Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][O-].[Na+].N1CCCCC1.[OH:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>S(=O)(=O)(O)O>[Cl:1][C:16]1[C:17]([OH:19])=[CH:18][C:11]([OH:10])=[C:12]([CH:15]=1)[CH:13]=[O:14]
Reactant: O=Cc1ccc(O)cc1O
Reactant: [O-]Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCNCC1
Product: O=Cc1cc(Cl)c(O)cc1O
Temperature: 0 °C

Procedure:
Sodium hypochlorite (75 mL, 0.055 mol) and piperidine (4.68 g, 0.055 mol) were cooled to 0° C., combined cautiously and added dropwise over 2 h to a solution of 2,4,-dihydroxybenzaldehyde (6.91 g, 0.05 mol) in 50% aqueous sulfuric acid (150 mL) while cooling to 0° C. After three additional hours, the precipitate was collected via filtration in quantitative yield. 1H NMR indicates that it is about 65% 5-chloro-2,4-dihdroxybenzaldehyde, with the balance being 3-chloro-2,4-dihdroxybenzaldehyde. The product can be purified via column chromatography and/or repeated recrystallizations from toluene. However, the 3-chloro-2,4-dihdroxybenzaldehyde does not react in the next reaction, so the product was used without further purification.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([F:12])=[CH:4][C:3]=1[N+:13]([O-])=O.C(N(CC)CC)C>C(O)C.[Pd]>[F:12][C:5]1[CH:4]=[C:3]([NH2:13])[CH:2]=[C:7]([C:8]([F:10])([F:11])[F:9])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1Br
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(F)cc(C(F)(F)F)c1

Procedure:
2-Bromo-5-fluoro-1-nitro-3-trifluoromethyl-benzene (XVIII) (55.5 g) is dissolved in 500 mL of ethanol. Triethylamine (19.63 g) and palladium on charcoal (6 g, Pd/C 10%, Engelhard 4505) are added and the mixture is subjected to hydrogenation at 20-25° C. After 20 hours reaction time, the consumption of hydrogen had ceased. The hydrogen pressure is released and the solution is separated from the catalyst by filtration on Cellflock. The filter residue comprising the catalyst is washed with ethanol (2×100 mL). The filtrate and wash fractions are combined and the solution thus obtained is concentrated at 45° C. under reduced pressure to a final volume of ca. 400 mL. Toluene (400 mL) is added and the resulting solution is concentrated to a final volume of ca. 250 mL to obtain a suspension. The precipitate is removed by filtration and the filter cake is washed with toluene (2×100 mL). The solution is concentrated again to a final volume of 200 mL and the formed precipitate is removed again by filtration. The filter cake is washed with toluene (3×50 mL). The process of dilution with toluene, concentration and filtration is repeated until no substantial precipitation occurred in the toluene solution. Finally, the solvent is evaporated at 45-50° C. under reduced pressure and the residue is dried in vacuo at 45° C. to obtain 3-fluoro-5-trifluoromethyl-phenylamine as a yellow oil. GC-MS: m/z: 179, 160, 151, 140, 132. The product is identical in GC and HPLC to a sample of 3-amino-5-fluoro-benzotrifluoride, purchased from ABCR (ABCR F01075). Also the NMR spectra are identical to the sample purchased from ABCR.
Reaction SMILES: [C:1]([C:3]1[CH:50]=[CH:49][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[O:47][CH3:48])[C:8](=[O:35])[C@@H:9]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2].[ClH:51]>O1CCOCC1.CCOCC>[ClH:51].[C:1]([C:3]1[CH:50]=[CH:49][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[O:47][CH3:48])[C:8](=[O:35])[C@@H:9]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2cc(C#N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C
Yield: 84 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (75 mg, 110 μmol) in 4 M HCl in dioxane (548 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (57.0 mg, 84% yield) as a white solid. MS m/z 584 (MH)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([B:11]([OH:13])[OH:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[N+:14]([O-])([OH:16])=[O:15]>C(OC(=O)C)(=O)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([B:11]([OH:13])[OH:12])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1ccc(B(O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-isobutyl-phenylboronic acid (0.9 g, 5.05 mmol) in acetic anhydride (9 mL) at −10° C., fuming nitric acid (0.4 mL) was added over 10 minutes. The mixture was stirred for 1 hour, warmed to room temperature and stirred for an additional 1.5 hours. The clear orange solution was added to 100 mL of ice, stirred for 3 hours and azeotroped with water (4×100 mL). The residue was partitioned between 25 mL each of ether and water and the ether layer was dried and evaporated to provide 0.75 g of yellow solid. The solid was dissolved in ethyl acetate (25 mL) and the solution was extracted with 1 N aqueous sodium hydroxide (2×25 mL). The combined aqueous extracts were acidified to pH 2 using 2N aqueous hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed once with water, dried and evaporated to provide 0.63 g of light yellow solid. Reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 76% solvent A (90% MeOH, 10% H2O, 0.1% TFA) and 24% solvent B (10% MeOH, 90% H2O, 0.1% TFA) provided 0.16 g of compound A as light yellow solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Br:16][C:17]([CH2:19]Br)=[CH2:18].[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:16][C:17](=[CH2:18])[CH2:19][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of diethyl acetamidomalonate (217 g, 1.0 mol) and 2,3-dibromopropene (240 g, 1.2 mol) in anhydrous tetrahydrofuran (2.50 L), under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in several portions. The reaction mixture was stirred at ambient temperature for 30 minutes, then heated to reflux. After heating for 18 hours, the resultant slurry was cooled to ambient temperature and suction filtered through a short pad of silica gel. The solid residue was washed with tetrahydrofuran (2×50 mL), and the filtrates were combined and concentrated. The residue obtained was dissolved in ethyl acetate (2.0 L), washed with water and brine, and then was dried over magnesium sulfate. Filtration and concentration gave a yellow oil which solidified upon drying. The resultant solid was recrystallized from a mixture of hot ethyl acetate/hexane to give 301 g (89%) of the desired product: m.p. 85°-87° C. 1H NMR (300 MHz, CDCl3) δ1.28 (t, J=7.4 Hz, 6H), 2.04 (s, 3H), 3.57 (s, 2H), 4.27 (m, 4H), 5.55 (bs, 1H), 5.61 (bs, 1H), 6.82 (broad, 1H); IR (KBr) 1745, 1635 cm-1Anal calcd for C12H18BrNO5 : C, 42.87; H, 5.40; Br, 23.77; N, 4.12. Found: C, 43.25; H, 5.56; Br, 22.97; N, 4.12.
Reaction SMILES: [F:1][C:2]1([F:44])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([C:18]4[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)[N:19]=4)=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:10][C:4]=2[O:3]1>C(O)(C(F)(F)F)=O>[F:44][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:17]([C:18]4[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=4)=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4c(c3)OC(F)(F)O4)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc3c(c2)OC(F)(F)O3)n1
Temperature: 25 °C
Yield: 3.8 %

Procedure:
A solution of 4-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.1352 g, 0.226 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature and the TFA was removed in vacuo. The residue was treated with a saturated solution of NaHCO3, the aqueous layer was extracted with DCM (3×15 mL), the layers were separated, the combined organic layers were dried and concentrated. The crude brown oil was dissolved in 2.5 mL of DMSO and purified by reversed phase chromatography (Gilson, 10-90% CH3CN in water with NH4OH additive: 0.1% v/v in each solvent). The fractions were concentrated in a Genevac Series II System to give 4-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (3.1 mg, 8.65 μmol, 3.83% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 12.11 (s, 1H); 8.80 (dd, J=7.8, 2.0 Hz, 1H); 8.37 (dd, J=4.6, 2.1 Hz, 1H); 8.15 (d, J=2.2 Hz, 1H); 7.87 (br. s., 1H); 7.77 (br. s., 1H); 7.55 (dd, J=8.8, 2.2 Hz, 1H); 7.35 (d, J=8.8 Hz, 1H); 6.95 (dd, J=7.9, 4.6 Hz, 1H); 2.44 (s, 3H). m/z (ESI, +ve ion) 359.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([O-])([O-])=O.[K+].[K+].[CH:28]1([CH2:34]Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: BrCC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCC2CCCCC2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (356 mg), K2CO3 (830 mg), n-Bu4NI (89 mg) in DMF (5 ml) was added cyclohexylmethyl bromide (202 μl) and the mixture was stirred for 1 day at room temperature. After addition of brine (40 ml), the resulting mixture was extracted with AcOEt. The extract was dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent; 9:1, Hexane/AcOEt→1:1, Hexane/AcOEt) to give N-(tert-butoxycarbonyl)-O-cyclohexylmethyl-L-tyrosine methyl ester (470 mg). The obtained compound (347 mg) was dissolved in 3N HCl/AcOEt (5 ml) and the mixture was stirred overnight. The solvent and excess HCl was removed in vacuo to give O-(Cyclohexylmethyl)-L-tyrosine methyl ester, hydrochloride salt.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([OH:34])[CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([OH:34])[CH2:29]1)=[O:11]
Reactant: N[C@H]1CCC[C@H](O)C1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CCC[C@H](O)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (345 mg, 1.26 mmol) was dissolved in dimethylformamide (10 ml) and triethylamine (865 μl, 11.8 mmol) was added followed by (1S,3S)-3-aminocyclohexanol hydroformate (200 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (715 mg, 3.73 mmol) and 1-hydroxybenzotriazole (185 mg, 1.37 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution (50 ml) and diethyl ether (50 ml). The organic was washed with sat. sodium bicarbonate solution (50 ml), water (25 ml) and brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 70:30) as eluant to give 5-fluoro-N-[(1S,3S)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (212 mg) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11](OC)[C:10]2[C:5](=[C:6]([Cl:19])[CH:7]=[C:8]([O:17][CH3:18])[C:9]=2[O:15][CH3:16])[N:4]=1.[NH3:20]>>[NH2:20][C:11]1[C:10]2[C:5](=[C:6]([Cl:19])[CH:7]=[C:8]([O:17][CH3:18])[C:9]=2[O:15][CH3:16])[N:4]=[C:3]([O:2][CH3:1])[N:12]=1
Reactant: N
Reactant: COc1nc(OC)c2c(OC)c(OC)cc(Cl)c2n1
Product: COc1nc(N)c2c(OC)c(OC)cc(Cl)c2n1

Procedure:
A mixture of 2,4,5,6-tetramethoxy-8-chloroquinazoline (2.1 g, 0.0073 moles) and saturated methanolic ammonia (60 ml) was warmed to 80° C. for 16 hours in a teflon lined acid digestion bomb. The crude reaction mixture was filtered, and the resulting solid was recrystallized twice from N,N-dimethylformamide, washed three times with methanol and dried under vacuum at 60° C. to afford the product (1.08 g), mp 203°-204° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18].C[O:21][C:22]([CH:24]=[CH2:25])=[CH2:23]>C1C=CC=CC=1>[Cl:1][C:2]1[C:15]2[C:10]([C:9]([OH:17])=[C:8]3[C:3]=1[C:4](=[O:19])[CH:5]1[CH:6]([CH2:25][CH2:24][C:22](=[O:21])[CH2:23]1)[C:7]3=[O:18])=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2
Reactant: C=CC(=C)OC
Reactant: O=C1C=CC(=O)c2c1c(Cl)c1cccc(O)c1c2O
Solvent: c1ccccc1
Product: O=C1CCC2C(=O)c3c(c(Cl)c4cccc(O)c4c3O)C(=O)C2C1

Procedure:
10-Chloro-8,9-dihydroxy-1,4-anthracenedione (compound 3) (100 mg), 2-methoxy-1,3-butadiene (564 mg) and dry benzene (10 ml) were heated in a sealed tube for 4 h at 130°. After cooling the crude solution was preparatively chromatographed on silica gel layers containing oxalic acid (2%) with chloroform as eluant. The major yellow band was recovered to give the product (compound 9) as a yellow crystalline solid (85 mg, 68%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1COCC1>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1ccncc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Isonicotinic acid N (15 g, 121.8 mmol, obtained from Aldrich Chemical Co.) was added to about 100 mL of thionyl chloride and the reaction mixture was stirred for about 17 h at about 25° C. After this period, excess SOCl2 was removed under reduced pressure to provide a white solid. About 400 mL of THF was added to the resulting solid and the solvent was removed under reduced pressure to provide isonicotinic acid chloride as a white powder. The white powder was dissolved in about 400 mL of THF. The solution was cooled to about 0° C. and 4-trifluoromethyl-aniline (21.6 g, 134.0 mmol, 1.1 eq., obtained from Aldrich Chemical Co.) and sodium bicarbonate (30 g, 365.4 mmol, 3.0 eq.) were added. The reaction mixture was stirred for about 5 min at about 0° C., warmed to about 25° C. over about 30 min, then heated to about 65° C. and kept at that temperature for about 1 h. After this period, the reaction mixture was cooled to about 25° C. and the THF was removed under reduced pressure. The residue was suspended in about 800 mL of ethyl acetate and washed with about 600 mL of aqueous 3N HCl. Separate aqueous and organic layers formed. The layers were separated and the aqueous layer was extracted three times with about 600 mL of ethyl acetate per extraction. The organic layer was combined with the post-extraction ethyl acetate aliquots. The combination was dried with Na2SO4 and the solvent was removed under reduced pressure to provide 32 g of the Compound of Formula O as a white solid (99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([NH:6][C:7]([N:26]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([O:15][CH3:14])[CH:17]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:8])=[O:5]
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1OC
Reactant: Cc1cccc(Cl)c1C(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(C)cccc2Cl)cc1OC
Yield: 75.1 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-6-methylbenzoyl isocyanate (0.793 g, 4.06 mmol), tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate-14, 1.2 g, 4.06 mmol) and DCM (30 mL) to afford 1.5 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:10][C@@H:9]([NH:11][S:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:14])=[O:13])[C@H:8]([OH:23])[CH2:7][CH2:6]1)=[O:4].[CH3:25][S:26](Cl)(=[O:28])=[O:27].CN1CCOCC1.Cl>C(#N)C.O>[CH3:25][S:26]([O:23][C@@H:8]1[CH2:7][CH2:6][C@H:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:24])[CH2:10][C@H:9]1[NH:11][S:12](=[O:13])(=[O:14])[NH:15][C:16]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:22])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Acetonitrile (30 ml) was added to a solution of tert-butyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (12.1 g) in acetonitrile (30 ml), and the obtained solution was then cooled to approximately 0° C. Thereafter, methanesulfonyl chloride (3.77 ml) was added to the reaction solution. N-methylmorpholine (6.81 ml) was added dropwise to the reaction mixture, and the obtained mixture was then stirred for approximately 3 hours. Thereafter, water (61 ml) was added to the reaction mixture, and a 6 mol/l hydrochloric acid solution was then added thereto to adjust the pH of the mixture to pH 3. Water (93 ml) was further added to the mixture, and the thus obtained mixture was then stirred for approximately 15 hours. Thereafter, the precipitated solid was collected by filtration and was then washed with a 27.5% acetonitrile aqueous solution (30 ml). The obtained solid was dried under reduced pressure to obtain the title compound (13.0 g, yield: 89%). The spectra of the resulting product, which were obtained using various devices, were matched with those obtained in Example 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[NH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][C:27]2[CH:32]=[C:31]([NH:33][C:34]([N:36]3[CH2:40][CH2:39][C@@H:38]([CH2:41][N:42]([CH3:44])[CH3:43])[CH2:37]3)=[O:35])[N:30]=[CH:29][N:28]=2)=[C:24]([F:47])[CH:23]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[CH3:44][N:42]([CH2:41][C@@H:38]1[CH2:39][CH2:40][N:36]([C:34]([NH:33][C:31]2[CH:32]=[C:27]([O:26][C:25]3[CH:45]=[CH:46][C:22]([NH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:23][C:24]=3[F:47])[N:28]=[CH:29][N:30]=2)=[O:35])[CH2:37]1)[CH3:43]
Reactant: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)C1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)C1
Reaction time: 1 h
Yield: 38 %

Procedure:
After adding a 2-(4-fluorophenyl)acetyl isothiocyanate-toluene (0.2 M, 2.2 ml) solution to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[(3S)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbonylamino}pyrimidine (105 mg) and (+)-10-camphorsulfonic acid (65 mg) in ethanol (2.5 ml) at room temperature, the mixture was stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=2:1, then ethyl acetate) to provide the title compound (60.5 mg, 38%) as white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>S(Cl)(Cl)=O>[NH:22]1[C:21]([NH:20][C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[N:5]=2)=[O:19])=[N:25][N:24]=[N:23]1
Reactant: Cc1cc(C(=O)O)nc(-c2cccc([N+](=O)[O-])c2)c1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2nnn[nH]2)nc(-c2cccc([N+](=O)[O-])c2)c1
Yield: 50.8 %

Procedure:
In the same manner as described in Example 13-(1), 4-methyl-6-(3-nitrophenyl)-2-pyridinecarboxylic acid (3.0 g), thionyl chloride (30 ml) and 5-aminotetrazole (1.2 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(3-nitrophenyl)-2-pyridinecarboxamide (1.92 g). M.P. 288°-290° C. (decomp.) (recrystallized from dimethylformamide)
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3].[C:20]1(C)[C:21](S(O)(=O)=O)=[CH:22][CH:23]=[CH:24][CH:25]=1>C(O)CCCCC>[CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][CH2:22][CH2:21][CH2:20][CH2:25][CH2:24][CH3:23])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[CH:18])[C:10]2=[O:19])=[N:6][N:5]=1)=[O:3]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O
Solvent: CCCCCCO
Product: C#CCN1CCC(OCCCCCC)N(c2nnc(S(C)=O)s2)C1=O

Procedure:
Tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), hexyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hexyloxy-2(1H)-pyrimidinone.