Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:14][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Reaction time: 8 h

Procedure:
To a solution of 61.3 (45 mg, 0.18 mmol) in DCM (0.9 mL) were added triethylamine (24 μL, 0.18 mmol) and thionyl chloride (19 μL, 0.26 mmol) at room temperature. The mixture was stirred overnight and concentrated to afford 61.4. The crude product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Temperature: 20 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (1.5 g, 5.74 mmol, 1.0 equiv.), t-BuNH2 (1.26 g, 17.22 mmol, 3.0 equiv.) in 1,4-dioxane (50 ml) was stirred at 20° C. for 4 h under nitrogen atmosphere. The reaction mixture was concentrated to give a residue, which was purified by silica gel chromatography (PE/EA 100:1 to 10:1 as eluent) to afford 5-bromo-N-tert-butylthiophene-2-sulfonamide (1.614 g, 94.3%) as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(Cl)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 3-chloro-N2-phenylbenzene-1,2-diamine (495 mg, 2.26 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (470 mg, 2.48 mmol), HOAt (338 mg, 2.48 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (477 mg, 2.48 mmol) and 4-methylmorpholine (0.550 mL, 4.97 mmol) in anhydrous DCM (15 mL) was stirred at RT for 19 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 22 h. After cooling to RT, volatiles were removed in vacuo and the residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as pale yellow oil (quantitative). LCMS: RT 3.83 min [M+H-tBu]+ 316.0.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29]O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[O:4][N:3]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: Oc1cc(-c2ccc(Oc3ccccc3)cc2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Oc3ccccc3)cc2)on1
Yield: 73.5 %

Procedure:
3-Hydroxy-5-(4-phenoxyphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.14 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.23 g, 74%) as a colorless powder.
Reaction SMILES: C([O:3][C:4](=[O:29])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:17]=2[F:27])=[CH:12][C:11]1=[O:28])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+:32]>O1CCCC1>[Li+:32].[F:27][C:17]1[C:18]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([O-:29])=[O:3])[C:11](=[O:28])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)[O-])N1CC(Oc2cccc(N3CCCC3)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.3 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.120 g, 0.29 mmol) in tetrahydrofuran (4 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 1.2 mL, 0.6 mmol). The mixture was stirred at 25° C. for 2 h, and the solvents evaporated. The residue was rinsed with diethyl ether which afforded (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid lithium salt (0.140 g, 100%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: O=C(CCCl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCC(=O)c1ccccc1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 330 mg, 1.08 mmol), tetrabutylammonium iodide (400 mg, 1.08 mmol) and 3-chloropropiophenone (Acros; 820 mg, 4.86 mmol) in dimethylformamide (6 mL) was heated at 100° C. for 3.5 h. The reaction mixture was cooled to room temperature. Dichloromethane (100 mL) was added and the solution was washed with water (4×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexane. The resulting material was dried under high vacuum at 70° C. for 3 h to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-oxo-3-phenyl-propyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (290 mg, 61%) as a tan solid. APCI(+)-MS (M+H) 437.
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])(=O)C.O.[I:24](O)(=O)=O>>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:7][CH2:6][CH2:5][I:24]
Reactant: CC(=O)OCCCC(c1ccccc1C)c1ccccc1C
Reactant: [O-][I+2]([O-])O
Solvent: O
Product: Cc1ccccc1C(CCCI)c1ccccc1C

Procedure:
The crude 2,2-di-(2-tolyl)-tetrahydrofuran 33a (28 g) was dissolved in acetic acid (250 mL). 5% palladium on Carbon black (3 g) was added and the mixture was hydrogenated in a Parr apparatus at 3 ato at 55° C. for 5 hrs. The catalyst was filtered off and the solvent was evaporated in vacuo. The remaining oil was subjected to CC (n-heptane/ethyl acetate--15:1) to give 4,4-di-(2-tolyl)-1-butanol (17 g). A solution of 4,4-di-(2-tolyl)-1-butanol (19 g) in acetic acid (400 mL) was boiled under reflux for 3 hrs. The cooled solution was evaporated in vacuo to give 4,4-di-(2-tolyl)-1-butyl acetate (17 g) as an oil. A solution of 4,4-di-(2-tolyl)-1-butyl acetate (9.2 g) in 57% aqueous iodic acid (150 mL) was boiled under reflux for 3 hrs. The cooled solution was poured into a mixture of ice and water and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo to give the title compound 34a (11.7 g) as an oil, which was used without further purification. 1H NMR (CDCl3) δ1.80-2.10 (m,4H), 2.28 (s,6H), 3.17 (t,2H), 4.26 (t,1H), 7.12 (s,8H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:14][CH:13]=2)=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl[6-hydroxy-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.42 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (48 mg, 1.2 mmol) (60% in oil). The resulting mixture was stirred at 0° C. for 10 min. To the mixture was added methyl 2-bromoisobutyrate (0.22 g, 1.2 mmol), and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate (0.31 g, 59.6%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.I[CH2:18][CH2:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)[CH2:13][CH:12]=1)[CH:6]=[CH:5]2
Reactant: ICCC1Cc2ccccc2C1
Reactant: Clc1ccc2c(ccn2-c2ccncc2)c1
Solvent: CC(=O)CC(C)C
Product: Clc1ccc2c(ccn2C2=CCN(CCC3Cc4ccccc4C3)CC2)c1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
A mixture of 5-chloro-1-(pyridin-4-yl)-1H-indole 26a (4.0 g), 2-(2-iodoethyl)indane 24a (4.8 g), and methyl isobutyl ketone (100 ml) was boiled under reflux for 20 h. The mixture was cooled, and a crystalline compound collected by filtration (6.5 g). Compound corresponding to 5.5 g was suspended in methanol (100 ml), and NaBH4 (1.5 g) was added in parts of 0.5 g. The resulting mixture was stirred at room temperature for I h, and the solvent was removed in vacuo. Conventional work up with ethyl acetate and water followed by purification on silica gel eluted with ethyl acetate-heptane (1:1) gave the crude product, which was crystallized (ethyl acetate) to give the title compound (1.1 g, 27%).
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4]1.[CH2:22]=[O:23]>O>[OH:23][CH2:22][N:2]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4]1)[CH3:1]
Reactant: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Reactant: C=O
Solvent: O
Product: CCOC(=O)c1cn(N(C)CO)c2c(F)c(F)c(F)cc2c1=O
Temperature: 100 °C

Procedure:
A suspension of ethyl 1-methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10 g) in water (100 ml) and 37% aqueous formaldehyde (100 ml) was heated to 100° C. for 1 hour. The mixture was cooled and the solid removed by filtration and washed with water. The resulting yellow colored solid was dried to constant weight in vacuo over phosphorus pentaoxide to yield ethyl 1-[N-(hydroxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.25 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.C(N(CC)CC)C>C(O)C.[Pd]>[N:12]1[C:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:24][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[S:14][C:13]=1[N:15]1[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[NH:17][C:16]1=[O:23]
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1ccccc1-2

Procedure:
A mixture of 49 mg (0.12 mmol) of 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione from Example 485, and 0.0334 ml (0.24 mmol) of triethylamine in 5 ml of ethanol was hydrogenated over 120 mg of 10% palladium on charcoal at 1 atm for 3 hours. The mixture was filtered through celite and concentrated in vacuum. The residue was purified on 4 g siligal column eluting the product with ethyl acetate gradient in heptane to give 493. Yield 20 mg (51%). MS(ESI+): 330.1
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH3:22])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:23]>CO.[OH-].[OH-].[Pd+2]>[ClH:23].[CH3:22][NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1
Reactant: CNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CNC1(C(N)=O)CNC1

Procedure:
To a suspension of 1-benzhydryl-3-methylaminoazetidine-3-carboxylic acid amide (I-3A-2b; 13.5 g, 45.8 mmol) in methanol (90 ml) was added concentrated aqueous HCl (8.0 ml, 96 mol), dropwise, to give a homogeneous solution. After the addition of 20% Pd(OH)2 on carbon (50% water; 4.1 g), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 7 hours. The mixture was filtered through a pad of Celite®, washing with copious amount of 9:1 methanol/water, and then 9:1 tetrahydrofuran/water until no product eluted (determined with ninhydrin stain). The filtrate was then concentrated, in vacuo, and the residue triturated from diethyl ether to give I-3A-2c (9.3 g, quantitative) as a brown solid: +APcI MS (M+1) 129.9; 1H NMR (400 MHz, CD3OD) δ 4.50 (d, J=12.0 Hz, 2H), 4.43 (d, J=12.9 Hz, 2H), 2.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:28]([N:41]1[CH2:44][CH:43](O)[CH2:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH:28]([N:41]1[CH2:44][CH:43]([O:12][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])[CH2:42]1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2Cl)cc1

Procedure:
A solution of 2,4′-dichlorobenzhydrol (7) (178 mmol), p-toluenesulphonic acid (198 mmol) and 1-benzhydryl-3-azetidinol (1) (99 mmol) in toluene (500 mL) was heated at reflux in a Dean-Stark apparatus for 40 minutes. The solution was cooled, washed with sodium hydrogen carbonate (saturated aqueous solution, 700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; (10% ethyl acetate:isohexane)] to finish the product as a yellow oil (17.8 g, 38%).
Reaction SMILES: C[O-].[Na+].[P:4]([O-:10])([O:8][CH3:9])([O:6][CH3:7])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:16]=[O:17].FC(F)(F)C(O)=O>CO>[CH3:9][O:8][P:4]([CH:16]([OH:17])[C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=1)(=[O:10])[O:6][CH3:7]
Reactant: COP(=O)([O-])OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(O)P(=O)(OC)OC)cc(OC)c1OC
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A round-bottom flask equipped with thermometer, condenser and gas inlet was charged with methanol (150 mL) and sodium methoxide (1.074 g, 20 mmol) and cooled to 0° C. under nitrogen protection. To a stirred solution were added subsequently dimethyl phosphate (19.52 g, 0.177 mol) and 3,4,5-trimethoxybenzaldehyde (30 g, 0.153 mol). A resulted solution was heated at 50° C. for 1 hour, cooled down to r.t. and treated with trifluoroacetic acid (4.6 ml). The mixture was concentrated under reduced pressure, the residue dissolved in EtOAc (300 mL), washed once with 18% brine, then once with saturated brine, dried over sodium sulfate. The filtered solution was concentrated until precipitation started. To the resulted suspension 1:1 mixture of t-butylmethyl ether and heptane was added (50 mL). Solid was filtered out, washed with two portions (20 mL) of the same solvent mixture and vacuum-dried to give 41.2 g (88%) of 1, LC purity 99.4% (AUC), m.p. 103-104° C.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[CH2:22](Br)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: BrCCc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccccc2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (1 g), phenethyl bromide (0.-67 g), anhydrous potassium carbonate (1.5 g) and acetonitrile (25 ml) was heated under reflux for 4 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×30 ml)--. The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.72 g, m.p. 134°-138° C., [α]D25 +13.3° (C 1.0, CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:13])=[C:9](\[CH3:12])/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][C@@H](CC1C=CC(O)=CC=1)C(OCC)=O)[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[C:10]([O:16][CH2:14][CH3:15])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(CO)=C(/C)c1ccc(Br)cc1
Product: CCOC(=O)/C(C)=C(/C)c1ccc(Br)cc1
Yield: 141.6 %

Procedure:
The title compound (0.83 g, 87% yield) was prepared from (E)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[CH:30][C:17]([NH:18][C:19]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=2[C:21]([OH:23])=O)=[CH:16][CH:15]=1.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:19]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=2[C:21]([NH:41][O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:23])=[CH:30][CH:31]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1
Yield: 95 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (1.90 g, 11.6 mmol), 2-(4-fluoro-anilino)-4,5-difluorobenzoic acid (Example N, 2.59 g, 9.7 mmol), O-benzylhydroxylamine hydrochloride (1.55 g, 9.7 mmol), and triethylamine (1.63 mL, 11.6 mmol) provided 3.43 g of the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[C:21]([F:35])([F:36])[F:20])[CH2:30][CH2:29]2)[O:13][N:12]=1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: COc1ccc(-c2cc(CCC=O)on2)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4C(F)(F)F)CC3)on2)c(OC)c1
Yield: 79.7 %

Procedure:
About 2 min after dissolving 3-[3-(2,4-dimethoxypheny)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-[2-(trifluoromethyl)benzyl]piperazine (8.0, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 23.5 hr and followed the same processes as in Example 1 to obtain 15.6 mg (83.2%) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12]N(C2C=CC(Br)=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:21][CH:22]1CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:22]([OH:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(O)CC1

Procedure:
Prepared according to the method for the preparation of 4-(4-bromophenyl)-piperazine-1-carboxylic acid tert-butyl ester, from 4-hydroxypiperidine (18.4 g), to give the title compound as a light orange oil that crystalised from hexane (25.6 g, 71%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CC=CC=1.[CH3:25][NH:26][C:27](=[S:30])[NH:28][NH2:29]>CN(C)C=O>[CH3:25][N:26]1[C:4]([CH2:3][O:2][CH3:1])=[N:29][N:28]=[C:27]1[SH:30]
Reactant: CNC(=S)NN
Reactant: COCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCc1nnc(S)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 192.4 %

Procedure:
5 g of methoxy-acetic acid (55.5 mmol) were dissolved in 70 ml of dimethylformamide. 11.73 g of 1,1′-carbonyldiimidazol (72.3 mmol) were added in portions within 10 min. After 30 min. at room temperature 23 ml of pyridine were added. Then 5.84 g of 4-methyl-3-thiosemicarbazide (55.5 mmol) were added and the obtained solution was stirred at room temperature overnight, and for an additional 3 h at 100° C. The solvent was evaporated, the residue dissolved in 70 ml of saturated aqueous sodium chloride solution and 30 ml of water. The aqueous layer was extracted six times with 100 ml of ethyl acetate each, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated to dryness to yield 17 g of the crude title compound, which was further purified by silica gel chromatography with ethyl acetate, thereby obtaining 7.1 g of the purified title compound.