Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[N:19][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:4]=2[CH:3]=1.[CH3:21][N:22]([CH2:27][C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]=1[CH3:33])[C:23](=[O:26])[CH:24]=[CH2:25].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][N:22]([CH2:27][C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]=1[CH3:33])[C:23](=[O:26])/[CH:24]=[CH:25]/[C:2]1[CH:20]=[N:19][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:4]=2[CH:3]=1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: CC(C)(C)OC(=O)N1CCCNc2ncc(Br)cc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C(=O)OC(C)(C)C)CCCN3)oc2ccccc12
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of tert-butyl 8-bromo-1,2,3,4-tetrahydropyrido[2,3-b][1,5]diazocine-5(6H)-carboxylate (45 mg, 0.13 mmol), N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (90 mg, 0.39 mmol) and (i-Pr)2EtN (0.11 mL, 0.66 mmol) in 3.75 mL of DMF:propionitrile (4:1) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (3.0 mg, 0.013 mmol) and P(o-tol)3 (8.0 mg, 0.026 mmol) then heated to 110° C. for 20 h. The hot mixture was filtered through a pad of celite and washed with ethyl acetate 2×20 mL. The filtrate was concentrated in vacuo to obtain crude brown oil product. The resulting crude product was subjected to prep HPLC purification to obtain pure product as an off-white solid. Yield 39 mg (60%); ESI MS m/z 491 [C28H34N4O4+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:33]([O:35][CH3:36])=[O:34])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: COC(=O)Cl
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.53 g, 1.53 mmol) and triethylamine (0.25 ml, 1.80 mmol) in dichloromethane (10 ml) at room temperature was added methyl chloroformate (0.14 ml, 1.80 mmol). The solution was stirred for 2 hours and then water added. The organic layer was separated, dried and evaporated to give a crude product, which was crystallized from ether. The crystalline material was then purified by chromatography on silica gel, eluting with acetone/dichloromethane (20/80) to give 0.33 g of 6-nitro-2,2-dimethyl-3-(methoxycarbonylamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 199° C.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[CH:21]=[C:20]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1.[Li]CCCC>C1COCC1>[C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[CH:21]=[C:20]1[F:40])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](C=C(I)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Tert-butyl((3aR,4R,6aR)-5-iodo-2,2-dimethyl-4,6a-dihydro-3H-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-4) (1.4 g, 2.7 mmol, 1 equiv) was dissolved in dry THF (18 mL) and N-fluorobenzenesulfonimide (1.0 g, 3.2 mmol, 1.2 equiv) was added. The resulting mixture was cooled to −78° C. and BuLi (3.2 mL, 8.0 mmol, 3 equiv, 2.5 M in hexanes) was added dropwise over 10 minutes. The mixture was stirred at the same temperature for 1 hour. Upon disappearance of the starting material, the reaction was quenched with the addition of 20 mL NH4Cl, extracted with EtOAc (3×20 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (80 g SiO2, 0-50% EtOAc in hexanes) to yield tert-butyl((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-5) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J=5 Hz, 2H); 7.75 (d, J=6.5 Hz, 2H); 7.35-7.44 (m, 6H); 5.27 (s, 1H); 4.77 (dd, J=6.0, 2.0 Hz, 1H); 4.39 (t, J=6.0 Hz, 1H); 4.46 (td, J=6.0, 2.0 Hz, 1H); 1.52 (s, 3H); 1.35 (s, 3H); 1.10 (s, 9H).
Reaction SMILES: C1(CCCCCCCCC2C=CC=CC=2C=O)C=CC=CC=1.[F:23][C:24]([F:39])([F:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][Mg]Br.CO[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[O:49][CH2:50][C:51]([CH3:54])([CH3:53])[N:52]=1>O1CCCC1>[F:23][C:24]([F:39])([F:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[O:49][CH2:50][C:51]([CH3:54])([CH3:53])[N:52]=1
Reactant: FC(F)(F)CCCCCCCCCCC[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: O=Cc1ccccc1CCCCCCCCc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCCCCC(F)(F)F)=N1

Procedure:
Following the procedures of Example 1(a), (b) and (c), 12,12,12-trifluorododecylmagnesium bromide (from 29.19 mmoles of 12,12,12-trifluorododecyl bromide and 25.71 mmoles of magnesium) was reacted with 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (20.17 mmoles) in tetrahydrofuran to give 2-[2-(12,12,12-trifluorododecyl)phenyl]-4,4-dimethyloxazoline. The oxazoline (14.39 mmoles) was converted to the methiodide salt and then reduced with sodium borohydride (13.43 mmoles) to yield the desired product as an oil.
Reaction SMILES: CO[CH:3]([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[SH:12][CH2:13]CCO>C1COCC1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>[C:4]1([CH:3]2[S:12][CH2:13][CH2:11][O:10]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCCS
Reactant: COC(OC)c1ccccc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C2OCCS2)cc1
Temperature: 25 °C
Yield: 105.8 %

Procedure:
To an oven-dried 250 mL flask fitted with a magnetic stirring bar and reflux condenser was introduced 0.4 g of Montmorillonite KSF, 1.65 g (10.8 mmol) of benzaldehyde dimethyl acetal in 35 mL of THF, followed by 1.0 g (10.8 mmol) of 3-mecapto-1-propanol in 5 mL of THF. The mixture was refluxed under nitrogen for 12 hours. After cooling to room temperature and filtered, the filtrate was washed with saturated NaHCO3 (2×20 mL), saturated NaCl (20 mL) and dried over MgSO4 (anhydrous). The solvent was evaporated; a chromatograph using silica gel [elution with Hexane/Et2O (70/30)] was obtained on the residue, yielding 1.9 g (97%) of 2-phenyl-1,3-oxathiolane. 1H-NMR (CDCl3): δ 1.74 (m, 1H), 2.11 (m, 1H), 2.82, (m, 1H), 3.22 (m, 1H), 3.81 (m, 1H), 4.35 (m, 1H), 5.80 (s, 1H), 7.36 (m, 3H), 7.49 (m, 2H). 13C-NMR (CDCl3): δ 25.73, 29.26, 70.74, 126.19, 128.46, 128.53, 139.52.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:15]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3c(C(N)=O)ncn23)c1

Procedure:
A mixture of 1.62 g. of 4-amino-5-imidazolecaboxamide hydrochloride, 3-dimethylamino-3'-methoxyacrylophenone, 0.82 g. of sodium acetate and 25 ml. of glacial acetic acid is refluxed for 10 hours. The mixture is evaporated to dryness and the residue worked up to give 4-(m-methoxyphenyl)imidazo[1,5-a]pyrimidine-8-carboxamide. This compound is treated as for Example 29 with trifluoroacetic anhydride to give the product of the example.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][CH:11]=1.C[Si]([C:20]#[N:21])(C)C.C(N(CC)CC)C>C(#N)C>[C:20]([C:7]1[C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:21]
Reactant: [O-][n+]1cccc(Oc2cccc(F)c2)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1Oc1cccc(F)c1

Procedure:
A mixture of 33.44 g of 3-(3-fluorophenoxy)pyridine N-oxide, 64.6 ml of trimethylsilyl cyanide and 45.9 ml of triethylamine in 180 ml of acetonitrile was refluxed for 4 hours. After the reaction mixture was concentrated, 200 ml of methylene chloride and 100 ml of 2M aqueous potassium carbonate was added to the residue and the mixture was stirred for a few minutes. The organic layer separated was washed with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated. The solid obtained was washed with isopropyl ether to yield 28.30 g of pale brown crystals, which were recrystallized from ethyl acetate to give slightly brown crystals, mp 92°-93° C.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.N([O-])=O.[Na+].B(F)(F)F.O1[CH2:25][CH2:24]OCC1>[H+].[B-](F)(F)(F)F.O.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([CH:24]=[CH:25][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:11]=[CH:10][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: O=c1[nH]c2ccc(C=Cc3ccccc3)cc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound obtained in Step B (1 g) is dissolved in HBF4 (10 ml) and the mixture is cooled to 0° C. 0.44 g of NaNO2 previously dissolved in water is then added and the reaction is stirred at 0° C. for 1 hour. The resulting precipitate is filtered off and washed with ether, ground with BF3 (4.5 mmol) and palladium acetate (0.2 mmol), and then placed under a nitrogen atmosphere before the addition of 15.1 ml of anhydrous dioxane. The reaction mixture is stirred for 5 hours at ambient temperature and then hydrolysis is carried out with 50 ml of water and extraction is carried out twice with 30 ml ether each time. The organic phase is dried over MgSO4 and then evaporated under reduced pressure. The resulting precipitate is washed with isopropyl ether and recrystallised from methanol.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([C:29]([OH:31])=[O:30])=[C:23]([CH3:28])[NH:24][C:25]=1[CH:26]=O>>[CH3:32][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([C:29]([OH:31])=[O:30])=[C:23]([CH3:28])[NH:24][C:25]=1[CH:26]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: Cc1[nH]c(C=O)c(CCCN(C)C)c1C(=O)O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c(C)c(C(=O)O)c1CCCN(C)C)C(=O)N2
Yield: 22.4 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (113 mg) was condensed with 4-(3-dimethylaminopropyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid (119 mg) to give 50 mg 4-(3-dimethylaminopropyl)-2-methyl-5-(5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [O:1]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[C:10]([C:14]#[N:15])=[N:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:21].[Na+].[Na+].OO.CCOCC>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[C:10](=[N:11][O:12][CH3:13])[C:14]([NH2:15])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CON=C(C#N)c1ccccc1Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OO
Agent: [Br-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Yield: 455.1 %

Procedure:
2-Phenoxy-α-methoxyiminobenzyl cyanide (E/Z=21/79)(1.26 g, 5 mmol) was dissolved in acetone (5 ml). Sodium carbonate (0.11 g, 1 mmol), tetra-n-butylammonium bromide (0.08 g, 0.25 mmol), 30% aqueous hydrogen peroxide solution (1.13 g, 10 mmol) were added, and the mixture was heated under reflux for 5 hours. After completion of the reaction, ether (50 ml) was added. The mixture was washed with a saturated aqueous solution of sodium thiosulfate, water and saturated brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (1.23 g, Yiled: 91.0%, E/Z=23/77).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10](=O)[NH:11][N:12]=[C:13]([CH3:22])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:22])=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cccc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2.16 g of 4-(2-chloro-6-fluorophenyl)-5-(4-chlorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.21 g of 3-chloro-4-(2-chloro-6-fluorophenyl)-5-(4-chlorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xvi) of the present invention).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C@@H:9]2[CH2:11][C@H:10]2[NH:12]C(=O)OC(C)(C)C)=[CH:7][CH:6]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:4]=1>O1CCOCC1>[ClH:2].[Cl:2][C:3]1[C:8]([C@@H:9]2[CH2:11][C@H:10]2[NH2:12])=[CH:7][CH:6]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 189.3 %

Procedure:
HCl in dioxane (1 mL) was added to a solution of tert-butyl (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (100 mg, 0.242 mmol) in dioxane (2 mL) at 0° C. and stirred for 3 h at RT. After completion, the solvent was evaporated, residue was triturated with Et20 and dried to afford trans-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride (80 mg, 95%) as white solid.
Reaction SMILES: CO[C:3](=[O:28])[CH:4]([N:11]([CH:25]([CH3:27])[CH3:26])[C:12]([NH:14][CH:15]1[CH:22]2[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:24][CH:16]1[CH2:17]3)[CH2:21]2)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C.C12CC3CC(CC(C3)C1N1C=C(C3C=CC=CC=3)N(C(C)C)C1=O)C2>C(Cl)Cl.CCCCCCC.C(Cl)Cl.CC#N>[CH:22]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:24][CH:16]([CH2:17]3)[CH:15]1[N:14]1[C:3](=[O:28])[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:11]([CH:25]([CH3:26])[CH3:27])[C:12]1=[O:13])[CH2:21]2
Reactant: COC(=O)C(c1ccccc1)N(C(=O)NC1C2CC3CC(C2)CC1C3)C(C)C
Agent: CC(C)n1c(-c2ccccc2)cn(C2C3CC4CC(C3)CC2C4)c1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(C)N1C(=O)N(C2C3CC4CC(C3)CC2C4)C(=O)C1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
In this case, treatment of (3-adamantan-2-yl-1-isopropyl-ureido)-phenyl-acetic acid methyl ester with diisobutylaluminium hydride as described in example 1, step B] did not result in the formation of the desired material. Alternatively, (3-adamantan-2-yl-1-isopropyl-ureido)-phenyl-acetic acid methyl ester (200 mg) was dissolved in DCM (3 mL) and toluene (3 mL) under argon and treated with sodium dihydrido-bis-(2-methoxyethoxy)-aluminate (Red-Al™, 3.5 M in toluene, 0.09 mL) at −78° C. After addition of the reducing agent, the mixture was stirred at −78° C. for 30 minutes and was then allowed to warm to 0° C. The reaction mixture was quenched with 1M potassium sodium tartrate solution (10 mL) and then poured into 25% HCl (25 mL) containing a small amount of ice. The aqueous mixture was saturated with NaCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and evaporated to give a crude product. This material was subjected to flash chromatography using a gradient of 10 to 40% ethyl acetate in heptane followed by a second flash chromatography using DCM and by DCM/CH3CN 9:1 as eluents. This procedure provided 3-adamantan-2-yl-1-isopropyl-5-phenyl-imidazolidine-2,4-dione (116 mg) as the major product whereas the desired material 1-adamantan-2-yl-3-isopropyl-4-phenyl-1,3-dihydro-imidazol-2-one was obtained as the minor component (colorless oil, 14 mg). MS (EI): 336.2 (M+).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].Cl.[C:42]([C:44]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)#[N:43].C(=O)([O-])[O-].[Na+].[Na+]>CO>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:47]2[CH2:48][CH2:49][C:44]([C:42]#[N:43])([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:45][CH2:46]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(CCCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)CC1
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (150 mg) and 4-cyano-4-phenylpiperidine hydrochloride (70 mg) in methanol (5 ml) was stirred at reflux temperature in the presence of sodium carbonate (100 mg). After 2 hours, the reaction mixture was evaporated under reduced pressure. The residue was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(4-cyano-4-phenylpiperidino)propyl]-2-(1H-indol-3-ylmethyl)piperazine (89 mg) as a powder.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br>>[CH:1]1([O:7][CH2:8][C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1COC1CCCCC1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](COC3CCCCC3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.8 %

Procedure:
(2S,4R)-Methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (194 mg, 0.57 mmol) (from example 84, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 4.52 mL, 25.80 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(Cyclohexyloxymethyl)piperidin-4-yl)isoxazol-3(2H)-one (4.5 mg, 3%). 1H NMR (600 MHz, dmso) δ 1.04-1.24 (m, 6H), 1.33-1.46 (m, 2H), 1.57-1.66 (m, 2H), 1.73-1.88 (m, 4H), 2.56-2.67 (m, 1H), 2.68-2.80 (m, 2H), 2.99-3.06 (m, 1H), 3.07-3.84 (m, 3H), 5.70 (s, 1H). HRMS Calculated for [C15H24N2O3+H]+: 281.1865. Found: 281.1893
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Cl:1][C:2]1[C:3]([O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:5]([O:8][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)Oc1cc(OC(=O)CCCCC)c(Cl)cn1
Yield: 34.9 %

Procedure:
The general procedure of Example 5 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 2.75 g of hexanoyl chloride to produce 1.22 g of the title compound in a yield of 26%.
Reaction SMILES: CC(OC1C=CC=C([N+]([O-])=O)C=1)(C(OCC)=O)C(OCC)=O.[N+:23]([C:26]1[CH:42]=[CH:41][C:29]([O:30][CH2:31][C:32]2[CH:33]=[C:34]([C:37]([O:39][CH3:40])=[O:38])[O:35][CH:36]=2)=[CH:28][CH:27]=1)([O-])=O>>[NH2:23][C:26]1[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]2[CH:33]=[C:34]([C:37]([O:39][CH3:40])=[O:38])[O:35][CH:36]=2)=[CH:41][CH:42]=1
Reactant: COC(=O)c1cc(COc2ccc([N+](=O)[O-])cc2)co1
Agent: CCOC(=O)C(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Product: COC(=O)c1cc(COc2ccc(N)cc2)co1

Procedure:
In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, 4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan was reduced to provide 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan. 1H NMR (CDCl3): δ 7.15 (d, 1H, J=3.5 Hz), 7.05 (t, 1H, J=8.2 Hz), 6.50 (d, 1H, J=3.5 Hz), 6.37-6.27 (m, 3H), 5.01 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)=O>Cl.[Zn]>[SH:2][C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(Cl)cc1S(=O)(=O)Cl
Agent: Cl
Agent: [Zn]
Product: COC(=O)c1ccc(Cl)cc1S
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Over a period of 1.5 hours, 243.5 g (3.7 mol) of zinc powder were added a little at a time to a suspension of 205 g (0.75 mol) of methyl 2-chlorosulfonyl-4-chlorobenzoate in 1 l of concentrated hydrochloric acid and 375 g of ice. The mixture was stirred for another 3 hours and slowly heated to 70° C. After 2 hours at this temperature, the mixture was cooled. The reaction mixture was allowed to stand at room temperature for 12 hours and then extracted with ethyl acetate, the combined organic phases were dried and the solvent was removed. This gave 125.4 g (83%) of methyl 2-mercapto-4-chlorobenzoate.