Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:11]1[C:12](=[O:22])[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15](=O)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:7]([C:11]1[C:12](=[O:22])[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15](=[N:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1cnccn1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A 97.1 ml quantity of pyridine was dissolved in 944 ml of dichloroethane, and 32.9 ml of titanium tetrachloride was added thereto. The resulting mixture was refluxed with heating for 15 minutes. To the mixture were then added 132.2 g of 2,6-di-tert-butyl-1,4-benzoquinone and 57.1 g of aminopyrazine, and the mixture was refluxed with heating for 42 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with dichloromethane. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=3:7), giving 82.8 g of Compound 1a.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C:51]2([C:54]([F:57])([F:56])[F:55])[CH2:53][CH2:52]2)=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C:51]3([C:54]([F:57])([F:56])[F:55])[CH2:52][CH2:53]3)=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=C(NC1(C(F)(F)F)CC1)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)NC6(C(F)(F)F)CC6)cn5)C4)c3)ncnc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
N,N-Diisopropylethylamine (0.71 mL, 4.1 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.70 g, 1.4 mmol) and 5-chloro-N-[1-(trifluoromethyl)cyclopropyl]pyrazine-2-carboxamide (0.36 g, 1.4 mmol) in NMP (5.0 mL). The reaction mixture was stirred at 125° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-80%) to afford the desired product (0.90 g). LCMS (M+H)+: m/z=639.2.
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([NH:12][CH:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:14]([OH:23])[C:15]([F:22])([F:21])[C:16](OCC)=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)C>[CH2:2]([O:9][C:10]([NH:12][CH:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:14]([OH:23])[C:15]([F:22])([F:21])[C:16]([NH2:1])=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: CCOC(=O)C(F)(F)C(O)C(CC(C)C)NC(=O)OCc1ccccc1
Solvent: CCOCC
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(O)C(F)(F)C(N)=O

Procedure:
A stream of dry ammonia was bubbled at -78° C., through a solution of 0.820 g (2.2 mmol) of 4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-6-methylheptanoic acid, ethyl ester in anhydrous diethyl ether (10 mL). After saturation, the temperature was allowed to rise to room temperature with stirring. The excess ammonia was removed, and the solvent evaporated in vacuo. The residue was taken off in pentane to yield the expected amide in quantitative yield as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:26](OCCC(C)C)=O>C(Cl)(Cl)Cl>[F:13][C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:26]=[CH:12]2
Reactant: CC(C)CCON=O
Reactant: COC(=O)c1cc(F)cc(C)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2-amino-5-fluoro-3-methylbenzoate (1.0 g, 5.5 mmol) from Step C above in chloroform (15 mL) was added acetic anhydride (1.2 ml) while maintaining the temperature below 40° C. The reaction mixture was stirred at room temperature for 90 min then potassium acetate (157 mg, 1.6 mmol) and isoamyl nitrite (1.62 ml, 12 mmol) were added to it. The reaction mixture was heated to reflux for overnight. The reaction mixture was cooled to room temperature, extracted with dichlormethane, washed with water, saturated sodium bicarbonate and brine. The organic extract was dried (Na2SO4) and concentrated in vacuo to afford a red solid, which was purified by column chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford methyl 5-fluoro-1H-indazole-7-carboxylate (455 mg, 43%) as a yellow brown solid: 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.96 (dd, J=9.0, 3.0 Hz, 1H), 7.81 (dd, J=9.0, 3.0 Hz, 1H), 3.98 (s, 3H); MS (ESI+) m/z 195.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2.[I-:18].[Na+]>CC(C)=O>[I:18]/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2
Reactant: [I-]
Reactant: O=C(/C=C/Cl)CCCCC1CCC2CCC1C2
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)CCCCC1CCC2CCC1C2
Yield: 84.4 %

Procedure:
A solution of 3.2 g (13 mmol) of 1-chloro-7-(bicyclo-[3.2.1]oct-2-yl)-1E-hepten-3-one and 7.5 g (50 mmol) of sodium iodide in 25 ml of dry acetone (distilled from potassium carbonate) was refluxed for 18 hr under nitrogen. The solvent was removed in vacuo, and the residue was taken up in 50 ml of water and then extracted three times with 30 ml portions of ether. The combined ether extracts were washed with aqueous sodium thiosulfate, dried (MgSO4) and evaporated in vacuo to yield 3.8 g (88%) of 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1-E-hepten-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:17])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 68.2 %

Procedure:
A solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred at ambient temperature while 4 ml (0.06 mole) of 57% ammonium hydroxide was slowly added. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the resulting solid collected by filtration (5 g). Recrystallization from isopropanol yielded 3.7 g (59%) of fine beige crystals, m.p. 188°-189° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(Cl)(Cl)Cl>[N+:23]([C:11]1[O:10][C:9]2[C:12]3[C:17]([C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O-:28])=[O:24]
Reactant: O=C(O)c1cc2c(-c3ccccc3)coc2c2ccccc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc2c(-c3ccccc3)c([N+](=O)[O-])oc2c2ccccc12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
The product of Step A is dissolved partially in 125 ml. of hot chloroform, and 1 g. of dinitrogen tetraoxide is added. The mixture is stirred at 20° C. for about 1 day. The mixture is evaporated to provide a residue which is triturated with isopropyl alcohol. The residue is separated by filtration and recrystallized from acetic acid to provide light yellow crystals of 2-nitro-3-phenylnaphtho-[1,2-b]furan-5-carboxylic acid, m.p. 286°-288° c. (dec.).
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][CH2:7][CH:8]([OH:13])[CH:9](O)[CH2:10][Cl:11].S(=O)(=O)(O)O>C(Cl)CCl>[CH:2]([CH:1]1[O:13][CH:8]([CH2:7][Cl:6])[CH:9]([CH2:10][Cl:11])[O:5]1)([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: OC(CCl)C(O)CCl
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CC(C)C1OC(CCl)C(CCl)O1

Procedure:
A three-neck 5-mL flask fitted with a thermometer, mechanical stirrer, addition funnel, condenser and positive nitrogen atmosphere was charged with EDC (200 mL), isobutyraldehyde (11.3 g, 0.157 mole), and 1,4-dichloro-2,3-butanediol (25.0 g, 0.157 mole). Concentrated sulfuric acid (23.2 g) was added dropwise to the agitated mixture over thirty minutes, during which time a slight exotherm was noticed and the flask was immersed in an ice bath to maintain a reaction temperature of 17°-19° C. Stirring was then continued at ambient temperature (20° C.) for five hours.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.CN(C=O)C>O>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: C1COCCN1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(OCCCCl)cc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCCCN4CCOCC4)cc3c21
Temperature: 50 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
Potassium carbonate (530 mg, 3.84 mmol), morpholine (92 mg, 1.06 mmol), and 8-(3-chloropropoxy)-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (350 mg, 0.96 mmol) were added to 15 mL of DMF and heated to 50° C. for 18 hours. Analysis by LC/MS indicated the presence of two peaks and the reaction mixture was cooled and poured into 500 mL of deionized water. After three hours, no precipitation was observed. Sodium chloride (250 g) was added to the mixture and the mixture was stirred vigorously overnight. The precipitate was collected by filtration, dissolved in dichloromethane, and purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60). The resulting material was concentrated under reduced pressure, crystallized from acetonitrile, and dried under high vacuum to yield 36 mg of 2-methoxymethyl-8-(3-morpholin-4-ylpropoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 193-196° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]([C:9](=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=1)[C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])#[N:8]>>[C:7]([C:9](=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[C:24]([O:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=1)[C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])#[N:8]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)Oc1cc(C=C(C#N)C(=O)OCCc2ccccc2)ccc1O
Product: CCOC(=O)Oc1ccc(C=C(C#N)C(=O)OCCc2ccccc2)cc1OC(=O)OCC

Procedure:
Further, reduction of the amount of ethyl chloroformate to 1/2 in the above-described process selectively provided phenethyl 2-cyano-3-(3-ethoxycarbonyloxy-4-hydroxyphenyl)-2-propenoate (Compound 17).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:17][N:18]([CH2:24][C:26]3[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH2:19][CH2:20][O:21]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C(N(CC1CNCCO1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CO
Product: O=C(O)c1ccc(CN2CCOC(CN[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(morpholin-2-ylmethyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide (100 mg, 0.305 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 4-formylbenzoate (60.0 mg, 0.365 mmol) and sodium triacetoxyborohydride (97 mg, 0.457 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was then quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved into methanol (3.00 mL) and sodium hydroxide (6M, 0.5 mL, 3.00 mmol) was added. The mixture was stirred at room temperature for 18 h and purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 81 mg of product (HCl salt) as white solid. MS: (M+H)+=367.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.36 (m, 1H), 1.50 (br. s., 1H), 2.93 (br. s., 2H), 3.10 (br. s., 2H), 3.35 (br. s., 2H), 4.05 (br. s., 2H), 4.36 (br. s., 2H), 7.10-7.39 (m, 5H), 7.74 (br. s., 2H) 8.01 (m, 2H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.ClC1C=CC(C(NN)=O)=CC=1.[CH3:22][N:23]=[C:24]=[O:25].C(N=C=O)C>>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:9][NH:10][C:24]([NH:23][CH3:22])=[O:25])=[O:8])=[CH:3][CH:4]=1
Reactant: CN=C=O
Reactant: NNC(=O)c1ccncc1
Agent: CCN=C=O
Agent: NNC(=O)c1ccc(Cl)cc1
Product: CNC(=O)NNC(=O)c1ccncc1

Procedure:
When, in the procedure of Example 1, isonicotinic acid hydrazide is substituted for 4-chlorobenzoic acid hydrazide and methyl isocyanate is substituted for ethyl isocyanate, the title compound is obtained.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].CCCCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOCC>[CH2:32]([O:31][C:29](=[O:30])[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 124.9 %

Procedure:
To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et2O cooled to −78° C. was added 3.6 mL of tert-butyl]ithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) concentrated under reduced pressure The residue was chromatographed (2-5% EtOAc-hexanes) to give 1.23 g (88%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:18][C:19]([CH3:39])([CH3:38])[CH2:20][C:21]([NH:23][C:24]1[C:25]([CH3:37])=[C:26]([CH3:36])[C:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29](=[O:34])[C:28]=2[CH:35]=1)=[O:22].O>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:29]2([OH:34])[C:28]3[CH:35]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][C:19]([CH3:18])([CH3:38])[CH3:39])[C:25]([CH3:37])=[C:26]([CH3:36])[C:27]=3[O:31][C:30]2([CH3:33])[CH3:32])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (1.65 mL, 10.9 mmol) in THF (20 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 M hexane solution, 6.4 mL, 10.2 mmol), and the resulting mixture was stirred for 30 minutes. To the reaction solution was added dropwise at −78° C. a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (1.0 g, 3.30 mmol) obtained in Reference Example 65 in THF (10 mL), and the resulting mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.38 g (yield: 92%) of N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide as an amorphous powder. To a mixed solution of the obtained N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (300 mg, 0.66 mmol) in acetone (4 mL)-water (0.3 mL) was added pyridinium p-toluenesulfonate (5 mg, 0.03 mmol), and the mixture was stirred for 30 minutes. The reaction solution was cooled to room temperature, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from THF-diisopropyl ether to obtain 194 mg (yield: 72%) of the title compound. Melting point: 189-190° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>C(O)(C)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)C(O)Cc1ccc(O)cc1
Yield: 96.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid were dissolved in 50 ml of isopropyl alcohol, and 0.3 g of 10% palladium on charcoal was added thereto. The mixture was stirred at 25° C. under atmospheric pressure for 6 hours in a hydrogen stream. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 9.8 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([CH2:20][CH2:21][CH2:22][N:23](C)[CH3:24])[C:10]=2[CH:26]=1)(=[O:5])=[O:4].N#CN.C(O)(=O)C.Cl>O>[CH3:27][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:10]=2[CH:26]=1)(=[O:4])=[O:5]
Reactant: CN(C)CCCC1c2ccccc2C=Cc2ccc(S(=O)(=O)N(C)C)cc21
Agent: Cl
Agent: N#CN
Solvent: CC(=O)O
Solvent: O
Product: CNCCCC1c2ccccc2C=Cc2ccc(S(=O)(=O)N(C)C)cc21

Procedure:
3-Dimethylsulfamoyl-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 17, Step B. The cyanamide (0.28 g., 0.00071 mole) together with 2.8 ml. of glacial acetic acid, 2.0 ml. of water and 0.4 ml. of concentrated hydrochloric acid is heated to refluxing for 29 hours. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in water. The aqueous solution is made alkaline with sodium hydroxide and the oily base that separates is extracted into ether. The washed and dried ether extract is evaporated under reduced pressure, leaving 3-dimethylsulfamoyl-5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene as an oil weighing 170 mg. The base may be converted to the hydrogen oxalate salt by dissolution in absolute ethanol, addition of an equimolar quantity of oxalic acid dissolved in ethanol, and precipitation by the addition of ether. After repeated recrystallizations from absolute ethanol and from isopropyl alcohol, the hydrogen oxalate melts at 133.5°-135.5°C., des.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
Trans-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (171 mg, 0.44 mmol) (from example 49, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. Sodium hydroxide (0.117 mL, 0.44 mmol) dissolved in water (0.200 mL) was added dropwise and the solution stirred for 20 min. Hydroxylamine (50% by weight in water, 0.024 mL, 0.44 mmol) was then added and stirring was continued for 3.5 h. The mixture was then transferred to a prewarmed 80° C. solution of 6 M hydrogen chloride (2.290 mL, 13.74 mmol) and stirring was continued at 80° C. for 20 min. The solvent was evaporated in vacuo and DCM (50 mL) and water (50 mL) were added. The phases were shaken, separated and the organic phase dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 19 mL/min. (2S,4S)-Methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (49.0 mg, 31.2%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.58-1.70 (m, 1H), 1.85-2.06 (m, 2H), 2.60 (d, 1H), 2.73-2.96 (m, 2H), 3.73 (s, 3H), 4.04-4.44 (m, 1H), 5.42-5.78 (m, 2H), 6.92-7.05 (m, 2H), 7.38 (t, 1H). MS m/z 355 (M+H)+