Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9]>C=CC1C=CN=CC=1.Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:7]([O:11][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)(=[O:10])[CH:8]=[CH2:9]
Reactant: C=CC(=O)O
Reactant: C1=COCCC1
Agent: C=Cc1ccncc1
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OC1CCCCO1
Temperature: 65 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 310 mL (2.75 mol) of 3,4-dihydro-2H-pyran, 99.1 g (94 mL, 1.38 mol) of acrylic acid, 5 g of crosslinked poly(4-vinylpyridine hydrochloride) (Fluka Chemical Corp., catalog number 82803, 6 meq/g), and 0.5 g of phenothiazine was warmed until an exothermic reaction caused the temperature to rise to 99° C. An ice bath was used to cool the mixture to 65° C., and the mixture was stirred at 65° C. for 18 hours. After cooling to room temperature, the mixture was filtered to remove the catalyst. NMR analysis of the filtrate showed the presence of 2-tetrahydropyranyl acrylate and 3,4-dihydro-2H-pyran with little or no acrylic acid. The mixture was stirred with anhydrous sodium carbonate and calcium hydride for 1 hour. After removal of excess 3,4-dihydro-2H-pyran in a rotary evaporator, distillation over calcium hydride, anhydrous sodium carbonate, and phenothiazine gave 136.6 g of 2-tetrahydropyranyl acrylate, b.p. 66°-70° C. (3.2 mm).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][O:2]1.[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18]>>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:16]3[S:12][C:13](=[O:18])[NH:14][C:15]3=[O:17])=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2c(c1)COC2
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)COC3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 1,3-dihydro-2-benzofuran-5-carbaldehyde (intermediate 4) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:14]3[C:9]([C:10]([NH2:15])=[N:11][CH:12]=[N:13]3)=[C:8]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]([CH:24]=3)=[N:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=4)[CH:7]=2)[CH2:2]1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:25]([N:21]1[CH:20]=[C:19]2[C:23]([CH:24]=[C:16]([C:8]3[CH:7]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:2]4)[N:14]4[C:9]=3[C:10]([NH2:15])=[N:11][CH:12]=[N:13]4)[CH:17]=[CH:18]2)=[N:22]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.2 %

Procedure:
A mixture of 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol), N,N-dimethylglycine (24 mg, 0.23 mmol), EDCl (41 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol), and N,N-diisopropylethylamine (102 μL, 0.59 mmol) in DMF (1.8 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 30% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 21 mg (22%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.26-7.39 (m, 5 H), 7.13 (dd, 1 H), 6.62 (s, 1 H), 5.65 (s, 2 H), 4.26 (t, 1 H), 4.00 (t, 1 H), 3.90 (dd, 1 H), 3.66 (dd, 1 H), 3.31-3.21 (m, 4 H), 2.99-3.11 (m, 1 H), 2.30 (s, 6 H); ES-MS m/z 495.47 [M+H]+, HPLC RT (min) 2.03.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([CH:35]([OH:38])[CH2:36][NH2:37])[CH:29]=1>>[OH:38][CH:35]([C:30]1[CH:29]=[CH:28][CH:33]=[C:32]([OH:34])[CH:31]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NCC(O)c1cccc(O)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cccc(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35–1.50 (m, 2 H), 1.80–2.00 (m, 2 H), 2.06 (s, 3 H), 2.50–2.90 (m, 5 H), 3.45–3.60 (m, 2 H), 4.55–4.65 (m, 1 H), 5.55 (brs, 1 H), 6.60–6.70 (m, 1 H), 6.70–6.85 (m, 4 H), 6.86 (d, J=9.3 Hz, 2 H), 7.11 (t, J=7.8 Hz, 1 H), 7.58 (d, J=8.7 Hz, 2 H), 7.68 (d, J=8.7 Hz, 2 H), 9.35 (s, 1 H), 10.33 (s, 1 H); MS (ES) m/z: 525.4 (MH+); HRMS Calcd. for C27H33N4O5S (MH+): 525.2172. Found: 525.2177.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[CH3:21][O:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: COC1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC1CCN(C2CCNCC2)CC1
Reaction time: 8 h

Procedure:
A suspension of 2.1 (5.87 mmol) 1′-benzyl-4-methoxy-[1,4′]bipiperidinyl and 1.0 g 10% Pd/C in 50 mL MeOH and 20 mL water was hydrogenated for 8 h at RT and 3 bar hydrogen pressure. The catalyst was removed by suction filtering, the filtrate was concentrated by evaporation i.vac., the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[O:22]=[C:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]#[N:33])[C:26]=2[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.B.CSC.C(Cl)Cl>[OH:22][C@@H:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:32]#[N:33])[C:26]=2[CH2:25][CH2:24]1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: ClCCl
Solvent: CSC
Solvent: Cc1ccccc1
Product: N#Cc1cccc2c1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a 3-neck flask with an internal thermometer and an addition funnel was added (R)-(+)-2-methyl-CBS-oxazaborolidine solution in toluene (3.0 mL) and borane-dimethylsulfide (300 μL). The reaction was stirred at room temperature for 10 min then diluted with DCM (25 mL). Borane-dimethylsulfide (6.0 mL) was added and, after stirring for 5 min, the reaction was cooled to −20° C. 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile INT-1 (4.7 g, 30 mmol) in DCM (25 mL) was added dropwise by addition funnel over 20 min while maintaining the reaction at −20±5° C. The reaction was stirred for 1 h then quenched by the dropwise addition of MeOH (20 mL). After hydrogen evolution ceased, MeOH (30 mL) was added and removed by heating at atmospheric pressure. MeOH (50 mL) was added in two and removed by heating twice. All the solvent was evaporated to give a solid which was recrystallized from EA (9 mL) and hexane (22 mL). The compound was filtered and washed with 5:1 hexane/EA (30 mL) to provide 3.73 g (78%) of (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile INT-2 as a white powder. LCMS-ESI (m/z) calculated for C10H9NO: 159.1; found 160.1 [M+H]+, tR=2.39 min. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 5.28 (d, J=4.1 Hz, 1H), 3.23 (ddd, J=17.0, 8.7, 4.4 Hz, 1H), 3.04-2.90 (m, 1H), 2.64-2.51 (m, 1H), 2.00 (dddd, J=13.4, 8.7, 7.1, 5.7 Hz, 1H), 1.91 (d, J=5.4 Hz, 1H). Chiral HPLC: (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile was eluted in 20% IPA in hexane: >99.9% ee, tR=7.42 min. The (R)-enantiomer was obtained in an analogous fashion using (S)-(−)-2-methyl-CBS-oxazaborolidine. tR for (R)-enantiomer=6.79 min.
Reaction SMILES: [CH:1](/[C:9]1[CH:10]=[CH:11][C:12]2[O:13][CH2:14][C:15](=[O:19])[NH:16][C:17]=2[N:18]=1)=C\C1C=CC=CC=1.CSC.C(Cl)Cl.C[OH:27]>>[O:19]=[C:15]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH:1]=[O:27])=[N:18][C:17]=2[NH:16]1
Reactant: O=C1COc2ccc(/C=C/c3ccccc3)nc2N1
Reactant: CO
Solvent: CSC
Solvent: ClCCl
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: -78 °C
Yield: 77 %

Procedure:
6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.2 g, 27 mmole) was dissolved in 5:1 CH2Cl2/MeOH (500 mL) and the solution was cooled to −78° C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (9.9 mL, 135 mmole) was added to the solution, and the reaction was stirred at −78° C. for 3 hr, then at RT overnight. The solvent was removed in vacuo, and the residue was triturated and stirred with Et2O (150 mL). The solid was collected, washed with additional Et2O, and dried to afford the title compound (3.4 g, 77%): MS (ES) m/e 179.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:13][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 8 h
Yield: 584.3 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (4.0 g, 2.3 mmol), morpholine (3.45 ml, 41 mmol) and anhydrous potassium carbonate (3.2 g, 23 mmol) in N,N-dimethylacetamide (40 ml) was stirred at 130-140° C. under nitrogen overnight. The reaction mixture was then cooled to room temperature, poured onto ice and allowed to stand for 2-3 h. The yellow-brown precipitate was collected by filtration to afford 5-morpholino-2-nitroaniline (3.0 g, 58%), mp 183-185° C. (lit. (8) mp 187.5° C.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N+:8]([O-:10])[C:7]([CH3:11])=[CH:6][N:5]=1)(O)=[O:2].B#B.C(O)C.C([O-])([O-])=O.[K+].[K+]>COCCOCCOC.O1CCCC1>[OH:2][CH2:1][C:4]1[CH:9]=[N+:8]([O-:10])[C:7]([CH3:11])=[CH:6][N:5]=1
Reactant: Cc1cnc(C(=O)O)c[n+]1[O-]
Agent: B#B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: COCCOCCOC
Product: Cc1cnc(CO)c[n+]1[O-]
Temperature: 0 °C
Yield: 88 %

Procedure:
Method B--To a solution of 2-carboxy-5-methyl-pyrazine-4-oxide (1.5 g) in diethylene glycol dimethyl ether (80 ml) addition was made at 0° C. under an atmosphere of nitrogen of a solution (1 M) of diborane in tetrahydrofuran (30 ml). To the reaction mixture maintained for 3 hours at 0° C. and 1 hour at room temperature, cautious addition was made of ethanol (50 ml) and then of a 0.5 M solution of alcoholic potash (25 ml). The resultant solution after evaporation at reduced pressure was taken up with chloroform which, on evaporation to dryness, gave 1.2 g of 2-hydroxymethyl-5-methyl-pyrazine-4-oxide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:17][C:16](=O)[CH2:15][S:14][CH2:13][C:12](=O)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:24]([O:23][CH2:22][CH:18]1[CH2:19][NH:20][CH2:21][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][NH:17]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CSCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1
Agent: Cl
Solvent: C1CCOC1
Product: c1ccc(COCC2CNCC(COCc3ccccc3)NCCSCCN2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5,9-Bis(benzyloxymethyl)-1-thia-4,7,10-triazacyclododecane-3,11-dione (0.352 g, 0.769 mmol) was dissolved in dry THF (10 ml) and cooled to 0° C. A 1 M solution of borohydride -THF complex in THF (5 ml) was added under nitrogen and the mixture was stirred for 1 hour at ambient temperature and refluxed for 0.5 hours. To the cooled solution was added 2 M hydrochloric acid (3 ml) and the resulting mixture was evaporated to dryness. Water (1 ml) and 25% ammonia solution (1 ml) was added and the mixture was extracted 3 times with 4 ml chloroform. The combined extracts were concentrated in vacuo and gave a yellow oil which showed absence of carbonyl bands in IR. Yield: 0.29 g (88%), FAB MS: 430(M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O>>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: COC(=O)CN
Product: COC(=O)CNCc1ccc(OC)c(O)c1
Yield: 47 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 3-hydroxy-4-methoxybenzaldehyde. Yield 47%. MS M+H calculated 226.1; found 226.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].S(=O)(=O)(O)[OH:11]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[O:11]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(F)ccc1Cl
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cc(F)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40 ml) was treated dropwise with concentrated sulfuric acid (40 ml) with cooling on ice. Subsequently, a solution of chromic anhydride (9.3 g) in acetic anhydride (40 ml) was added dropwise over a period of 2 hours. At the same temperature, the mixture was stirred for 1 hour, and added to an ice-water. The mixture was extracted with diethyl ether and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml), combined with water (4 ml) and concentrated sulfuric acid (4 ml), and heated with stirring at 100° C. for 30 minutes. After allowed to stand to cool, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to a column chromatography on a silica gel to obtain 2-chloro-5-fluorobenzaldehyde (1.6 g).
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([OH:14])=[O:13].O>C(O)(=O)C>[Cl:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: ClCl
Reactant: Cc1cccc(C)c1CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
At 10-15° C., 9.22 g [130 mmol] of chlorine gas are slowly introduced into a solution of 16.4 g [100 mmol] of 2,6-dimethylphenylacetic acid in 100 ml of glacial acetic acid. The reaction mixture is then stirred at room temperature for 16 hours and then poured into 500 ml of water. The precipitated solid is filtered off with suction, washed with water and dried. This gives 18.8 g of a white solid which, according to GC(sil.), has the following composition: 86.4% of 3-chloro-2,6-dimethylphenylacetic acid (corresponds to a yield of 81.8% of theory), 8.8% of dichloro-2,6-dimethylphenylacetic acid (isomer 1), 3.8% of dichloro-2,6-dimethylphenylacetic acid (isomer 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:4]=1.[H-].[Na+].[CH2:24]([O:26][CH2:27]Cl)C>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([N:14]([CH2:24][O:26][CH3:27])[S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:6]=1
Reactant: CCOCCl
Reactant: COc1cc(OC)nc(C(C(=O)NS(C)(=O)=O)C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN(C(=O)C(c1nc(OC)cc(OC)n1)C(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 of 2-(4,6-dimethoxypyrimidin-2-yl)-3-methyl-N-methylsulfonylbutyric acid amide was placed in a round bottom flask, and was dissolved in 50 ml of DMF. To the resultant solution, was gradually added 0.28 g of 60% sodium hydride, and the mixture was stirred at room temperature for one hour. Thereafter, 1.0 g of chloromethyl ethyl ether was added dropwise to the resultant mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water, and was extracted with 200 ml of diethyl ether, followed by drying with anhydrous sodium sulfate. After filtrating the inorganic salt, the solvent was distilled off under reduced pressure. An only product thus obtained was purified by silica gel column chromatography (developing solvent: N-hexane/ethyl acetate=10/1) to obtain 1.8 g of the aimed product of colorless transparent viscous liquid (yield=78.3%) having a refractive index (n20/D) of 1.4976.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(OCC)(=O)C.[OH-].[Na+]>ClC1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(C)OC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 120 °C
Reaction time: 23 h
Yield: 45.3 %

Procedure:
2-Propyl 4-chloropyridine-2-carboxylate (3.13 g) was dissolved in chlorobenzene (9.5 ml). 4-Nitrophenol (3.28 g) was added thereto, followed by stirring at 120° C. for 23 hr. 4-Nitrophenol (1.09 g) was added thereto, followed by stirring at 120° C. for 3 hr. The reaction mixture was allowed to cool down to room temperature. Ethyl acetate (50 ml) and a 1N aqueous solution of sodium hydroxide (50 ml) were added to the reaction mixture and stirred. Insoluble matter was precipitated, which was dissolved by addition of THF (50 ml). The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide (50 ml×3) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1 to 1:1). Fractions containing the target compound were concentrated under reduced pressure, and dried under reduced pressure to provide the titled compound as pale brown crystals (2.147 g, 45%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[S:12])SC)(=[O:3])[CH3:2].[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCOCC1.O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9]([SH:12])=[N:15][N:14]=[N:13]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCNC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCCCn1nnnc1S
Reaction time: 4 h
Yield: 48.7 %

Procedure:
A mixture of a solution of methyl N-(3-acetamidopropyl)dithiocarbamate (193 g) in dioxane (610 ml) and a solution of sodium azide (79.42 g) in water (500 ml) was refluxed under stirring for 4 hours. Dioxane was distilled off and the remaining aqueous layer was washed with diethyl ether (150 ml×2), adjusted to pH 1 with 17.5% hydrochloric acid, and cooled in an ice bath. Precipitates were collected by filtration and washed with ice-water to give white powder of 1-(3-acetamidopropyl)-1H-tetrazol-5-thiol (91.75 g), mp. 152° to 154° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][CH:11]([CH3:13])[CH3:12].[N:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[C:18]=[O:19]>ClCCl>[CH3:12][CH:11]([N:10]([CH2:9][C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:7]=1)[C:18]([NH:17][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=1)=[O:19])[CH3:13]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)NCc1cccc(-c2nccs2)c1
Solvent: ClCCl
Product: CC(C)N(Cc1cccc(-c2nccs2)c1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of N-[3-(1,3-thiazol-2-yl)benzyl]propan-2-amine (35 mg, 0.15 mmol, 1.0 eq) in dichloromethane (2.5 mL) was added 1-isocyanato-4-(trifluoromethoxy)benzene (30 mg, 0.15 mmol, 1.0 eq) and the reaction was stirred at 23° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by reverse phase liquid chromatography (Gemini-NX C18, 5 μm, 30×100 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 1-propan-2-yl-1-[3-(1,3-thiazol-2-yl)benzyl]-3-[4-(trifluoromethoxy)phenyl]urea as a white solid. 1H NMR (500 MHz, DMSO): δ 8.58 (s, 1 H); 7.93-7.88 (m, 2 H); 7.80-7.75 (m, 2 H); 7.56 (d, J=8.7 Hz, 2 H); 7.45 (t, J=7.7 Hz, 1 H); 7.38 (d, J=7.7 Hz, 1 H); 7.22 (d, J=8.6 Hz, 2 H); 4.63 (s, 2 H); 4.54-4.48 (m, 1 H); 1.12 (d, J=6.6 Hz, 6 H). LRMS m/z (M+H) 436.1 found, 436.1 required.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][F:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][F:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: COC(=O)Cl
Reactant: NC[C@@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CCF)C(=O)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CCF)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.022 ml, 0.282 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-(2-fluoro-ethyl)-1,3-dihydro-iridol-2-one (0.080 g, 0.188 mmol) and diisopropylethylamine (0.137 ml, 0.752 mmol) in dichloromethane (2 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as an off white solid. HPLC r.t. 3.93 min; 1H NMR (300 MHz, CDCl3) 7.32 (m, 1H), 7.25 (m, 1H), 5.15 (m, 1H), 4.77 (m, 1H), 4.75 (t, J=5.1 Hz, 1H), 4.57 (t, J=4.8 Hz, 1H), 4.22 (t, J=5.1 Hz, 1H), 4.14 (t, J=4.8 Hz, 1H), 4.02 (t, J=9 Hz, 2H), 3.80 (dd, J=6.6, 9 Hz, 1H), 3.69 (s, 3H), 3.61 (s, 2H), 3.50-3.69 (m, 2H); MS for C16H17F2N3O5 m/z 370.0 (M+H)+.