Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH2:19]>CO>[CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1[NH:19][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Solvent: CO
Product: CNC1=C(N=O)C(=O)NC1=Cc1ccccc1
Yield: 50 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 ml (0.25 mmol) methylamine solution for two minutes. The compound 5-benzylidene-4-methylamino-3-nitroso-1,5-dihydropyrrol-2-one was obtained in a yield of 50% after recrystallization from methanol. The compound decomposes at 220° C.
Reaction SMILES: FC(=C(F)F)[CH2:3][C:4]([OH:6])=[O:5].[Cl:10][C:11]([F:17])(Br)[C:12]([F:15])([F:14])[Br:13]>[Zn]>[Br:13][C:12]([F:15])([F:14])[C:11]([Cl:10])([F:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CC(F)=C(F)F
Reactant: FC(F)(Br)C(F)(Cl)Br
Agent: [Zn]
Product: O=C(O)CC(F)(Cl)C(F)(F)Br

Procedure:
A mixture of 1,1,2-trichlorotrifluoroethane (X) (9.37 g, 50 mmol), vinylidene chloride (4.85 g, 50 mmol), ammonium persulfate (11.41 g, 50 mmol), sodium formate (3.4 g, 50 mmol) and water (1.8 g, 0.1 mol) in DMF (80 mL.) was stirred (dry-ice/acetone condensor) at room temperature with air bubbling. After 30 min, an aliquot of the reaction mixture was acidified with dilute HCl, extracted with ether and analyzed by GC, which indicated the formation of two products. These products were identified by GC/MS (EI) as 4-chloro-3,4,4-trifluoro-2-butenoic acid and novel compound 3,4-dichloro-3,4,4-trifluorobutanoic acid (XI). The compound XI gives 3,4,4-trifluoro-3-butenoic add (IV) upon reaction with zinc. Under the above reaction conditions, 1-chloro-1,2-dibromotrifluoroethane (VI) gave 3-chloro-4-bromo-3,4,4-trifluorobutanoic acid (VIII) as one of the products.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 102.2 %

Procedure:
To a solution of compound 18a (15.0 g, 51.2 mmol) in MeOH (100 mL) was added Fe (9.06 g, 162 mmol) and saturated NH4Cl solution (100 mL). The resulting solution was stirred at 80° C. for 5 h. After cooling to rt, the mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:5 v/v) to obtain compound 18b as a black solid (13.0 g, 97% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H20N2O2: 249.2 (M+H). Found 249.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N+:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:50])[C:23]=1[CH2:24][S:25][C:26]1[N:27]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[C:28]([C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)([CH3:33])[CH3:32])=[CH:29][N:30]=1)[C:18](O)=[O:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:50])[C:23]=1[CH2:24][S:25][C:26]1[N:27]([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[C:28]([C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)([CH3:33])[CH3:32])=[CH:29][N:30]=1)[C:18]([NH:1][CH2:2][CH2:3][N+:4]([CH3:12])([CH3:13])[CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:9])=[O:10])=[O:19]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reactant: C[N+](C)(CCN)CCCS(=O)(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCC[N+](C)(C)CCCS(=O)(=O)[O-])cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
A solution of tert-butyl 2-(dimethylamino)ethylcarbamate (1.8 g, 7.98 mmol) and 1,3-sultone (1.07 g, 8.77 mmol) in toluene was heated 4 h at 60° C. to form a white solid. After cooling to room temperature, the solids were collected by filtration and rinsed with hexanes (2×30 mL). The solids were dissolved in DCM (5 mL) and charged dropwise with TFA (5 mL). After 30 min, the reaction mixture was concentrated under reduced pressure to yield 3-((2-aminoethyl)-dimethylammonio)propane-1-sulfonate as a white solid (2.15 g). This quartarnary amine (82 mg, 0.266 mmol) was added to a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)-propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (100 mg, 0.1776 mmol) in DMF (1 mL) followed by DIPEA (137 mg, 1.06 mmol) and HATU (74.2 mg, 0.195 mmol). After 20 min, the reaction was determined to be complete by LC-MS. The product mixture was concentrated and purified by HPLC (MeCN/H2O, 10-99%) to yield the title compound as a white solid (85 mg). 1H NMR (400 MHz, MeOD) δ 8.96 (t, J=5.3 Hz, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.60 (dd, J=10.0, 1.6 Hz, 1H), 7.28-7.18 (m, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H) 6.57-6.52 (m, 2H), 6.51-6.45 (m, 2H), 4.18 (s, 2H), 3.89 (t, J=5.5 Hz, 2H), 3.75 (s, 3H), 3.68-3.56 (m, 4H), 3.23 (s, 6H), 2.87 (t, J=6.7 Hz, 2H), 2.25 (dt, J=14.2, 7.1 Hz, 2H), 1.60 (s, 6H). LC-MS: 655.3 [M]+.
Reaction SMILES: [CH3:1][CH:2]([NH:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[H][H].[ClH:25]>[Pd]>[ClH:25].[CH3:1][CH:2]([NH:14][C:15]1[NH:20][CH:19]([CH3:21])[CH2:18][CH:17]([CH3:22])[N:16]=1)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: Cc1cc(C)nc(NC(C)Cc2ccc(C(C)(C)C)cc2)n1
Agent: [Pd]
Agent: Cl
Product: CC1CC(C)NC(NC(C)Cc2ccc(C(C)(C)C)cc2)=N1

Procedure:
A solution of the 2-(1-methyl-2-[4-t-butylphenyl]ethyl)amino-4,6-dimethylpyrimidine (1.24 g, 4.18 mmol) obtained in (iii) in 0.5M ethanolic hydrogen chloride (100 ml) was hydrogenated at about 3 atmospheres in the presence of 10% palladium on charcoal catalyst (320 mg) until hydrogen uptake had ceased. The solution was then filtered to remove the catalyst and the filtrate evaporated. Addition of dichloromethane (20 ml) and evaporation afforded 1.08 g 2-(1-methyl-2-[4-t-butylphenyl]ethyl)amino-4,6-dimethyl-3,4,5,6-tetrahydropyrimidine hydrochloride (in hemi-hydrate form) as an off-white foam, m.pt., 40°-45° C. M+ (--HCl) found: 301.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32]>C(O)(C)C.CN>[C:11]([CH2:10][NH:14][CH2:13][C@@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:23])[CH3:24])[OH:12])(=[O:12])[CH3:13]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Agent: CN
Solvent: CC(C)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNCC(C)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.050 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (Example 1b) in 1.0 ml of isopropanol and 0.10 ml of methylamine is stirred at 60° C. over 2 hours. The reaction mixture is concentrated by evaporation to dryness. The residue is dissolved in 2 ml of dichloromethane, admixed successively with 0.017 ml of pyridine and 0.026 ml of acetic anhydride and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with 1M HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.13 (95:5 dichloromethane-methanol); Rt=4.47 (gradient I).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C@@H:15]([N:26]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]#[N:51])[CH:41]=2)[C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][N:28]=2)[CH2:14][C@H:13]1[CH2:52][CH3:53])=[O:11])=[O:7])(C)(C)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[C:6]([CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C@@H:15]([N:26]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[C:42]([C:50]#[N:51])[CH:41]=2)[C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][N:28]=2)[CH2:14][C@H:13]1[CH2:52][CH3:53])=[O:11])([OH:7])=[O:5]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)O
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The compound obtained in Example 22 above (37 mg) was dissolved in 4N HCl/dioxane (2 ml) and stirred at room temperature for 6.5 hours. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; chloroform:methanol=1:0→17:3) to give the titled compound (26 mg). MS (m/z): 693 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16]>>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]2[C:15](=[O:16])[CH:14]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COC(=O)c1cnc(N)s1
Product: COC(=O)c1cn2c(=O)cc(CCl)nc2s1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-amino-thiazole-5-carboxylic acid, methyl ester (5 g) was reacted with ethyl 4-chloro-acetoacetate (10.6 g) in polyphosphoric acid (25 g) under stirring at 100° C. for 4 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was extracted with ethyl acetate and purified over a SiO2 column using n-hexane/ethyl acetate as eluent. Crystallization from isopropyl ether gave 7-chloromethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester, m.p. 139°-141° C. (2.75 g) which was reacted with triphenylphosphine (3.15 g) in acetonitrile (100 ml) under stirring at reflux temperature for 16 hours. After cooling the precipitate was filtered and washed with acetonitrile to give (2-carbomethoxy-5-oxo-5H-thiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenyl-phosphonium chloride, m.p. 180°-181° C. dec. (3.35 g) which was added under stirring to a suspension of 75% NaH (0.3 g) in dimethylsulphoxide (60 ml) and dichloroethane (40 ml) and reacted with 3-pyridine carboxaldehyde (1.4 g) at room temperature for 20 hours. The solution was then diluted with ice water and the crude precipitate was extracted with dichloroethane: the organic phase was separated and evaporated in vacuo to dryness. The crude residue was crystallized from isopropyl alcohol to give 7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (1.3 g) which was hydrolyzed by treatment with a mixture 37% HCl:acetic acid=1:1 (50 ml) at the reflux temperature for 40 hours. After cooling the reaction mixture was diluted with ice water and neutralized with 37% NaOH: the precipitate was filtered and washed with water until neutral. Crystallization from CHCl3 -ethanol gave 0.87 g of 7-trans-[2-(3-pyridyl)-ethenyl]-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 264°-267° C., N.M.R. (CDCl3 -CF3COOD) δp.p.m.: 6.95 (s) (1H, C-6 proton), 7.53 (d) (1H,β-ethenyl proton), 8.02 (d) (1H,α-ethenyl proton), 8.20 (dd) (1H, C-5 pyridyl proton), 8.60-9.03 (m) (2H, C-4 and C-6 pyridyl protons), 8.90 (s) (1H, C-3 proton), 9.11 (bs) (1H, C-2 pyridyl proton), JHαHβ =16 Hz.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[N:48]1([CH2:47][CH2:46][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: OCCN1CCOCC1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropyl azodicarboxylate (1.1 eq) was added dropwise to a stirred solution of 4-amino-3-nitrophenol (1.0 eq), triphenylphosphine (1.1 eq), and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 eq), in tetrahydrofuran at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, and the product was purified by silica gel chromatography (98:2 CH2Cl2:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine as a dark reddish-brown oil. LC/MS m/z 268. 0 (MH+), Rt 1.01 minutes. The nitroamine was reduced as in Method 1 to give the crude product which was used without further purification. LC/MS m/z 238.3 (MH+), Rt 0.295 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: CCCCCI
Product: CCCCCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrrole-carbonitrile (1.94 g, 7.3 mmol) was reacted, according to General Method A, with 1-iodopentane (1.5 g, 7.6 mmol) to afford the title compound, m.p. 128-131° C. (0.2 g, 8%); 1H-NMR (DMSO-d6) δ0.73 (t, J=7.3 Hz, 3H), 1.05 (m, 2H), 1.14 (m, 2H), 1.57 (m, 2H), 1.63 (s, 6H ), 4.04 (t, J=7.5 Hz, 2H), 6.28 (d, J=4 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 7.04 (d, J=4.5 Hz, 1H), 7.33 (dd, J=8.9, 2.0 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 10.41 (s, 1H), MS (APCI (−)) m/z 336 (M−H)−
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:12]([OH:14])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCCCc2ccccc21
Product: CCn1cc(CN(C(=O)C2CCCCc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 57 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxamide (0.36 g) was obtained.
Reaction SMILES: C([Li])CCC.[C:6]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH3:7].[CH:14]12[CH2:26][CH2:25][CH:21]([C:22](=[O:24])[CH2:23]1)[C:20]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=1>C1COCC1.C1(C)C=CC=CC=1>[C:10]([O:9][C:6](=[O:8])[CH2:7][C:22]1([OH:24])[CH2:23][CH:14]2[CH2:26][CH2:25][CH:21]1[C:20]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CC2CCC1c1ccccc12
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(O)CC2CCC1c1ccccc12
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.5 mL of DIPA in 6 mL THF were added dropwise 9.9 mL of n-butyllithium (2.5M in Hept) at −20° C. After 20 min, 12 mL of toluene were added and the solution was stirred for 30 min. The mixture was cooled to −50° C., 4.5 mL of tert.-butyl acetate were added and stirring was continued for 1 h at −50° C. Then, 2.5 g of rac-(1R*,8R*)-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-one dissolved in 6 mL of toluol were added and the solution was stirred at −50 to −20° C. over 2.5 h. The reaction mixture was poured on ice/aq. HCl, the organic phase was separated, washed with sat. aq. NaHCO3, dried over Na2SO4 and concentrated in vacuo. The crude reaction product was purified by CC with Hept/EtOAc (4:1) to yield 2.6 g of the major racemate, rac-(1R*,8R*,9R*)-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)-acetic acid tert-butyl ester as beige solid and 0.4 g of the minor racemate, rac-(1R*,8R*,9S*)-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]2[C:15]=1C=CC(=O)N2)[O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].C(OC1C=CC([C@@H](O)CBr)=CC=1[CH2:51][O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])C1C=CC=CC=1>>[N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:20]([CH2:51][O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH:15]=1)[OH:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 1, using Intermediate 7 in place of (R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one. ES/MS calcd. for C22H31N3NaO3Si+ 436.2. Found m/z=436.2 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:20][CH2:21][O:22][CH3:23])[C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[N+:16]([O-])=O.[H][H]>[Pd].CO>[CH3:23][O:22][CH2:21][CH2:20][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH2:16]
Reactant: COCCN(CCOC)C(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCCN(CCOC)C(=O)c1ccc(N)cc1N
Yield: 100.2 %

Procedure:
A two liter autoclave was charged with 65.0 g of N,N-bis(2-methoxyethyl)-2,4-dinitrobenzamide, 1000 ml of methanol and 2.7 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 800 psi hydrogen pressure while maintaining the temperature between 60°-100° C. Hydrogen uptake ceased after 30 min. The mixture was cooled, filtered, and the methanol removed at reduced pressure to give 53.2 g of N,N-bis(2-methoxyethyl)-2,4-diaminobenzamide, a red-brown viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[C:34](Cl)=[N:35][CH:36]=[C:37]([CH:43]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:34]2[C:33]([Cl:32])=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=2)[CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH3:22])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc([C@@H](C)N(CC2CCNCC2c2ccccc2)C(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc(OC)c3)C(c3ccccc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a mixture of 119 mg of the crude tert-butyl[(1R)-1-(3-methoxyphenyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 62 mg of ethyl 5,6-dichloronicotinate, and 39 mg of potassium carbonate was added 1.0 mL of DMSO at room temperature, and the mixed solution was stirred at 100° C. overnight. After cooling to room temperature, to the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 132 mg of ethyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinate as a colorless foamy substance. FAB+: 608
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1C=CC=C[N+]=1C.[CH2:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Yield: 77.2 %

Procedure:
2.0 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid, 2.02 g of 2-chloro-1-methylpyridinium iodide, 1.47 g of laurylalcohol, 1.60 g of triethylamine and 60 ml of tetrahydrofuran are treated in the same manner as described in Example 27. 2.4 g of lauryl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate are obtained. Yield: 77.4%
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[CH:22]1[C:27](O)=[CH:26][CH:25]=[C:24]([CH3:29])[CH:23]=1.C(N(CC)CC)C>S(Cl)(Cl)=O>[C:24]1([CH3:29])[CH:25]=[CH:26][C:27]([O:12][C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH:4]=3)[NH:8][N:7]=2)=[O:13])=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Reactant: Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2cc3c(C(=O)Oc4ccc(C)cc4)n[nH]c3cc2Cl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
A mixture of 6-chloro-5-(4-methoxyphenyl)-1H-indazole-3-carboxylic acid (547 mg, 1.81 mmol) in thionyl chloride (10 mL) was heated to 60° C. for 4 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and treated with p-cresol (399 mg, 3.61 mmol) followed by triethylamine (369 mg, 3.61 mmol). The reaction mixture was stirred for 16 hours and quenched with water (20 mL). The layers were separated and the organic phase was concentrated in vacuo. The residue was purified by flash chromatography (25-50% EtOAc/heptane) to give the title compound (192 mg, 27% yield).