Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[Cl:13].[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:13][C:4]1[C:5]([F:12])=[C:6]([O:9][CH2:10][CH3:11])[CH:7]=[CH:8][C:3]=1[C:28]1([OH:31])[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C@H:20]2[CH2:19][CH2:18][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:22][CH2:21]2)[CH2:30][CH2:29]1
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Reactant: CCOc1ccc(Br)c(Cl)c1F
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CCC2CCC(O)(c3ccc(OCC)c(F)c3Cl)CC2)CC1
Temperature: 43 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
1.0 g of well dried magnesium and 30 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 10.0 g of 1-bromo-2-chloro-4-ethoxy-3-fluorobenzene (6) dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 43 to 51° C., followed by stirring for 30 minutes. Thereafter, 21.2 g of 4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanone (7) dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 55° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 16.4 g of 1-(2-chloro-4-ethoxy-3-fluorophenyl)-4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanol (8). The resulting compound (8) was a yellow solid matter.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.[CH3:17][N:18](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[Zn+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:17]#[N:18])[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(Cl)n1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(C#N)n1
Temperature: 130 °C

Procedure:
Dissolve (S)-2-sec-butylamino-6-chloro-isonicotinic acid methyl ester (800 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium (0) (120 mg, 0.13 mmol), 1,1′-bis(diphenylphosphino)ferrocene (146 mg, 0.26 mmol), zinc dust (52 mg) and zinc (II) cyamide (387 mg, 3.3 mmol) in N,N-dimethylacetamide (6.6 mL)) in a previously nitrogen-filled sealed vessel. Flush the reactants with nitrogen before sealing and heat for 6 h at 130° C. Cool to room temperature, dilute with ethyl acetate and wash with 2 N ammonium hydroxide. Wash the organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 05:95 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: C([O-])C.[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([CH3:9])=O.[F:14][C:15]([F:41])([F:40])[C:16]1[CH:17]=[C:18]([NH:22][N:23]=[C:24](OS(C2C=CC(C)=CC=2)(=O)=O)[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:20][CH:21]=1>C(O)C.CCOC(C)=O>[CH2:12]([O:11][C:5]([C:6]1[C:24]([C:25]([F:26])([F:27])[F:28])=[N:23][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:40])([F:41])[F:14])[CH:17]=2)[C:7]=1[CH3:9])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OC(=NNc2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1 h

Procedure:
A solution of sodium ethanolate 21% (in ethanol, 0.75 ml, 2 mmol) was added to ethyl acetoacetate (0.25 ml, 1.97 mmol) in 3 ml ethanol at 0° C. After 1 h at 0° C., a solution of (2Z or E)-1-[3-(trifluoromethyl)phenyl]-2-(2,2,2-trifluoro-1-{[(4-methylphenyl)sulfonyl]-oxy}ethylidene)hydrazine (254 mg, 0.60 mmol) in 5 ml ethanol was added. Stirring was continued for 18 h at room temperature and then the yellow solution was diluted with EtOAc washed with water and brine. The combined organic layers were dried over magnesium sulfate and evaporated. Column chromatography (EtOAc:n-heptane 1:3) delivered the title compound as light yellow solid (107 mg, 48%). MS: 367.3 (MH+).
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].[Li]CCCC.C(NC(C)C)(C)C.[O:21]1[C:25](=[O:26])[CH2:24][C@H:23]2C=C[CH2:29][C@@H:22]12.CI>C1COCC1>[CH3:23][C@H:24]1[C:25](=[O:26])[O:21][C@@H:22]2[CH2:29][CH:7]=[CH:5][C@H:6]12
Reactant: O=C1C[C@H]2C=CC[C@H]2O1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H]1C(=O)O[C@@H]2CC=C[C@@H]21
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of lithium diisopropylamide, prepared by adding nBuLi (2.5 M sol. in hexanes, 1.36 mL, 3.39 mmol) to diisopropylamine (477 μL, 3.39 mmol) in THF (15 mL) at 0° C., was added a pre-cooled solution of known (3aS,6aR)-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one (+)-115 (350 mg, 2.82 mmol) in THF (5 mL+3 mL rinse) at −78° C., dropwise. The reaction mixture was stirred at this temperature for 30 min, then methyl iodide (352 μL, 5.65 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 6 h. The reaction mixture was quenched with 2 M aqueous HCl. The aqueous phase was extracted with Et2O (×3). The combined organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexanes/Et2O (5:1) to yield lactone 116 (369 mg, 95%) as a brown oil. TLC: Rf=0.54 (hexanes/EtOAc=2:1); [α]D20+54.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 5.74 (m, 1H), 5.59 (m, 1H), 5.12 (t, J=5.6 Hz, 1H), 3.13 (dd, J=3.8, 1.8 Hz, 1H), 2.65 (m, 2H), 2.52 (q, J=7.6 Hz, 1H), 1.33 (d, J=7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 180.0, 130.9, 129.4, 81.3, 53.8, 39.9, 39.2, 17.4.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([NH2:24])[CH3:23])=[N:20][CH:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([NH:24][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)[CH3:23])=[N:20][CH:21]=1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: C[C@@H](N)c1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-isopropylphenylacetic acid (0.356 g, 2.000 mmol), (1R)-1-(5-bromopyridin-2-yl)ethanamine hydrochloride (0.475 g, 2.000 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.383 g, 2.000 mmol), and 1-hydroxy-7-azabenzotriazole (0.272 g, 2.000 mmol) in 15.0 ml of CH2Cl2 was added slowly triethylamine (0.836 ml, 6.000 mmol). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (0-80% EtOAc/Hex) gave N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.503 (d, J=2.20 Hz, 1H); 7.740 (dd, J=2.20 Hz, J=8.30 Hz, 1H); 7.207 (d, J=8.30 Hz, 2H); 7.182 (d, J=8.30 Hz, 2H); 7.102 (d, J=8.30 Hz, 1H); 6.591 (br d, J=7.08 Hz, 1H); 5.094 (dq, J=7.08 Hz, 1H); 3.571 (d, J=15.87 Hz, 1H); 3.536 (d, J=16.11 Hz, 1H); 2.907 (sept, J=6.83 Hz, 1H); 1.391 (d, J=6.59 Hz, 3H); 1.254 (d, J=6.83 Hz, 6H); MS (Electrospray): m/z 361.0 (M+H).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1cccc[nH]1
Reactant: Ic1ccccc1
Product: O=c1ccccn1-c1ccccc1
Yield: 82 %

Procedure:
Following substantially the procedure of Example 1, 2-(1H)-pyridone is condensed with iodobenzene to give the 1-phenyl-2-(1H)-pyridone in 82% yield as a crystalline white product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][N:14](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]#[N:14])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1I
Reactant: CN(C)C=O
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]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 80 °C
Yield: 63 %

Procedure:
Add 4-chloro-1-iodo-2-trifluromethylbenzene (1500 mg, 4.89 mmol), zinc cyanide (345 mg, 2.94 mmol), and tetrakis(triphenylphosphine)palladium(0) (564 mg, 0.488 mmol) to anhydrous N,N-dimethylformamide (40 mL). Heat to 80° C. overnight. Cool to room temperature, dilute with toluene, wash with 2 N ammonium hydroxide (3×), saturated aqueous sodium chloride, dry, filter, concentrate to give a residue. Chromatograph the residue on silica gel eluting with hexanes/dichloromethane, to give 4-chloro-2-trifluoromethylbenzonitrile (630 mg, 63%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.67 (dd, 1H, J=8.4, 2.4 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C[Al](C)C.C([O:14][C:15]([C:17]1[S:21][C:20](/[CH:22]=[CH:23]/[C:24]2[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:26][O:27][C:28]=2[CH3:29])=[N:19][CH:18]=1)=O)C>O1CCOCC1.C1(C)C=CC=CC=1>[O:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:15]([C:17]2[S:21][C:20](/[CH:22]=[CH:23]/[C:24]3[C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:26][O:27][C:28]=3[CH3:29])=[N:19][CH:18]=2)=[O:14])[CH2:3][CH2:4]1
Reactant: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Reactant: NC1CCOCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NC2CCOCC2)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a stirred solution of 4-aminotetrahydropyran (123 mg, 1.22 mmol) in dioxane (3 mL) under argon and at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 mmol). After 1 h, a solution of 2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester (50 mg, 0.15 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. for 3 h. The reaction mixture was then cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 2.5% methanol in dichloromethane) gave the title compound (34 mg, 59%) as a white solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:9]=[C:10]([NH2:12])[N:11]=2)[C:7]=1[CH3:8].Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:9]=[C:10]([NH:12][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1c(Br)ccc2nc(N)nn12
Agent: Cl
Product: Cc1c(Br)ccc2nc(NC(=O)c3cccnc3)nn12

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 6-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A8), 4.0 g; 17.62 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (3.76 g; 21.1 mmol; 1.2 eq.) as a yellow solid (4.53 g; 77%). 1H NMR (DMSO-d6) δ 11.54 (s, 1H), 9.13 (d, J=2.3 Hz, 1H), 9.78 (dd, J=4.9, 1.5 Hz, 1H), 8.34 (dt, J=7.9, 1.8 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.63-7.54 (m, 2H), 2.8 (s, 3H). HPLC, Rt: 1.75 min. (purity 98.8%). LC/MS, M+(ESI): 334.2. CHN analysis: [C13H10N5OBr.1.0H20] Corrected: C, 44.59%; H, 3.45%; N, 20.00%. Found: C, 44.68%; H, 3.41%; N, 19.97%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1CCN(Cc2ccccc2)CC1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(OCCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a solution of 1.5 g (6.84 mmol) of 1-benzyl-4-(2-hydroxy-1-ethyl)piperidine (Acros Chemical), 3.8 g (34.2 mmol) of 4-fluorophenol and 3.6 g (13.7 mmol) of triphenylphosphine in 25 mL of ether at 0° C. was slowly added dropwise 2.15 mL (13.7 mmol) of diethylazodicarboxylate (DEAD). The reaction mixture was allowed to warm to rt and was stirred for 12 h. To the reaction mixture was added 70 mL of ether and it was filtered through a thin pad of celite. The filtrate was washed with sat'd Na2CO3 solution and sat's NaCl solution. It was dried over MgSO4, filtered and the filtrate concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 4:1) to give 0.85 g of the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:29]([Cl:31])=[O:30].O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:29]([Cl:31])=[O:30])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3)CC2)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3C(=O)Cl)CC2)CC1
Temperature: 0 °C

Procedure:
Solution prepared by dissolving 25.5 g of (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzene in 200 ml of methylene chloride was cooled to 0° C., and 24 g of aluminum chloride was added to the solution and stirred. To the solution was added dropwise little by little 21.5 g of oxalyl chloride, and its temperature was raised to room temperature and stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 200 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 18 g of (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzoylchloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][Br:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cc(Cl)ccc2n1C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(CBr)cc2cc(Cl)ccc21
Temperature: 80 °C

Procedure:
A solution containing 5-chloro-2-methyl-indole-1-carboxylic acid tert-butyl ester (3.0 g, 11.3 mmol), NBS (1.33 g, 11.3 mmol), and benzoyl peroxide (0.4 g, 1.13 mmol) in CCl4 (100 mL) is heated at 80° C. for 3 hours. An additional portion of NBS (0.65 g, 5.65 mmol), and benzoyl peroxide (0.2 g, 0.56 mmol) is then added and the reaction mixture is heated for an additional 3 hours. After cooling to ambient temperature, the reaction mixture is filtered. The filtrate is concentrated to a brown oil which is triturated with hexane to remove residual succinimide, filtered, and concentrated. The resultant oil (4.5 g, >100%) is used directly in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ1.72 (s, 9H), 4.88 (s, 2H), 6.63 (s, 1H), 7.27 (dd, J=9.0, 2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H) ppm; MS (EI): m/z 343 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]N2C(=O)CCC2=O)=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>CN(C=O)C>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:11][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc1
Reactant: NCCCC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCC(=O)NCCCC(=O)O)cc1
Reaction time: 16 h
Yield: 75.6 %

Procedure:
4-[10-(2,5-Dioxopyrrolidin-1-yloxycarbonyl)decyl]benzoic acid tert-butyl ester (300 mg, 0.65 mmol) was dissolved in DMF (3 ml) and 4-amino butyric acid (67 mg, 0.65 mmol). The mixture was stirred for 16 h under nitrogen. The solvent was removed under vacuum and AcOEt (35 ml) was added. The solution was washed with 0.2 N HCl and water (15 ml each). Sat. NaHCO3 was added (not intended) to the organic phase. DCM (50 ml) was added. Some of the organic phase was removed and DCM (100 ml) was added to the aqueous phase and allowed to stand overnight. The mixture was cooled on ice and the pH was adjusted to 1.9 with 4N HCl. The organic phase was isolated, dried over MgSO4 and concentrated under vacuum to yield on oil (220 mg, 76% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCCC1)([O:17][C:18](C)(C)[CH3:19])=O>>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:19][CH2:18][OH:17])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC[C@@H]1CCO

Procedure:
This compound is prepared in a manner analogous to that described in Example 3, but 1-Boc-hexahydroazepine is used insead of 1-Boc-pyrrolidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH:11]=[CH:12][C:6]=2[NH:5][CH:4]([CH2:23][C:24]([O:26]C)=[O:25])[C:3]1=[O:28].[OH-].[Na+]>CO>[CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH:11]=[CH:12][C:6]=2[NH:5][CH:4]([CH2:23][C:24]([OH:26])=[O:25])[C:3]1=[O:28]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3cccnc3)cc2CN(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1Cc2cc(C(=O)NCc3cccnc3)ccc2NC(CC(=O)O)C1=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of methyl (±)-4-methyl-3-oxo-7-[[[(3-pyridinyl)methyl]amino]-carbonyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (161.7 mg, 0.42 mmol), 1.0 N NaOH (1.3 mL, 1.3 mmol), and MeOH (4.2 mL) was stirred at 40° C. for 3 h, then at RT overnight The resulting solution was concentrated, and the residue was dissolved in H2O and CH3CN. The solution was acidified to pH 1 with TFA and was concentrated. The residue was crystallized from H2O to afford the title compound as an off-white, crystalline solid (120.9 mg, 60%): HPLC k′ 5.7 (PRP-1®, 8% CH3CN/H2O-0.1% TFA); 1H NMR (250 MHz, DMSO-d6) δ8.60-8.83 (m, 3H), 8.15 (br d, J=8.0 Hz, 1H), 7.75 (dd, J=7.9, 5.3 Hz, 1H), 7.49-7.60 (m, 2H), 6.56 (d, J=9.1 Hz, 1H), 6.38 (br s, 1H), 5.49 (d, J=16.5 Hz, 1H), 5.01-5.16 (m, 1H), 4.37-4.65 (m, 2H), 3.82 (d, J=16.5 Hz, 1H), 2.92 (s, 3H), 2.77 (dd, J=16.7, 9.0 Hz, 1H), 2.61 (dd, J=16.7, 4.9 Hz, 1 H, partially obscured by the residual solvent signal); MS (ES) m/e 369.0 (M+H)+. Anal. Calcd for C19H20N4O4.CF3CO2H: C, 52.29; H, 4.39; N, 11.61. Found: C, 52.45; H, 4.40; N, 11.56.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]34[CH2:23][C:20]([O:24]C)([CH2:21][CH2:22]3)[CH2:19][CH2:18]4)=[N:15][N:16]=2)[N:13]=1.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(C34CCC(O)(CC3)CC4)=NN=2)N=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]34[CH2:23][C:20]([OH:24])([CH2:21][CH2:22]3)[CH2:19][CH2:18]4)=[N:15][N:16]=2)[N:13]=1
Reactant: COC12CCC(c3nnc4cc(-c5ccc(Cl)cc5)c(-c5ccccc5Cl)nn34)(CC1)C2
Agent: OC12CCC(c3nnc4cc(-c5ccc(Cl)cc5)c(-c5ccccc5Cl)nn34)(CC1)CC2
Product: OC12CCC(c3nnc4cc(-c5ccc(Cl)cc5)c(-c5ccccc5Cl)nn34)(CC1)C2
Yield: 79.8 %

Procedure:
The title compound (36 mg, 79%) as a light yellow foam was prepared from 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(4-methoxybicyclo[2.2.1]heptan-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 17) (47 mg, 0.1 mmol) according to the procedures described for 4-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)bicyclo[2.2.2]octan-1-ol (Example 30). HPLC/MS (method A): retention time=3.60 min, (M+H)+=451.2.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with [1,4]-diazepan-5-one (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C34H40Cl2N5O3 [(M+H)+] 636.2503, observed 636.2504.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].S([O-])([O-])(=O)=O.[Mg+2:10]>C(=O)=O>[C:1](=[O:2])([O-:4])[OH:3].[Mg+2:10].[C:1](=[O:2])([O-:4])[OH:3]
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=C([O-])O

Procedure:
When the water-containing fibrous basic magnesium sulfate particles are dried in a drying oven, the CO2 gas present in the oven is dissolved in the water portion of the water-containing fibrous basic magnesium sulfate particles to produce carbonate ions. Further, the water portion in which CO2 gas is dissolved turns acidic. In the acidic water portion, Mg ions are released from the fibrous basic magnesium sulfate particles. The carbonate ion and Mg ion in the water portion are considered to form together magnesium hydrogen carbonate [Mg(HCO3)2], which is deposited in the form of a carbonate such as magnesium carbonate or basic magnesium carbonate.