Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C@H:17]2[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]2)=[C:4]([CH2:28][O:29][CH2:30][CH:31](Br)[CH2:32]Br)[CH:3]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:6][C:5]([C@H:17]2[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]2)=[C:4]([CH2:28][O:29][CH2:30][C:31]#[CH:32])[CH:3]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(Br)CBr)cc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 6 h
Yield: 53 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-2-((2,3-dibromopropoxy)methyl)-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (53.3 mg, 0.086 mmol) (prepared by bromination of compound I) in anhydrous ethanol (1.0 mL) was added potassium hydroxide (10.6 mg). The reaction mixture was refluxed and monitored by LC-MS. After 6 h, LC-MS showed the reaction was complete. The reaction mixture was concentrated and the residue was partitioned between EtOAc and water, the organic layer was separated, washed 2× with 1N HCl, 3× with brine, and dried over Na2SO4. Concentration gave the crude product, which was purified by preparative HPLC to yield 21 mg of title compound as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.42 (s, 1H), 7.11 (s, 4H), 4.85 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.51 (d, J=9.2 Hz, 1H), 4.23 (s, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.88 (d, J=12.4 Hz, 1H), 3.71-3.67 (m, 1H), 3.52-3.41 (m, 4H), 2.94 (s, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); LC-MS (m/z) 461 [(M+1)+], 515 [(M+45)−].
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:20])[CH:8]=2)[N:6]=1.C1COCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].O>>[OH:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[CH:8][C:9](=[O:20])[O:10]2)=[CH:15][CH:14]=1
Reactant: Cc1nc(-c2cc(=O)oc3cc(C(=O)O)ccc23)cs1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cc(=O)oc3cc(CO)ccc23)cs1
Temperature: 0 °C

Procedure:
To a solution of 4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carboxylic acid (250 mg, 0.87 mmol) in THF (10 mL) triethylamine (0.31 mL, 2.18 mmol) was added. The mixture was stirred until it became a clear solution. The reaction was then cooled to 0° C. and isobutylchloroformate was added dropwise (230 uL, 1.74 mmol). After 1 hour stirring at 0° C. a solution of sodium borohydride in water (132 mg, 3.48 mmol in 3.5 mL) was added slowly and the mixture was stirred for another hour. The reaction mixture was quenched with a saturated ammonium chloride solution and the product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 8.26 (d, 1H), 8.07 (s, 1H), 7.42 (s, 1H), 7.35 (d, 1H), 6.64 (s, 1H), 4.80 (d, 2H), 4.56 (t, 1H), 2.85 (s, 3H).
Reaction SMILES: C(#N)CC.[OH-:5].[Ca+2:6].[OH-].O.[C:9](N)(=[O:12])[CH2:10][CH3:11]>>[C:9]([O-:12])(=[O:5])[CH2:10][CH3:11].[Ca+2:6].[C:9]([O-:12])(=[O:5])[CH2:10][CH3:11]
Reactant: CCC(N)=O
Reactant: [OH-]
Agent: [Ca+2]
Solvent: CCC#N
Solvent: O
Product: CCC(=O)[O-]
Temperature: 200 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Propionitrile (311.5 g, 5.66 mol, supplied by Solutia Inc., refined: 99.6% min) was charged into a one gallon 316 stainless steel autoclave through a funnel. Calcium hydroxide (229.3 g, 3.09 mol, supplied by Mississippi Lime, CODEX Hydrated Lime), and deionized water (1007.2 g, 55.9 mol) were mixed to produce a slurry and charged to the autoclave through the same funnel. A second portion of deionized water (345.1 g, 19.2 mol) was used to rinse the calcium hydroxide slurry container and was charged to the autoclave through the funnel. The autoclave was pressurized with nitrogen to 45-55 psig (310.3-379.2 KPa), and the pressure relieved to under 25 psig (172.4 KPa). This cycle was repeated two additional times to purge most of the air from the system. The pressure control valve was set to 260 psig (1792.6 KPa), and a nitrogen flow (100 std cm3/min) through the reactor vapor space was started. The autoclave agitator was started and the contents were heated to 200° C. with a mixture of steam and water under pressure in an internal coil. After the autoclave contents had been at 200° C. for one hour, the nitrogen flow was increased to 200 cm3/min to improve the control of the autoclave pressure. After the autoclave contents had been at 200° C. for a total of two hours, the steam was turned off and the reactor pressure was released through a vapor line heated to over 200° C. over a period of 40 minutes. The water and ammonia that flashed from the autoclave was trapped by passing it into a scrubber containing 4862.6 grams of ice water. This scrubber solution weighed 5414.9 grams after all of the autoclave pressure had been released. After the autoclave contents had cooled to less than 60° C. they were drained and weighed (925.1 g). Deionized water (237.2 g) was added to dissolve all of the calcium propionate. This diluted product was analyzed by the HPLC method described in Example 1 and found to contain 28.0% calcium propionate (326 g, 1.75 mol, 62% yield), 119 ppm of propionamide, and no detectable propionitrile. The scrubber solution was found to contain 0.34% calcium propionate and 1.58% ammonia. From the amount of calcium propionate in the scrubber, it was concluded that approximately 66.4 grams of the product was carried into the scrubber by entrainment and that 400 grams of water and 85.5 grams of ammonia were flashed from the autoclave. This represents 90% of the ammonia that would be expected from complete hydrolysis of the propionitrile charged to the autoclave. No attempt was made to quantify the amount of calcium propionate remaining in the reactor after the product was drained.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[N+:11]([C:14]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:24])([O-:13])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:23][C:20]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[C:15]2[C:19]=1[C:18](=[O:24])[CH2:17][CH2:16]2)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: O=C1CCc2c([N+](=O)[O-])ccc(O)c21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCSP(=O)(OCC)Oc1ccc([N+](=O)[O-])c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-nitro-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product, O-ethyl S-propyl O-(4-nitroindan-1-on-7-yl) thiophosphate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:23][CH2:24][N:25]([S:32]([CH:29]5[CH2:31][CH2:30]5)(=[O:34])=[O:33])[CH2:26][CH2:27]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCNCC4)ncc3O2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCN(S(=O)(=O)C5CC5)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared by treatment of 4-(5-piperazin-1-yl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester with cyclopropylsulfonyl chloride in dichloromethane in the presence of triethylamine. LC (method 10): tR=1.47 min; Mass spectrum (ESI+): m/z=493 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9](N2[C@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(F)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of (4R)-3-[(2R)-2-(4-fluorophenyl )propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (2.59 g, 9.28 mmol) in 160 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (8.4 mL, 74.2 mmol) followed by LiOH (780 mg, 18.6 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (54 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 1.43 g (8.51 mmol, 92%) of (2R)-2-(4-fluorophenyl)propanoic acid; [α]D=−61.5° (C=1.04, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–11.4 (br, 1H), 7.31–7.24 (m, 2H), 7.04–6.97 (m, 2H), 3.72 (q, 1H, J=7.3 Hz), 1.49 (d, 3H, J=7.3 Hz); ESMS m/e: 167.2 (M−H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.4 %

Procedure:
A mixture of 2,4′-dibromoacetophenone (56.08 g, 0.20 mol) and potassium thiocyanate (21.57 g, 0.22 mol) in 1 L of absolute ethanol was stirred under nitrogen at room temperature for 5 h. The reaction was added to 2 L of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane, and then dried under high vacuum to give 2-(4-bromophenyl)-2-oxoethyl thiocyanate (50.39 g, 98%) as a white solid, mp 148-149° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]([CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nccn2CCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Add 4-(1H-imidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (40 g; 0.16 mol; 1.0 equiv), powdered KOH (35.6 g; 0.64 mol; 4.0 equiv), 2-(2-bromo-ethoxy)-tetrahydropyran (66.2 g; 0.32 mol; 2.0 equiv) to DMSO (250 mL) and stir at RT for 2 h. Quench the reaction with water and extract with EA. Evaporate the organic layer to give the title compound (58 g; 97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Yield: 79.3 %

Procedure:
A stirred suspension of methyl 3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)-4-nitrobenzoate (6.5 g, 18.4 mmol) in ethyl acetate (500 mL) is hydrogenated over 10% palladium on carbon (2.6 g) under balloon pressure for 4 h. The catalyst is removed by filtration through Celite, washing well with ethyl acetate. The solvent is evaporated to afford the title compound (4.72 g, 80%) as a white solid. LCMS (Method T) 1.39 min, 324.70 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH:15]=[CH:16][CH3:17])=[CH:13][CH:14]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH2:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(-c2ccc(OCC)c(F)c2F)[se]1

Procedure:
3.65 g (11.0 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)-5-propenylselenophene are hydrogenated in 35 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:EtOAc=4:1→2:1). The further purification is carried out by recrystallisation from n-heptane. 2-(4-Ethoxy-2,3-difluorophenyl)-5-propylselenophene is obtained as a colourless solid (m.p. 64° C.).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].C(N(CC)CC)C.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([S:28]([CH:27]=[CH2:26])(=[O:30])=[O:29])[CH2:11][C:10]2=[O:15])=[CH:16][CH:17]=1)#[N:3]
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCN(Cc2ccc(C#N)cc2)C(=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a solution of 1-(4-cyanobenzyl)-2-piperazinone hydrochloride (3.85 g) and triethylamine (12.5 ml) in dichloromethane (50 ml) was added dropwise a solution of 2-chloroethanesulfonyl chloride (4.08 g) in dichloromethane (10 ml) at 0° C., and the mixture was stirred at 0° C. for 4 hours. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of 1-(4-cyanobenzyl)-4-vinylsulfonyl-2-piperazinone (3.15 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:14])[N:7]=1
Reactant: CC(C)(N)C(=O)NCC(F)(F)F
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1ncc(C#N)c(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 90 °C

Procedure:
2,4-dichloropyrimidine-5-carbonitrile (E. F. Godefroi, J. Org. Chem., 1962, 27(6), 2264-6) (0.10 g, 0.57 mmol), 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide. 1TFA (Meinke, Peter T.; Shih, Thomas L.; Fisher, Michael H., U.S. Pat. No. 6,221,894 B1) (0.171 g, 1.14 mmol) and DIPEA (0.39 mL, 2.29 mmol) were combined in anhydrous THF (5 mL) in a sealed tube and heated to 90° C. for 18 hours, before cooling to room temperature. The solvent was evaporated in vacuo and the residue purified by flash chromatography (40 g SiO2, pentane/ethyl acetate, 30-70% over 14 column volumes) to afford the title compound as a colorless waxy solid (0.036 g, 19.7%).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH2:4].Cl.[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28](=[NH:31])OC)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9].C(OCC)(=O)C>CO>[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]([NH:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH3:6])=[NH:31])[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9]
Reactant: CCC(C)CN
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)CNC(=N)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of (2RS)-2-methylbutylamine (3.18 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate hydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is taken up with ethyl acetate (50 cc). The solution is washed with distilled water (50 cc) alkalinized to pH 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column of neutral alumina (height: 23 cm; diameter: 2.1 cm), eluting with mixtures of ethyl acetate and cyclohexane in proportions (by volume) of 20:80 (850 cc) and 10:90 (500 cc), then with pure ethyl acetate (500 cc) and finally with mixtures of ethyl acetate and methanol in proportions (by volume) of 95:5 (500 cc), 90:10 (500 cc) and 80:20 (500 cc and collecting 50-cc fractions. The first litre is discarded and fractions 40 to 56 are then combined, concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-[ (2RS)-2-methylbutyl]-2-phenothiazinecarboxamidine (1.33 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.C(O)(=O)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1.[Zn].[O-2].[O-2].[Mn+4]>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[N:8]=[CH:9][C:4]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cc2)nc1
Reactant: CS(=O)(=O)Cl
Agent: [Mn+4]
Agent: [O-2]
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)nc1

Procedure:
{4-[(5-nitropyridin-2-yl)oxy]phenyl}methanol was subjected to reduction of nitro group by using zinc and acetic acid, the obtained compound reacted with methanesulfonyl chloride in pyridine, and the obtained compound was subjected to oxidation by using manganese dioxide to give the title compound having the following physical data.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][OH:23])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][S:2]([CH3:1])(=[O:4])=[O:3])=[O:24])([CH3:16])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (6.5 mL, 84 mmol) was added slowly to a solution of Et3N (16.0 mL, 114 mmol) and (3-hydroxy-propyl)-carbamic acid tert-butyl ester (13.4 g, 76.5 mmol) in CH2Cl2 (200 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 and the organic fractions were then dried (MgSO4) and concentrated in vacuo. The title compound was isolated as a colorless oil: yield 18.9 g (98%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[C:13]([CH3:23])([O:18][Si](C)(C)C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[C:13]([OH:18])([CH3:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O[Si](C)(C)C)CN(C(=O)OCc2ccccc2)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OCc2ccccc2)CCC1=O

Procedure:
The thus-obtained N-benzyloxycarbonyl-3-methyl-3-trimethylsilyloxy-4-piperidone is dissolved in THF .(450 mL) and concentrated hydrochloric acid (50 mL) is added. The resultant solution is stirred at 23° C. for 24 h and concentrated to an oily residue. The residue is suspended in a saturated sodium bicarbonate solution (250 mL) and the resultant suspension is extracted with ether (2×100 mL). The organics are combined, dried (MgSO4), filtered and concentrated to give crude N-benzyloxycarbonyl-3-hydroxy-3-methyl-4-piperidone as an oil: 17.2 g.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]([C:19]1[CH:23]=[CH:22][O:21][CH:20]=1)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:2]1([C:1]2[O:18][C:17]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccoc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccoc1
Yield: 79.5 %

Procedure:
2.0 g of ethyl 3-benzoylamino-3-(3-furylcarbonyl)propionate, 15 ml of chloroform and 4.9 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.5 g of ethyl 2-[2-phenyl-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 79.0%
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:28]([NH:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:30])[CH3:29].CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:28]([NH:31][C:32]1[CH:33]=[C:34]([NH:35][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)[CH:36]=[CH:37][CH:38]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cn1cc(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3cnn(C)c3)n2)c1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (51 mg, 0.14 mmol) in NMP (0.8 mL) was added 3-acetamidoaniline (24 mg, 0.16 mmol) and pTsOH.H2O (27 mg, 0.14 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (40 mg). MS found for C18H20N8O2 as (M+H)| 381.5. λ=242.8.