Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([N:9]([CH2:22][CH:23]([OH:31])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)C1C=CC=CC=1.C(OCC)(=O)C>CO.[Pd]>[ClH:30].[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][CH2:22][CH:23]([OH:31])[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccc(Cl)cc2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CCNCC(O)c2ccc(Cl)cc2)cc1OC
Reaction time: 1.5 h

Procedure:
Similarly 5.42 g. (0.02 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 4.64 g. (0.03 mol) of p-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine. The hydrochloride of this ethylamine is dissolved in methanol and hydrogenated with 0.5 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature and 60 psi. for about 90 minutes. The filtered reaction mixture is evaporated in vacuo to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine hydrochloride, m.p. 167°-171° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([O:18][CH2:19]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CCOCC>[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([O:18][CH2:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Brc1ccccc1
Reactant: CCCCCC(CCCCl)OCCl
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CCCCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A solution of bromobenzene (13.18 g., 0.084 mole) in ether (50 ml.) is added to a suspension of Mg (2.04 g., 0.084 mole) in ether (50 ml.) dropwise so as to maintain a gentle reflux. After complete addition of the bromobenzene, the mixture is heated on a steam bath for an additional hour. The reaction mixture is then cooled to 5°-10° C. by means of an ice-water bath, and 1-chloro-4-chloromethoxynonane (19.05 g., 0.084 mole) is added dropwise over 15 minutes. The resulting suspension is stirred for 18 hours at room temperature. The reaction mixture is diluted with ether (100 ml.), cooled to 0°-5° C., and cold water (75 ml.) is added with vigorous stirring while the temperature is kept below 5° C. Let stir at 0°-5° C. for about 15 minutes. The aqueous phase is separated from the ether phase (A), and the aqueous layer is extracted with ether (150 ml., B). Organic solution A is combined with B, washed with H2O (100 ml.), 5% K2CO3 (100 ml.), again with H2O (100 ml.), finally with saturated NaCl solution, and is dried over anhydrous Na2SO4. Removal of the solvent in vacuo yields 1-chloro-4-benzyloxynonane (19.28 g., 0.072 mole, 85.7% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([NH2:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[F:9][C:10]1[C:15]([F:16])=[C:14]([C:17](O)=[O:18])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[CH3:22]>>[CH3:1][CH:2]([CH:4]([NH:8][C:17](=[O:18])[C:14]1[C:13]([F:20])=[C:12]([F:21])[C:11]([CH3:22])=[C:10]([F:9])[C:15]=1[F:16])[CH:5]([CH3:7])[CH3:6])[CH3:3]
Reactant: CC(C)C(N)C(C)C
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Product: Cc1c(F)c(F)c(C(=O)NC(C(C)C)C(C)C)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using 2,4-dimethylpentan-3-amine and 2,3,5,6-tetrafluoro-p-toluic acid (90%). 1H NMR (CDCl3) δ 0.91 (d, J=6.7 Hz, 6H), 1.00 (d, J=6.8 Hz, 6H), 1.85 (m, 2H), 2.29 (m, 3H), 3.82 (m, 1H), 5.52 (bd, 1H). MS (306.1, M+H) m.p. 184-187° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)#[CH:36]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([C:36]#[C:35][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:3][CH:4]=2)/[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccccn3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (370 mg, 0.636 mmol; example 4) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and 2-ethynylpyridine (118 mg, 1.144 mmol) was added under argon atmosphere. The solution was cooled; tetrakis(triphenylphosphine)palladium (59.0 mg, 0.051 mmol) and copper(I) iodide (19.3 mg, 0.102 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane (60 mL). The solution was washed with water (2×20 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-[4-(pyridin-2-ylethynyl)phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH:46](Br)[CH3:47]>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:46]([CH3:47])[CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1C
Temperature: 85 °C

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (300 mg, 0.572 mmol) and potassium carbonate (316 mg, 2.29 mmol) in butanone (4 ml) was added 1,2-dibromopropane (0.072 ml, 0.686 mmol). The reaction was heated to 85° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided a yellow solid. The solid was recrystallized from MeOH. The solid was filtered, washed with MeOH, and dried to provide the title compound as a yellow solid which was dissolved in acetone and concentrated (3×). The light yellow solid was collected and dried under to provide the title compound as a 1:1 mixture of rotational diastereoisomers (75.1 mg, 0.133 mmol, 23%): mp 201-204° C.; 1H NMR of mixture (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.18 (dd, J=10.8, 7.4 Hz, 6H), 7.84-7.73 (m, 8H), 7.45-7.30 (m, 8H), 7.30-7.23 (m, 2H), 7.20 (d, J=6.7 Hz, 1H), 7.12 (dd, J=7.8, 1.2 Hz, 1H), 4.43-4.33 (m, 1H), 4.16 (dd, J=12.6, 6.3 Hz, 1H), 3.48 (dt, J=13.3, 6.7 Hz, 1H), 3.37 (dd, J=10.8, 6.2 Hz, 1H), 3.24 (dt, J=13.7, 6.9 Hz, 1H), 3.08-2.92 (m, 3H), 1.33-1.16 (m, 18H); ESIMS m/z 566 (M+H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13](I)[C:9]=1[C:10]([OH:12])=[O:11].[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1>CN(C=O)C>[F:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([N:20]2[N:21]=[CH:22][CH:23]=[N:19]2)[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: c1c[nH]nn1
Reactant: Cc1ccc(I)c(C(=O)O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in WO2008/069997. Cs2CO3 (6.98 g, 21.4 mmol) was added portionwise to a RT solution of 2-fluoro-6-iodo-3-methyl-benzoic acid (3.0 g, 10.7 mmol) in DMF (15 mL) under argon followed by 1H-1,2,3-triazole (1.24 mL, 21.4 mmol) and Cu(I)I (103 mg, 0.536 mmol) and the resulting blue suspension was stirred at 80° C. overnight. The reaction mixture was quenched with 2M aq. HCl and filtered through a celite plug before being extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a pale yellow solid. LC-MS B: tR=0.55 min; [M+H]+=222.01.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:19])[CH:13]=2)[N:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:19])[CH:13]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3ccc(C)cc3nc2OC)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2cc(C)ccc2nc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To 2-(2,4-dimethoxybenzylamino)-3-methoxy-6-methylquinoxaline (4.48 g, 13.2 mmol), 30 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethanee and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 2.01 g of the titled compound (yield, 81%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Temperature: 90 °C
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) and [1,1′-Bis-(diphosphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2dppf) (74 mg, 0.091 mmol) were stirred in DMSO (2 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.06-8.02 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.52-7.49 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@:11]3([OH:28])[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([OH:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:4]1.[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33]Br)[CH3:30].O>O1CCCC1>[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33][O:27][C@H:19]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:17]([CH2:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:9]2([CH3:10])[C@:11]3([OH:28])[CH2:12][CH2:13][C@@H:8]2[C:5]2[CH:6]=[CH:7][O:3][CH:4]=2)[CH2:18]1)[CH3:30]
Reactant: CCOC(CBr)OCC
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1)OCC

Procedure:
To a suspension of 5.5 g of NaH (60% dispersion in mineral oil) in 400 ml of dry tetrahydrofuran 7.0 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377) were added at room temperature in a nitrogen atmosphere. The mixture was kept at reflux for 6 hrs, then 26 ml of bromoacetaldehyde diethylacetal were added; the suspension was kept at reflux temperature for 4 hrs, 50 ml of water were added cautiously, and the tetrahydrofuran was distilled under reduced pressure. The residue was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 6.9 g of 3β-(2,2-diethoxy-ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, as a dense oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1.[H][H]>C(O)C.[Pd]>[NH2:15][C:13]1[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=1
Reactant: Cc1ccc(-c2cc([N+](=O)[O-])cn(C)c2=O)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2cc(N)cn(C)c2=O)c(C)c1
Reaction time: 5 h
Yield: 41.8 %

Procedure:
To a solution containing 0.17 g (0.66 mmol) of 3-(2,4-dimethylphenyl)-1-methyl-5-nitropyridin-2(1H)-one in 50 ml of ethanol was added 0.10 g of 10% palladium on carbon (Degussa type; 50% wet). The flask was fitted with a balloon of hydrogen and allowed to stir for 5 h. The reaction was filtered through GF/F paper and the filtrate concentrated under reduced pressure to afford 0.063 g (41.9%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[S:8]1[CH2:11][CH2:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: BrCCBr
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCS2
Temperature: 100 °C
Yield: 72.7 %

Procedure:
A mixture of 2-aminothiophenol (5 g, 40 mmol), 1,2-dibromoethane (3.75 g, 20 mmol), K2CO3 (13.8 g, 100 mmol) in THF (30 mL) was heated at 100° C. for 16 h. After completion of reaction, water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (using 100-200 mesh silica) and the desired product was eluted at 15% EtOAc in hexane) to obtained 2.2 g of desired product.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1cccc(Cl)c1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1c(F)cccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-6-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[O:30][CH:31]=[CH2:32]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][C:29]([O:30][CH:31]=[CH2:32])=[O:33])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=COC(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=COC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (138 μl, 0.99 mmol) and vinyl carbonochloridate (36.2 μl, 0.40 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(vinyloxycarbonylamino)acetate (70 mg; 64% yield). The product was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([C@@:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]([F:11])([F:10])[CH2:8][O:7][CH2:6][C:5]([NH2:12])=[N:4]1)[CH3:2].[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C@@:3]1([C:13]2[CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:15][C:14]=2[F:19])[C:9]([F:10])([F:11])[CH2:8][O:7][CH2:6][C:5]([NH2:12])=[N:4]1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC[C@]1(c2ccccc2F)N=C(N)COCC1(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)COCC1(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-ethyl-6,6-difluoro-5-(2-fluoro-phenyl)-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (1.2 mmol) in sulfuric acid (5.0 ml) was added at 0° C. red fuming nitric acid (1.9 mmol) over a period of 20 min and stirring was continued for 30 min. The solution was dropped slowly into ice/water (60 ml), the pH was adjusted to 9 by addition of aqueous 4 N NaOH and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silca-NH2 using n-heptane/ethyl acetate to give (R)-5-ethyl-6,6-difluoro-5-(2-fluoro-5-nitro-phenyl)-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine as a pale yellow solid. MS: m/z=318.1 [M+H]+.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[CH:7]=1)(=O)C.[CH3:18][S:19]([O-:21])=[O:20].[Na+]>CC(C)=O.O>[CH3:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([CH2:5][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:7]1
Reactant: CS(=O)[O-]
Reactant: CC(=O)OCc1cn(C)c2ccccc2c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21

Procedure:
To a solution of 3-acetoxymethyl-1-methyl-4-quinolone (0.8 g.) in acetone (15 ml.) was added a solution of sodium methanesulphinate (0.53 g.) in water (10 ml.). The mixture was boiled under reflux for 24 hours. Further sodium methanesulphinate (0.14 g.) was added and the mixture was boiled under reflux for 4 hours. Acetone was evaporated from the mixture, causing the separation of a white solid which was recrystallised from industrial methylated spirit to give 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 195°-197°.
Reaction SMILES: C(S([CH:6]1[N:9]([CH:10]([C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[S:25])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:33])[CH2:7]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[O:33]=[C:8]1[N:9]2[CH:6]([S:25][C:24]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:10]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[CH2:7]1
Reactant: C=CCS(=O)C1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=S)Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2ccccc2)SC2CC(=O)N12
Yield: 17.7 %

Procedure:
A stirred solution of 97 mg of 4-nitrobenzyl 2-(4-allylsulphinylazetidin-2-on-1-yl)-3-phenoxy-3-thioxopropionate and 52 mg of triphenylphosphine in 2 ml of dry dioxan was heated under an argon atmosphere under reflux for 15 minutes. The mixture was then evaporated in vacuo to dryness; chromatography over silica gel afforded 14 mg of the title compound (18% theoretical yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>ClCCl>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:20])=[CH:17][CH:16]=1
Reactant: NCCCO
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A reaction vessel was charged with 7.51 g of 3-amino-1-propanol, 2.53 g of triethylamine and 50 ml of dichloromethane, and 5.21 g of 4-trifluoromethylbenzoyl chloride was slowly added dropwise under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was successively washed with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then concentrated, which afforded 5.25 g of 3-(4-trifluoromethylbenzamido)propan-1-ol (85% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[C:32]1([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccccc1)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid phenyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using phenyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 530.2 [M]+.