Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[S].II.[SH2:19]>ClC1C=CC=CC=1Cl>[CH3:14][C:9]1[C:8]2[NH:7][C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:15])[S:19][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: S
Reactant: Cc1ccccc1Nc1ccccc1C
Agent: II
Agent: [S]
Solvent: Clc1ccccc1Cl
Product: Cc1cccc2c1Nc1c(C)cccc1S2
Temperature: 180 °C
Yield: 15 %

Procedure:
To a reaction vessel were combined di(2-tolyl)amine (11.7 g, 59.3 mmol), elemental sulfur (3.9 g, 121.65 mmol, 2 eq.), crushed iodine (0.44 g, 1.73 mmol, 3 mol %) followed by o-dichlorobenzene (22 mL). Added an outlet to a dilute bleach solution (for hydrogen sulfide evolution) then put under argon. Refluxed at 180° C. for 4 h and removed solvent under reduced pressure. Purified by column chromatography with 2.0% ethyl acetate/98% hexane to obtain the desired product as white crystals (2 g, 8.8 mmol, 15% yield). Alternatively, the reaction was cooled to about 60° C. then hexane was added for extraction. Repeated hot hexane extractions of reaction until the product was no longer obtained in residue (about four times). Combined hexane extractions and concentrated in vacuo. Purified resulting residue either through repeated hot acetone/isopropanol crystallizations (or triturations) or flash column chromatography using 2% ethyl acetate/98% hexane to obtain product as white crystals (2.92 g, 12.8 mmol, 28% yield).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH3:29]>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2c3c(nn2CC)CCNCC3)cc1
Yield: 100.9 %

Procedure:
The title compound (140 mg) was prepared according to Example 193 using 213 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 232 mg of 4-ethylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.39 (m, 2H), 7.27-7.26 (m, 2H), 4.65 (br s, 2H), 4.05-4.00 (m, 2H), 3.8-3.6 (m, 2H), 3.18-3.00 (m, 2H), 2.88-2.81 (m, 2H), 2.76-2.71 (m, 2H), 1.32-1.24 (m, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH:19](=O)[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:19][CH:20]([CH3:22])[CH2:21][NH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1
Reactant: CC(C)C=O
Reactant: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-aminopiperidine-1,3-dicarboxylate (1.83 g), isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, the concentrate was basified with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1)-ethyl acetate 100%-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (1.42 g) as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH3:10][O:11][C:12](=[NH:17])[CH:13]=[C:14]([NH2:16])[CH3:15].[Cl-].[CH2:19]([O:21][C:22](=[O:26])[C:23](O)=O)[CH3:20].O>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH3:15])[N:16]=[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:26])[N:17]=1
Reactant: COC(=N)C=C(C)N
Reactant: CCOC(=O)C(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nc(C)cc(OC)n1
Reaction time: 1 h

Procedure:
182 ml of triethylamine in 50 ml of dichloromethane are added dropwise at -30° C. to a stirred suspension of 70.2 g of methyl-3-amino-2-butenimidate dihydrochloride in 350 ml of dichloromethane. Stirring is continued for 0.5 hour at this temperature, and 42 ml of oxalic acid ethyl ester chloride are then added dropwise. Stirring is continued for 1 hour at -30° C., and the mixture is allowed to come to room temperature in the course of 12 hours. The organic phase is stirred several times with water, dried over Na2SO4 and concentrated. After filtration over silica gel (eluent: CH2Cl2), the residue is distilled in vacuo. This gives 51.5 g of ethyl 4-methoxy-6-methylpyrimidine-2-carboxylate of boiling point 105°-115° C./-0.05 mbar.
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([CH3:18])=[C:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClS([N:38]=[C:39]=O)(=O)=O.CN(C)C=O>>[C:39]([C:8]1[C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)(=[O:27])=[O:28])=[C:10]([CH3:18])[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:38]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)Cn1c(C2CCCCC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CCCCC1
Yield: 71.7 %

Procedure:
General procedure II was followed using ethyl 2-(5-cyclohexyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (642 mg, 1.36 mmol), chlorosulfonyl isocyanate (0.147 mL, 1.70 mmol) and N,N-dimethylformamide (0.105 mL, 1.36 mmol) to afford ethyl 2-(3-cyano-2-cyclohexyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (485 mg, 0.975 mmol, 72% yield) as a white sticky foam.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:38][CH3:39])[CH2:40][CH3:41])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(8E,12E,14E)-7-acetoxy-6,21-dihydroxy-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (101 mg, 156 μmol) was dissolved in methylene chloride (1 mL). 4-dimethylaminopyridine (59.7 mg, 48.9 μmol) was added to the solution, and the solution was cooled to 0° C. Benzoyl chloride (28.0 μL, 241.0 μmol) was added to the solution, and the solution was stirred at room temperature for two hours. The reaction solution was diluted with ethyl acetate (20 mL), and the dilution was washed with purified water (4 mL) twice and brine (4 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=5:1→4:1) to obtain the title compound (107 mg, 142 μmol, 91.0%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[CH:18]([OH:21])[CH2:19][CH2:20][C:15]2=[N:14]1.[OH2:22]>C1C=CC=CC=1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH:17]=[C:20]2[CH2:19][C@@H:18]([OH:21])[C@@H:16]([OH:22])[C:15]2=[N:14]1
Reactant: OC1CCc2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)cc21
Reactant: O
Solvent: c1ccccc1
Product: O[C@@H]1Cc2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (62) (5 g) in Benzene (50 mL) p-TSA (500 mg) was added and the resulting mixture was heated at reflux for 6 hr. while water formed in the reaction was removed using a Dean-Stark Trap. The reaction mixture was allowed to cool down to room temperature and washed with water (5×50 mL). The organic layer was concentrated in vacuo to obtain an oil which was dried on a high vacuum and directly used in next step. To a solution of above product (4.8 g) in 1:1 t-BuOH/H2O (100 mL) was treated with NMO (3 g) and OsO4 (380 mg). The resulting mixture was stirred at RT for 12 hr. Aq. NaHCO3 (300 mL) and EtOAc (300 mL) were then added, and the product was extracted in to EtOAc. Organic phase was separated, and the concentrated in vacuo to obtain compounds (80) and (84) which were separated on silica (EtOAc:Hexane 2:3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2](=[CH:14][CH:15]=[CH:16][C:17]([CH3:21])(O)[CH:18]=[CH2:19])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13].[BrH:22].O>CCOCC>[CH3:1][C:2](=[CH:14][CH:15]=[CH:16][C:17]([CH3:21])=[CH:18][CH2:19][Br:22])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13]
Reactant: C=CC(C)(O)C=CC=C(C)C#CC1=C(C)CCCC1(C)C
Reactant: Br
Solvent: O
Solvent: CCOCC
Product: CC(C#CC1=C(C)CCCC1(C)C)=CC=CC(C)=CCBr
Reaction time: 0.25 h

Procedure:
2.84 g of the alcohol III prepared as described in Example 1 were dissolved in 50 ml of ether and an equimolar amount of a solution of HBr in ether was added dropwise at -70° C., whilst stirring. The reaction mixture was then kept for 15 minutes at from -60° to -70° C. and thereafter for 15 minutes at -15° C. 30 ml of water were then added and the organic phase was separated off, washed neutral, dried and concentrated. 3.2 g of a residue (crude yield 93.5%) were left; the structure of the material was determined by IR, NMR and UV spectroscopy.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOCc1c(OC)cccc1C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOCc1c(OC)cccc1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 110 %

Procedure:
Into a 200 mL round bottom flask was added 6.6 g (0.0297 mol) of 2-allyloxymethyl-3-methoxy benzoic acid and 40 mL of ethyl acetate. 24.05 g of a 25% pentafluorophenol (6.01 g, 0.0327 mol) solution in ethyl acetate was added while stirring. The reaction flask was placed into a water bath and while stirring small portions of DCC (6.2 g, 0.030 mol) were added. The stirring continued overnight at room temperature. The reaction was filtered through two Whatman #541 filters to remove the DCU precipitate. The ethyl acetate solution was concentrated to yield 12.8 g (110% yield), indicating presence of DCC and DCU. This was confirmed by TLC (1:1 ethyl acetate:hexane), which indicated a Rf of 0.72 plus other less polar compounds (12 stain indicates about 85% purity). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.7 (d, 1H), 7.45 (t, 1H), 7.15 (d, 1H), 6.0-5.9 (m, 1H), 5.3-5.1 (2 d, 2H), 4.88-4.83 (d, 2H), 4.06 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].CCN(CC)CC>CCCCCC>[Br:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:11])([F:12])[F:13]
Reactant: FC(F)(F)c1ccccc1C=C(Br)Br
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccccc1C=CBr
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
A solution of 1-(2,2-dibromo-vinyl)-2-trifluoromethyl-benzene (989 mg, 3 mmol), and Et)2POH (0.75 ml, 6 mmol) in Et3N (0.83 ml, 6 mmol) was stirred at 5° for 4 h. Hexane was added, and stirred for further 10 min. The mixture was extracted with hexane, washed with brine and dried over Na2SO4. Evaporation of the solvent and chromatography (hexane) gave 1-(2-bromo-vinyl)-2-trifluoromethyl-benzene (674 mg, 90%) as a colorless liquid. IR (KBr): 1600, 940 cm-1. MS (EI): 251 (M).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8]>O.CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1csnn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(C(=O)O)c1csnn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.2 %

Procedure:
A solution of sodium hydroxide (0.47 g.) in water (10 ml.) was added to a solution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (anti isomer) (2.1 g.) in methanol (20 ml.) and the resulting mixture was stirred for 6 hours at ambient temperature. Methanol was removed from the reaction mixture and to the residue was added water. The resulting mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted twice with ether (50 ml.). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give oil of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1.3 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCOCC1.O.C(OCC)(=O)C.Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(CNS(C)(=O)=O)c1
Reaction time: 12 h
Yield: 81.5 %

Procedure:
The product of step C (900 mg, 2.00 mmol) was diluted with dioxane (10 mL) followed by the addition of LiOH—H2O (126 mg, 3.00 mmol) dissolved in water (2 mL). After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M cartridge eluting with methylene chloride:MeOH (95:5) to yield 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamido-methyl)phenoxy)benzoic acid (710 mg, 81.4% yield) as a clear oil.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)([OH:3])=O.[CH2:13]([CH:15](C(O)=O)C(O)=O)[CH3:14].O1C=CCCC1>>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)(=[O:3])[CH2:14][CH2:13][CH3:15]
Reactant: O=C(O)c1noc2ccccc12
Reactant: CCC(C(=O)O)C(=O)O
Agent: C1=COCCC1
Product: CCCC(=O)c1noc2ccccc12

Procedure:
Using 3.7 g (23 retool) of 3-carboxy-1,2-benzisoxazole prepared in accordance with a known process [J. Amer. Chem. Soc., 97, 7305 (1975)], 3.34 g (25 mmol) of ethylmalonic acid and 6.4 g of 3,4-dihydropyran, 3-butyryl-1,2-benzisoxazole was obtained as colorless crystals by similar treatment to Example 28-(4). Analytical results of the crystals obtained: Yield: 3.5 g (85%). Melting point: 33°-35° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br/C(=C\C)/C(O)=O.CNC.IC1C=C(NC2C3C(=CC=C(N[C:49](=[O:56])[CH:50]=[CH:51][CH2:52][N:53]([CH3:55])[CH3:54])C=3)N=CN=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:49](=[O:56])[CH:50]=[CH:51][CH2:52][N:53]([CH3:55])[CH3:54])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(I)c3)c2c1
Agent: C/C=C(\Br)C(=O)O
Agent: CNC
Product: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
4-[(3-bromophenyl)amino]-6-aminoquinazoline is reacted with bromocrotonic acid and dimethylamine, as is described hereinabove in Compound 5, to give N-{4-[(3-bromophenyl)amino]quinazoline-6-yl}4-(dimethylamino)-2-butenamide.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16]O)(=[O:4])=[O:3].O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:16][C:8]1[N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: CS(=O)(=O)CCn1c(CO)nc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)CCn1c(CCl)nc2ccccc21
Yield: 33 %

Procedure:
To a solution of crude (1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazol-2-yl)methanol in DCM (30 mL) was added SOCl2 (5 mL). The mixture was heated to reflux and monitored by LCMS. After the reaction completed, the solvents was evaporated. The residue was redissolved in DCM (100 mL) and washed with saturated NaHCO3 (2×30 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude product (600 mg, yield: 33%) as oil. MS obsd. (ESI+) [(M+H)+]: 273.1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[O:53][CH2:52]C1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH:23]2[CH2:52][OH:53])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OCC1COCCN1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCOCC2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and morpholin-3-ylmethanol and isolated as light-yellow gum (13.3 mg, 68%). MS (m/e): 417.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[C:33]1([NH:39][C:40]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)[N:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(Br)nc(Oc2cccc(OC(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.0 g (0.0027 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethoxy)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. The obtained solution was cooled in a dry ice-acetone bath in an argon atmosphere and mixed with 2.6 ml of a 1.6M-hexane solution of BuLi (0.0027×1.5 mol), followed by stirring for about 10 minutes. After 0.74 g (0.0027×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about 45 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The obtained fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][C@H:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(OC2C=CC(O[C@H](C)C(O)=O)=CC=2)=CC=1.C(Cl)(=O)C(Cl)=O.[Na].[C:54]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:55][C:56]([CH3:58])=[O:57]>CCOCC.CN(C=O)C>[C:56]([C@H:55]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:54]([O:60][CH2:61][CH3:62])=[O:59])(=[O:57])[CH3:58]
Reactant: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: C[C@@H](Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)[C@H](C(C)=O)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the procedure of Example 12, (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid chloride is prepared from (R)-2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid (1.0 g, 3.06 mmol) and oxalyl chloride (0.6 ml) in ether (10 ml) and DMF (2 drops). The acid chloride is then reacted with the sodium salt of ethyl acetoacetate (0.084 g of sodium and 0.480 g of ethyl acetoacetate) to give ethyl (R)-2-acetyl-4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (XVIII; Q1 is CH, Y is hydrogen, Z is trifluoromethyl and R3 is ethyl).