Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:7][CH:8]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2cccc(OC)c2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2cccc(OC)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of ethyl 2-[(3-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.17 g, y. 29%).
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(O)C>[CH2:4]([CH:3]([CH2:6][CH3:7])[CH2:2][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH3:5]
Reactant: CCC(CC)CBr
Reactant: NCCCCO
Solvent: CCO
Product: CCC(CC)CNCCCCO
Temperature: 75 °C
Yield: 80.8 %

Procedure:
A mixture of 3-bromomethyl-pentane (3.0 g, 20 mmol) and 4-amino-1-butanol (5.06 mL, 55 mmol) in ethanol (20 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with dichloromethane (50 mL). The organic layer was partitioned with water (50 mL) and the aqueous layer extracted with dichloromethane (20 mL). Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as an oil (2.8 g). 1H NMR (d6-DMSO, 400 MHz) δ (ppm): 3.37 (t, J=6.0 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H), 2.37 (d, J=5.2 Hz, 2H), 1.43-1.41 (m, 4H), 1.31-1.24 (m, 5H), 0.81 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:4][CH2:3]1.Cl.[Cl-].[C:22](O)(=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[N+:25]([O-:29])[CH:24]=1>N1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:22]([C:23]2[CH:24]=[N+:25]([O-:29])[CH:26]=[CH:27][CH:28]=2)=[O:30])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: CC1CCN(Cc2cccc(OCCCN)c2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC1CCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)CC1
Temperature: 0 °C
Yield: 30.6 %

Procedure:
To a mixture of 0.023 mol of 3-[3-(4-methylpiperidinomethyl)phenoxy]propylamine and 30 ml of pyridine, stirred at 0° C., 0.047 mol of nicotinic acid 1-oxide chloride hydrochloride is added, portionwise; then the mixture is stirred for 1 hour at room temperature and the solvent is evaporated under reduced pressure. The residue is taken up with N hydrochloric acid and the salts thus obtained are eliminated by filtration, then the mixture is extracted 3 times with 100 ml of ethyl acetate and sodium hydroxide is added thereto to basic pH. The mixture is extracted with ethyl acetate containing 10% ethanol, the organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. An oil which crystallizes slowly is obtained. The product is triturated in diethyl ether and filtered to give 4.5 g of crude product which is chromatographed on silica in a mixture methanol: chloroforme 15:35 and crystallized from ethyl acetate. Thus 2.7 g of N-[3-[3-(4-methylpiperidinomethyl)phenoxy] propyl]-3-pyridinecarboxamide 1-oxide are obtained, SR 58037, m.p. 109°-111° C.; yield: 35% of the theoretical value.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[O:15]1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.CCCCCC.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH:20]=[CH:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)[O:15]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(C=Cc2ccc(C(F)(F)F)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.4 %

Procedure:
To a solution of dry diisopropylamine (5.0 mL, 35.7 mM) in dry tetrahydrofuran (150 mL) at -78° C., was added dropwise a 2.3N solution of n-butyllithium in hexane (15.5 mL, 35.7 MM). After the reaction solution was stirred 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (3.0 g, 23.8 mM) in tetrahydrofuran (25 mL) was added dropwise. Hexamethylphosphoramide (6.4 mL, 35.7 mM) was then added dropwise after 30 minutes. Finally, p-trifluoromethylbenzaldehyde (4.0 g, 28.5 mM) in tetrahydrofuran (25 mL) was added in one portion. The reaction solution was stirred 15 minutes when trifluoroacetic anhydride (10.5 mL, 76 mM) was added. Again the reaction solution was stirred 15 minutes when triethylamine (5.9 mL, 48 mM) was added and the mixture was allowed to warm to room temperature. The reaction mixture was partitioned between diethyl ether (50 mL) and saturated aqueous sodium chloride (100 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL), and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber liquid. The crude product was purified by chromatography (silica gel, petroleum ether-ethyl acetate) to give yellow crystals (3.2 g, 71% yield), m.p. 94°-95° C.
Reaction SMILES: Cl.[CH2:2]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[CH:3]([CH3:5])[CH3:4].O=S(Cl)Cl.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[S:28].CCN(CC)CC>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:2]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[CH:3]([CH3:5])[CH3:4].[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]1[N:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[C:7]([CH3:11])([CH3:10])[CH2:8][S:28]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: CC(C)CNC(C)(C)CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(C)(C)N1CC(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
N-Isobutyl-1,1-dimethyl-2-hydroxyethanamine was prepared in a manner analogous to Method B4a. HCl was bubbled into a solution of N-isobutyl-1,1-dimethyl-2-hydroxyethanamine (1.45 g, 10 mmol) in toluene (20 mL) until saturation. SOCl2 (10 mmol) was added to the solution dropwise at room temp., stirred at room temp. for 1 h and at 50° C., for 1 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in CHCl3 (20 mL). To the resulting solution was added 2-methyl-4-nitro-phenyl isothiocyanate (1.94 g, 10 mmol), then a solution of Et3N (10 mmol) in CHCl3 (10 mL) was added dropwise at room temp. The resulting mixture was heated at the reflux temp. for 3 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and the resulting solution was sequentially washed with a 10% aq. NaOH solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (9% EtOAc/pet. ether) and the resulting solids were recrystallized (pet. ether) to give 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-thiazolidine (0.6 g, 63%): mp 97° C. When appropriate, the product was converted into the HCl salt by dissolving the free base (5 mmol) in Et2O (50 mL) and treating this solution with a 2N ethereal HCl solution until no more solid precipitated. The resulting slurry was filtered and the resulting solids were washed with Et2O (25 mL) followed by EtOAc (25 mL).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:18][CH:17]=2)=[CH:21][C:22]=1[O:27][CH3:28]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 1,1-dimethylethyl{(1R)-1-methyl-2-[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate (Intermediate 51, 350 mg) in dry dichloromethane (7.5 mL), TFA (2.5 mL, 32.4 mmol) was slowly added and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge (10 g) to afford the title compound as a colourless oil (258 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N:24]1[CH:25]=[CH:26][C:21]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:22][CH:23]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccncc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccncc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-mercapto-pyridine.
Reaction SMILES: [Na].[CH2:2]([C:9]1[O:10][C:11](=O)[C:12](=[CH:14][OH:15])[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:18][O:19][C:20](=[NH:22])[NH2:21]>C(#N)C>[CH3:18][O:19][C:20]1[NH:22][C:14](=[O:15])[C:12]([NH:13][C:9](=[O:10])[CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:11][N:21]=1
Reactant: COC(=N)N
Reactant: O=C1OC(Cc2ccccc2)=NC1=CO
Agent: Cl
Agent: [Na]
Solvent: CC#N
Product: COc1ncc(NC(=O)Cc2ccccc2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Acetonitrile (15 ml) was added to 2-benzyl-4-hydroxymethylene-5-oxazolone sodium salt (1.00 g, 4.44 mmol) and O-methylisourea hydrochloride (0.49 g, 4.44 mmol), and the mixture was stirred overnight at 80° C. The mixture was concentrated under reduced pressure, water (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Then, the precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-phenylacetylamino-1,6-dihydropyrimidine (0.94 g, 3.64 mmol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]2[N:10]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=[CH:12][C:5]=12
Reactant: Brc1cncc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
To a stirring suspension of NaH (1.3 g) in anhydrous THF (25 ml) at −5° C. was added 4-bromo-1H-pyrrolo[2,3-c]pyridine (prepared for example as described in patent US2005/0090529, 5 g) in anhydrous THF (75 ml) over 10 min. The reaction was stirred at −5° C. for 10 min then benzenesulfonyl chloride (3.6 ml) in anhydrous THF (25 ml) was added over 10 min. The reaction was stirred at 0° C. for 1 h then quenched with water. The layers were separated and the aqueous was re-extracted with ethyl acetate. The organics were combined, washed with brine, dried over magnesium sulfate, filtered and then evaporated to yield a residue that was triturated using methanol (25 ml). The resulting solid was collected by filtration, washed sparingly with methanol then dried in vacuo at 45° C. overnight to give title compound, 7.9 g.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[C:9]=2[F:11])[N:4]([CH3:16])[CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[C:9]=2[F:11])[N:4]([CH3:16])[CH:3]=1
Reactant: COC(=O)c1ccc2c(c(Cl)cn2C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(Cl)c2c(F)c(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The ester thus obtained was dissolved in a mixture of tetrahydrofuran (10 mL), methanol (10 mL) and dichloromethane (3 mL). 2 M sodium hydroxide (4.31 mL) was added and the mixture stirred at room temperature for 3 h. Further 2 M sodium hydroxide (4.31 mL) was added and the reaction stirred at room temperature for 16 h. The mixture was concentrated in vacuo, diluted with water and ethyl acetate added. The resultant emulsion was acidified with 1 M hydrochloric acid (pH=2-3) and extracted with ethyl acetate. The combined ethyl acetate phases were dried and concentrated to give the title compound (0.274 g) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+].C.Cl>CN(C)C=O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([S:7]([CH2:10][C:11]2[NH:16][N:15]=[N:14][N:12]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cc2nnn[nH]2)cc1

Procedure:
97.5 parts of p-tolylsulphonyl-acetonitrile are stirred together with 39 parts of sodium azide, 32 parts of ammonium chloride and 200 parts of dimethylformamide for 10 hours at 120°-130° C. The dimethylformamide is distilled off in vacuo, and the residue is dissolved in 1000 parts of water with the addition of sodium hydroxide to give pH 9. The solution is treated with animal charcoal, and precipitation is effected at pH 2-3 by the addition of hydrochloric acid. Recrystallisation of the precipitate from isopropanol yields 85 parts of 5-(p-tolylsulphonylmethyl)-tetrazole in the form of white crystals which melt at 206°-208°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1.C([O-])(=O)C.[K+].[Br:30]Br>C(O)(=O)C>[Br:30][C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=2)[C:19]#[N:20])[CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:1])[C:10]12[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: BrBr
Reactant: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1cc(F)cc(-c2cc(Br)c3c(c2)C2(CCCCC2)C(=O)N3)c1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A mixture of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (0.40 g, 1.23 mmol) and potassium acetate (0.13 g, 1.3 mmol) in glacial acetic acid (3 mL) at room temperature was treated with a solution of bromine (1.05 eq, 0.21 g, 1.3 mmol) in a glacial acetic acid (3 mL). After stirring for 1 h the mixture was poured onto ice (20 g). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The organic layers were combined, washed sequentially with 10% aqueous sodium thiosulfate (20 mL), water (2×10 mL), saturated sodium bicarbonate (10 mL) and brine (15 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give the title compound (0.21 g, 43%) as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 217° C. 1H NMR (CDCl3; 300 MHz) δ 1.56-2.04 (m, 10H), 7.33 (dddd, 1H, J=1.25, 2.3, 3.6 and 9.0 Hz), 7.45 (m, 1H), 7.47 (m, 2H), 7.54 (m, 1H), 7.60 (m, 1H). MS ((−)−ESI) m/z 399 [M−]. Anal. Calcd for C20H16BrFN2O1: C, 60.17; H, 4.04; N, 7.02. Found: C, 60.03; H, 4.08; N, 6.83.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C:11]([CH3:23])([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:24])[N:4]=[C:3]1[N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CCOC(C)=O.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:40])([CH3:1])[C:3]([N:25]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:4][C@:5]3([CH3:24])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl N-[(4aR,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxo-4a,5-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (105 mg, 0.180 mmol) and 10% Pd/C (58 mg, 0.054 mmol) in EtOAc (1.1 mL) and MeOH (1.1 mL) was stirred under hydrogen atmosphere for 16 hours. The mixture was passed through a celite cake and rinsed with ethyl acetate and ethanol. The filtrate was concentrated in vacuo to afford the title compound (99 mg, 0.180 mmol, 100% yield) as a white foam. MS m/z=574.3 (M+Na).
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH:7]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[C:23]([CH3:29])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].[C:37]([O:41][CH3:42])(=[O:40])[CH2:38]O>C1(C)C=CC=CC=1>[CH3:42][O:41][C:37](=[O:40])[CH2:38][O:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:35])[CH3:36])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:11]([CH3:30])[CH:12]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:22][C:23]=1[CH3:29]
Reactant: COC(=O)CO
Reactant: CCC(CC)(c1ccc(CO)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(COCC(=O)OC)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Yield: 0 %

Procedure:
To a solution of enantiomer 1 of [4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-methanol, (2.10 g, 4.10 mmol) and PhCH3 (10 mL) is added methyl glycolate (6.5 mL, 81.89 mmol) and MeReO3 (0.02 g, 0.082 mmol). The solution is heated at a reflux for 2 hours with the use of a Dean-Stark trap. The solution is concentrated and chromatographed to give the title compound (0.96 g, 1.64 nmol, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([Si:5]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[O:6][CH:7]1[C:11]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:26][SiH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:12]([O:14][N:15]2C(=O)C3C(=CC=CC=3)[CH2:16]2)=O)[O:10][CH:9]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[CH:8]1[O:52]C(=O)C)([CH3:4])([CH3:3])[CH3:2].CNN.CO.C=O>ClCCl>[C:1]([Si:5]([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[O:6][CH:7]1[C:11]([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:26][SiH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH2:12][O:14][N:15]=[CH2:16])[O:10][CH:9]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[CH:8]1[OH:52])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC1C(n2ccc(=O)[nH]c2=O)OC(C(=O)ON2Cc3ccccc3C2=O)(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C=O
Agent: CNN
Solvent: ClCCl
Solvent: CO
Product: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
This transformation is performed smoothly in high yield using published procedures (Bhat, B., et. al., J. Org. Chem. 1996, 61, 8186-8199). Generally, a portion of Compound 16 is dissolved in dichloromethane and cooled to −10° C. To this solution is added methylhydrazine (2.5 eq.). After 1-2 hours of stirring at 0° C., the mixture is diluted with dichloromethane, washed with water and brine, dried with anhydrous Na2SO4, filtered, and evaporated. The resulting residue is immediately redissolved in a 1:1 mixture of ethyl acetate:methanol, and treated with 20% (w/w) aqueous formaldehyde (1.1 eq.). After an hour at room temperature, the mixture is concentrated then purified by silica gel chromatography to give Compound 17.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+]>CO>[CH3:13][O:12][C:9]1[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][S:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CSc1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To (6-methoxy-2′-phenylsulfanylmethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.24 mmol) in MeOH was added lithium hydroxide (a spatula tip), and the reaction was stirred at 65° C. overnight. After acidic work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][Cl:28].[ClH:34]>C(C(C)=O)C>[ClH:28].[ClH:34].[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1OC
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Agent: Cl
Solvent: CCC(C)=O
Product: COc1ccc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 87.4 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole) and 1.87 g (0.01 mole) of 3,4-dimethoxybenzyl chloride were dissolved in 20 ml of methyl ethyl ketone, and the resulting solution was heated at the refluxing temperature for 7.5 hours. After the reaction liquid was left to cool, dry hydrogen chloride gas was passed through the liquid while cooling the liquid to precipitate 1-(3,3-diphenylpropyl)-4-(3,4-dimethoxybenzyl)piperazine dihydrochloride. The crystals of this salt were recrystallized from an ethanol and ether mixed solvent to obtain 4.4 g (87.4% yield) of pure crystals with a melting point of 184°C.