutanoate (6a) at rt. The resulting mixture was heated at 70° C. overnight (12 h). The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was complete, the reaction mixture was diluted with 25 mL of ethyl acetate and filtered to remove cesium carbonate. The filtrate was washed with saturated aqueous NaHCO3 solution, dried over Na2SO4 and evaporated to give tert-butyl 4-(2-(4-ethoxy-4-oxobutoxy)phenyl)-piperazine-1carboxylate 21a which was purified by silica gel chromatography using a gradient elution of ethyl acetate and hexane. Colorless oil (1.1 g, 78%). 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=6.4 Hz, 3H); 1.45 (s, 9H); 2.14 (q, J=7.2 Hz, 2H); 2.53 (t, J=7.2Hz, 2H); 3.00 (br s, 4H); 3.58 (br s, 4H); 4.04 (t, J=6.4 Hz, 2H); 4.12 (q, J=6.4 Hz, 2H); 6.84-6.97 (m, 4H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)N[C@@H](CO)[C@@H](O)c2ccccc2)cc1
Yield: 18.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 5.7 g of (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol, 5 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 250 ml of benzene, 250 ml of absolute methanol and 4.34 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained having an Rf=0.27 (thin layer chromatography over silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[O:38][C:37](=[O:39])[CH2:36][C:35](=[O:40])[CH2:34]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[O:38][C:37](=[O:39])[CH:36]([CH2:7][C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[C:35](=[O:40])[CH2:34]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cn1ccnc1C=O
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nccn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 1-methyl-1H-imidazole-2-carbaldehyde was substituted in place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (CDCl3): δ 1.44-1.70 (bm, 8H), 2.0 (m, 2H), 2.20 (m, 3H), 2.30 (m, 2H), 2.99 (m, 2H), 3.01 (M. 2H), 3.46 (s, 3H) 3.78 (m, 1H), 3.89 (s, 3H), 6.72 (d, J=2.15 Hz, 1H), 6.83, (d, J=2.15 Hz, 1H), 6.90 (s, 1H), 7.14, (d, J=3.07 Hz, 1H), 7.24 (d, J=3.06 Hz, 1H). Anal. Calcd. For C25H31O3N2Cl: C, 67.78; H, 7.05; N, 6.32. Found: C, 67.48; H, 7.25; N, 6.37.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([F:27])=[CH:29][CH:30]=2)=[O:39])[CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(CC(N)C(O)c2ccc(F)cc2)cc(OC(F)(F)C(F)F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: Cc1cc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (197 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (234 mg, 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2].[CH2:26]([NH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH3:28]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:29]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH2:26][CH2:27][CH3:28])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: CCCNCC1CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Product: CCCN(Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-nitro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with propyl(cyclopropylmethyl)-amine to give 8-nitro-1-[[(cyclopropylmethyl)propylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 35 8-Fluoro-1-[[(cyclopropylmethyl)ethylamino]methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].O>[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:15][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ncc(Br)cc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a 20 mL scintillation vial, 5-bromo-3-iodo-2-methoxypyridine (Alfa Aesar, 2.02 g, 6.43 mmol), methanesulfonamide (Fluka, 0.645 g, 6.78 mmol), copper (I) iodide (Strem, 0.122 g, 0.643 mmol), cesium carbonate (Aldrich, 5.27 g, 16.1 mmol) and water (0.60 ml, 33.3 mmol) were mixed into DMF (6 mL). The reaction mixture was stirred at 105° C. for overnight. Then the mixture was heated in a microwave reactor (Biotage) at 120° C. for 30 min. The reaction mixture was partitioned between Tris-HCl buffer (1 M, pH 7.0) (20 mL) and EtOAc (20 mL). The aq phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aq NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (100 g, eluent: EtOAc in hexanes 0% to 50%) to afford N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (1.06 g, 59% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.97 (d, J=2.19 Hz, 1H) 7.90 (d, J=2.19 Hz, 1H) 6.72 (br. s., 1H) 4.00 (s, 3H) 3.04 (s, 3H). m/z (ESI, positive ion): 280.8, 282.8 [M+1, M+3].
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3][S:2]1.Cl.[CH3:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][NH2:15].P(C#N)(OCC)(OCC)=O>CN(C)C=O.O1CCCC1>[S:1]1[CH2:5][CH:4]([C:6]([NH:15][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:16])=[O:8])[CH2:3][S:2]1
Reactant: COC(=O)CCN
Reactant: O=C(O)C1CSSC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)C1CSSC1
Yield: 9.4 %

Procedure:
The reaction was carried out as described in Example 97, but using 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, 5 ml of anhydrous tetrahydrofuran, 1.01 ml of torethylamine, 502 mg of β-alanine methyl ester hydrochloride and 0.55 ml of diethyl cyanophosphate. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 2:2 by volume mixture of ethyl acetate and hexane, to obtain 73 mg of the title compound as pale yellow crystals having an Rf value of 0.41 (silica gel thin layer chromatography; using a 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC>[Cl-].[Cl-].[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.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: C#CC(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)c1cc2ccc(F)cc2c(=O)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 5-fluoro-2-iodobenzoic acid (9.04 g, 34.0 mmol), but-3-yn-2-ol (5.7 mL, 5.46 g, 78.0 mmol), ZnCl2 (4.62 g, 34.0 mmol), Pd(Ph3P)4 (1.96 g, 1.7 mmol), Et3N (14.2 mL, 10.3 g, 102.0 mmol) and DMF (50 mL) was stirred under argon at 100° C. for 2 hours. After the removal of the volatiles under vacuum, the residue was chromatographed (silica gel, ethyl acetate in hexanes, 0-50%) to provide intermediate 7-fluoro-3-(1-hydroxyethyl)-1H-isochromen-1-one as a brown oil (5.93 g, 84%). MS m/z 209.2 [M+H]+; 1H NMR (500 MHz, CDCl3-d): 6 ppm 7.91-7.96 (1H, m), 7.43-7.47 (2H, m), 6.55-6.59 (1H, m), 4.67 (1H, q, J=6.52 Hz), 1.57 (3H, d, J=6.62 Hz).