Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].S(O[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C1C=CC(C)=CC=1)(=O)=O>C1C=CC=CC=1.[Na]>[O:26]([CH2:25][CH2:24][O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2)cc1
Agent: [Na]
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OCCOc2ccccc2)CC1(C)C

Procedure:
30 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol were dissolved in 250 parts of benzene and 4 parts of sodium added. The solution was heated overnight at reflux temperature and then cooled. 38 parts of 2-phenoxyethanol tosylate were added dropwise and the solution heated at reflux for 5 hours. On cooling the precipitate was filtered off and the filtrate evaporated on vacuo. Treatment of the residue with dilute hydrochloric acid and then basification with dilute sodium hydroxide to a pH 10 was followed by extraction with ether. Evaporation afforded a pale yellow oil which was chromatographed on alumina to give 4-(2'-phenoxyethoxy)-1,2,2,6,6-pentamethylpiperidine as a colourless oil which gave the following elemental analysis by weight:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[S:11][C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=1>>[CH2:1]([NH:8][C:16]([C:12]1[S:11][C:10]([Br:9])=[N:14][C:13]=1[CH3:15])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccccc1
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Yield: 60 %

Procedure:
Following the procedure as described in Preparation 7, making variations as required to use benzylamine in place of pyridin-3-ylmethanamine to react with 2-bromo-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a yellow solid in 60% yield: 1H NMR (300 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 5.99 (br s, 1H), 4.56 (d, J=5.7 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 311.2 (M+1), 313.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.O>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 30.9 %

Procedure:
To a stirred mixture of 2-amino-5-fluoro-3-nitrobenzotrifluoride (554 mg, 2.47 mmol) in ethanol (10 mL) was added SnCl2.2 H2O (2.78 g, 12.36 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h, cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried over Mg2SO4 and evaporated to give 148 mg (30%) of 2,3-diamino-5-fluorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.666 (s, 2H); 3.676 (s, 2H); 6.610 (dd, 1H, J1 =2.4 Hz, J2 =9.0 Hz), 6.703 (dd, 1H, J1 =2.4 Hz, J2 =9.0 Hz).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)[CH2:37][CH2:36]1.[OH-].[Na+]>ClCCl>[C:16]([O:15][C:13](=[O:14])[NH:1][C@@H:2]([C:10](=[O:12])[NH:49][CH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH:38]2[CH2:37][CH2:36][O:35][CH2:40][CH2:39]2)[CH2:47][CH2:46]1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC1CCN(CC2CCOCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of dichloromethane and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of dichloromethane cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. After a process control, 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate compound (12) is crystallised from ethyl acetate, to obtain 14.29 g of white solid. Yield 83%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (5° C.) of 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (11 Kg, 38.8 mol, step 7) and Et3N (7.04 L, 50.6 mol) in DCM (55 L) was added methanesulphonyl chloride (2.97 L, 38.4 mol) so that the internal temp <10° C. After stirring for 0.5 h at 5° C. the solution was used below in step 9.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:15]O>C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1ccc(Cl)cc1

Procedure:
The compound (I) may be synthesized by reacting 4-chlorobenzaldehyde, sodium formate, hydroxylamine hydrochloride and formic acid to form 4-chlorobenzonitrile, which may be nitrated to form 4-chloro-3-nitrobenzonitrile. Finally, this compound is reacted with the appropriate amine to obtain the desired compound (I) of the present invention.
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[C:13]1([CH:12]2[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:2][O:1]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(OC)c1ccccc1
Reactant: OCCCCC(O)CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCCCC1COC(c2ccccc2)O1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
To a solution of 1,2,6-trihydroxyhexane (10.0 g, 74.6 mmol) and benzaldehyde dimethylacetal (15.0 g, 98.7 mmol) in dry DMF (10 mL) was added Amberlyst 15 (5.0 g). The mixture was stirred at 100° C. for 5 min, then cooled and filtered. The filtrate was concentrated and residue obtained was re-dissolved in ethyl acetate. After being washed with water and brine, the solution was dried over Na2SO4. The crude product obtained after evaporation of the solvent was chromatographed on silica eluting with ethyl acetate. Concentration of the proper fractions afforded 11.0 g (66%) of the tide product (a mixture of diastereomers) as a colorless oil: 1H NMR (CDCl3, 300 MHz, ppm) 7.48 (m, 2H), 7.39 (m, 3H), 5.92 (s, 0.4H), 5.80 (s, 0.6H), 4.3-4.1 (m, 2H), 3.64 (m, 3H), 1.8-1.4 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:60])([C:56]([F:59])([F:58])[F:57])[CH2:46][CH2:47][CH2:48][S:49][CH2:50][C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:52]3[CH2:53][CH2:54][CH2:55][C@H:51]3[CH2:50][S:49][CH2:48][CH2:47][CH2:46][C:45]([F:44])([F:60])[C:56]([F:57])([F:58])[F:59])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC[C@@H]2Cc3cc(OCc4ccccc4)ccc3[C@H]3CC[C@]4(C)C(=O)CC[C@H]4[C@H]23)cc1
Reactant: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Yield: 72.5 %

Procedure:
Under the conditions of Example 23h, 4.58 g of 3-benzyloxy-7α-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one is reacted with 3.17 g of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, worked up, and the crude product is chromatographed on silica gel with hexane/ethyl acetate. 3.9 g of 3-benzyloxy-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentyl-thiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22 =+32.5°(c=0.117 in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C=O)C>[CH2:18]([N:11]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:14]=[CH:13][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:12])[CH3:19]
Reactant: CCI
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCCc2ccc(OC)cc21
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A mixture of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (2.6 g, 13.6 mmol), NaH (648 mg, 27 mmol) and iodoethane (3 ml, 37 mmol) in anhydrous DMF (50 ml) was vigorously stirred and heated at 100° C. for one hour. The reaction mixture was evaporated under reduced pressure to dryness and the residue dissolved in 100 ml ice-cold water. The resulting brown emulsion was extracted three times with chloroform, the combined extracts were washed with 2% solution of HCl and brine. The organic phase was treated with decolorizing carbon, stirred at room temperature for an hour and filtered through Celite. After drying over anhydrous magnesium sulfate the filtrate was evaporated to dryness. The residual oil was purified by gravity column chromatography on silica gel using 30% THF in n-hexane as an eluent to yield 2.2 g (74%) of the desired compound as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[S:11]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1)[C:12]#[N:13]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CSc1ccc(N)c(N)c1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a suspension of 2-nitro-4-thiocyanato-aniline, 22,3 g. of powdered iron, 50 ml. or 96% ethanol and 50 ml. of water a solution of 2,2 g. of ammonium chloride and 15 ml. of water is added dropwise under stirring at the boiling point of the mixture. Stirring is continued for a further 15 minutes, whereupon the reaction mixture is filtered until warm. To the filtrate 250 ml. of water are added. After cooling the precipitated crystals are filtered off. Thus 12.2 g. of 4-thiocyanato-1,2-diamino-benzene are obtained. Yield: 74%. M.p.: 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.C([Li])CCC.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:25]=[C:26]([C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.[OH-].[Na+]>C1COCC1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:26]([C:34]([CH3:38])([CH3:39])[C:35]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])=[O:36])[CH:25]=[C:24]([C:23]([F:40])([F:22])[F:41])[CH:29]=1
Reactant: CNc1cnc(Cl)cc1-c1cccnc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 0.19 g (0.81 mmol) (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine in 8 ml THF were added 0.52 ml (0.83 mmol) of a 1.6 M solution of n-butyllithium in hexanes at −78° C. After 15 min 0.28 g (0.88 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added. The reaction mixture was allowed to warm to room temperature during 30 min. After addition of a 0.2 M aqueous sodium hydroxide solution the mixture was extracted with three portions of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. Flash chromatography gave 0.30 g (73%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous DCM (100 ml). The resulting solution was treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The reaction mixture was stirred at room temperature. When LCMS showed completion of the reaction, the reaction was quenched with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 120 °C

Procedure:
1-Fluoro-2-methyl-4-nitrobenzene (9.75 g), phenol (7.10 g), and of Cs2CO3 (41.0 g) were dissolved in 100 mL of DMF and heated to 120° C. overnight. The reaction mixture was taken up in EtOAc and washed with water and brine, and dried over Na2SO4. The solution was concentrated to provide 2-methyl-4-nitro-1-phenoxybenzene as an oil, which was used in Step B without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:15]([CH3:17])[CH3:16])([CH3:14])[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-]>>[CH3:14][C:10]([N:15]([CH3:17])[CH3:16])([CH2:11][OH:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN(C)C(C)(Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: [H-]
Product: CN(C)C(C)(CO)Cc1ccc(Cl)c(Cl)c1

Procedure:
--in esterifying an acid (III), then, when R1 and/or R2 are hydrogen, in methylating the amine with formaldehyde and Formic acid to obtain an ester of (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropionic acid (II) ##STR6## in which R is lower alkyl, iv)--in reducing the ester (II) by a metal or organometal hydride to obtain (+/-)3-(3,4-di-chlorophenyl)-2-dimethylamino-2-methylpropan-1-ol or cericlamine (INN) of formula (I) and in making the addition salt with hydrochloric acid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCS(=O)(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C(=O)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 159.8 %

Procedure:
To a solution of [2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (5.6 g, 18.2 mmol) in CH2Cl2 (70 mL) was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. After removal of CH2Cl2 and excess trifluoroacetic acid under reduced pressure, 2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g, yield 100%) was obtained as a white solid. MS (M+H)=207.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>[OH-].[Na+]>[CH2:10]([O:17][C:18]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A 4-piperidone hydrochloride monohydrate (15.3 g) was dissolved in 2N aqueous solution of sodium hydroxide (100 mL). To the solution was added a benzyloxycarbonyl chloride (20.4 g) at 0° C. The mixture was stirred for 1 hour. The reaction mixture was neutralized with 2N hydrochloric acid, and the aqueous solution was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated to give the title compound (23.3 g) having the following physical data.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>CCCCCC.O1CCCC1>[CH3:6][C:7]1[CH:11]=[C:10]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[S:9][N:8]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1ccsn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C2(O)CCC3(CC2)OCCO3)sn1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
At −78° C., 1.5 M of n-butyllithium in hexane (6.7 mL) was slowly added to a solution of 3-methylisothiazole (1.0 g, 0.010 mol) in tetrahydrofuran (15 mL) over a period of 20 min. After being stirred for another 30 min, 1,4-dioxa-spiro[4.5]decan-8-one (1.56 g, 0.00999 mol) in tetrahydrofuran (5 mL) was added within 10 min. The reaction mixture was stirred for another 2 hour at −78° C. and allowed to warm up overnight to room temperature. After quenching with with brine, the mixture was extracted with EtOAc. The organic layer was dried and concentrated. Chromatography on silica gel eluting with hexane/EtOAc (1:5˜1:1) provided 1.8 g (70.6%) of the title compound. MS (M+H)+ 256.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:9][C:8](=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=1)[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccc(C)cc1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a suspension of sodium hydride (a 60% dispersion in liquid paraffin, 15.0 g, 375 mmol) in N,N-dimethylformamide (160 ml) was added at 0° C. a solution of triethyl 2-phosphonopropionate (87.7 g, 368 mmol) in N,N-dimethylformamide (10 ml) and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction solution was added 4-methylbenzaldehyde (43.3 g, 361 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 66.7 g (91% yield) of the oily title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](Cl)=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](N(CCC)C1CC2C(=CC=CC=2C(OC)=O)OC1)CC.[Li]C>O1CCCC1.[Cu]I>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=[O:16])[CH3:21])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)Cl)c2C1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Agent: [Cu]I
Agent: [Li]C
Solvent: C1CCOC1
Product: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), prepared from 3-dipropylamino-5-methyloxycarbonylchroman (Example 2) analogous to the procedure used in Example 3, in dry tetrahydrofuran (20 ml), was added to a pre-formed solution of lithium dimethylcuprate; prepared from MeLi and CuI, in 200 mL tetrahydrofuran at -78° C. The solution was stirred for 15 minutes at -78° C. and was then allowed to reach room temperature during 10 minutes. Then, 30 mL H20 was slowly added. The organic phase was decanted, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. The title compound was crystallized as salt from ethyl acetate. Mp 106°-108° C. (oxalate).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>CC(O)C.N1CCCCC1>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=C1Cc2c(I)cccc2N1
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Temperature: 23 °C
Yield: 65.2 %

Procedure:
A mixture of 1,3-dihydro-4-iodo-2H-indol-2-one (404.1 mg, 1.56 mmol) (see Fukuyama et al., supra) and pyrrole-2-carboxaldehyde (163.2 mg, 1.72 mmol) (Aldrich) in 2-propanol (6.2 mL) was treated with 2 drops of piperidine. The reaction mixture was heated at reflux for 24 h and then allowed to cool to 23° C., at which time, the reaction mixture was filtered. The solid was washed several times with cold distilled water and then allowed to air dry to provide pure (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (341.8 mg, 65%) as a yellow solid which was used without further purification. (MP 256-258° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH:7]1([C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(CO)C1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
Oxalyl chloride (7.8 g, 61.42 mmol) in methylene chloride (60 mL) at −78° C. was treated with dimethylsufoxide (8.4 g, 107.5 mmol). After stirring at −78° C. for 10 minutes, the mixture was treated with 2-cyclohexyl-2-methylpropanol (4.8 g, 36.86 mmol) in 15 ml of methylene chloride. The mixture was allowed to stir at −78° C. for 30 minutes and then treated with triethylamine (15.54 g, 153.6 mmol). The reaction mixture was stirred for 10 minutes and then stirred an additional 5 minutes at 0° C. The mixture was quenched with saturated aqueous ammonium (10 mL) chloride and extracted with diethyl ether (2×50 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and concentrated under vacuo. The crude product was redissolved in diethyl ether and the resulting precipitate was filtered through a pad of Celite. The solution was concentrated under reduced pressure to provide 4.5 g of 2-cyclohexyl-2-methylpropanal as an oil.