Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[NH:62]1[CH2:67][CH2:66][CH2:65][C@@H:64]([NH2:68])[CH2:63]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:62]2[CH2:63][C@H:64]([NH2:68])[CH2:65][CH2:66][CH2:67]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: N[C@@H]1CCCNC1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (4 gm) and methyl isobutyl ketone (MIBK 100 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (3.7 gm) and (R)-piperidine-3-amine dibenzoyl-D-tartrate (6.1 gm) were added to the reaction mixture at 26° C. The reaction mixture was heated to 100° C. and maintained at that temperature for 6 hours. The reaction mixture was cooled to 30° C. and filtered, and the salt was washed with MIBK (8 mL). The filtrate was charged into another flask and added slowly 10% aqueous acetic acid solution (40 mL) and stirred for one hour at 26° C. The aqueous layer was separated and washed with 12 mL of dichloromethane. The aqueous layer was charged into another flask and 40 mL of dichloromethane and 20 mL of 16% aqueous sodium hydroxide solution was added drop-wise at 26° C. The mixture was stirred for one hour at 26° C. and the organic layer was separated and the aqueous layer was extracted with 20 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Isopropyl alcohol (8 mL) was added to the residue and evaporated under vacuum at below 45° C. Isopropyl alcohol (16 mL) was added to the residue and stirred for 2 hours at 26° C. Filtered the compound and washed with isopropyl alcohol (4 mL) and dried the compound at 60° C. under vacuum to give 3.2 gm of Linagliptin. PXRD pattern: FIG. 2, Chemical Purity: 98.68%, Chiral Purity: 99.82%, S-isomer content: 0.12%, Regio impurity: 0.57%, Bromo impurity: 0.28%
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[CH:14][N:13]=3)[CH:9]=2)[CH:4]=[C:3]1[C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21].C(N(CC)CC)C.Cl[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:52]=1[O:61][C:62](=[O:64])[CH3:63])=[O:50].O>CCOC(C)=O>[CH3:19][N:18]([C:15]1[CH:14]=[N:13][C:12]([O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[C:3]([C:20]([N:22]4[CH2:23][CH2:24][N:25]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][CH:30]=5)[CH2:26][CH2:27]4)=[O:21])[N:2]3[CH3:1])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:59])([F:60])[F:58])=[CH:53][C:52]=1[O:61][C:62](=[O:64])[CH3:63])=[O:50]
Reactant: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)Cl
Reactant: CNc1ccc(Oc2ccc3cc(C(=O)N4CCN(Cc5ccc(OCC(F)(F)F)cc5)CC4)n(C)c3c2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(Oc2ccc3cc(C(=O)N4CCN(Cc5ccc(OCC(F)(F)F)cc5)CC4)n(C)c3c2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a stirred solution of 2-acetoxy-4-trifluoromethyl-benzoic acid (180 mg, 0.73 mmol) in CH2Cl2 (6 mL) were added oxalyl chloride (0.08 mL, 0.91 mmol) and DMF (1 drop). The reaction mixture was stirred at room temperature for 1 hour. CH2Cl2 and excess oxalyl chloride were removed in vacuo. Acetic acid 2-chlorocarbonyl-5-trifluoromethylphenyl ester was obtained as a colorless oil (190 mg) and used in the following step without further purification. To a stirred solution of [1-Methyl-6-(5-methylaminopyridin-2-yloxy)-1H-indol-2-yl]{4-[4-(2,2,2-tri-fluoroethoxy)benzyl]piperazin-1-yl}methanone (340 mg, 0.6 mmol) in AcOEt (4 mL) were added triethylamine (0.13 mL, 0.91 mmol) and acetic acid 2-chlorocarbonyl-5-trifluoromethyl-phenyl ester (190 mg, 0.73 mmol) in AcOEt (3 mL) under ice cooling. The reaction mixture was stirred for 10 minutes at 0° C. Water was added to the reaction mixture, and the aqueous layer was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to afford 0.46 g of the title compound as a white powder.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][CH:17]([CH3:28])[CH2:18][NH:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1C(N)=O.CO>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][CH:17]([CH3:28])[CH2:18][N:19]1[C:20]2[N:21]=[CH:22][NH:23][C:24]=2[C:4](=[O:5])[NH:6][C:7]1=[S:8]
Reactant: CCOC(=O)N=C=S
Reactant: CC(CNc1nc[nH]c1C(N)=O)OCc1ccccn1
Solvent: CO
Solvent: ClCCl
Product: CC(Cn1c(=S)[nH]c(=O)c2[nH]cnc21)OCc1ccccn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.246 mL, 2.18 mmol) was added to a suspension of 4-{[2-(pyridin-2-ylmethoxy)propyl]amino}-1H-imidazole-5-carboxamide (0.500 g, 1.82 mmol, obtained from Example 20(c)) in dichloromethane (10 mL). After 0.5 h, methanol (2 mL) was added. The solvent was removed in vacuo and acetone (5 mL) and another portion of ethoxycarbonyl isothiocyanate (0.246 mL, 2.18 mmol) were added. After o.n. stirring, the reaction was concentrated in vacuo. To the residue was added 1 N NaOH (10 mL) and the resulting solution was heated for 4 h at 100° C. After cooling to r.t., 2 N HCl was added until pH˜6. The mixture was concentrated in vacuo. The product was purified by preparative HPLC resulting in 54.3 mg (9% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1.C([Mg]Cl)(C)C.C1(=O)CCC1>CCOCC>[F:8][C:4]1[C:3]([O:9][CH3:10])=[C:2]([C:15]2([OH:14])[CH2:11][CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1c(F)cccc1Br
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Agent: O=C1CCC1
Solvent: CCOCC
Product: COc1c(F)cccc1C1(O)CCC1
Temperature: 0 °C

Procedure:
To a 3-L round-bottom flask were added a stire bar, 2-bromo-6-fluoroanisol (75.00 g, 370 mmol) and dry THF (1460 mL). The flask was purged with nitrogen and cooled to 0° Celsius before adding 2.0 M i-PrMgCl in THF (408 mL, 916 mmol) over the course of 15 min. The resultant mixture was stirred for 2 hours before adding cyclobutanone (34 mL, 455 mmol). The resultant mixture was stirred for 0.5 hour before diluting with Et2O (2.50 L) and washing with saturated NH4Cl followed by brine. The organic layer was isolated, dried over MgSO4, filtered and concentrated to dryness to give the crude product. Subjecting the residue to FCC gave the title compound (55.58 g). 1H NMR (400 MHz, CDCl3) δ 6.98-6.88 (m, 3H), 3.90-3.90 (s, 3H), 2.46-2.42 (m, 2H), 2.31-2.28 (m, 2H), 2.04 (m, 1H), 1.67-1.64 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:12])=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[F:22][C:23]([F:29])([F:28])[CH2:24][C:25](Cl)=[O:26]>ClCCl>[F:22][C:23]([F:29])([F:28])[CH2:24][C:25]([NH:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[C:8]=1[CH3:12])=[O:26]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: Cc1c(N)nc2ccc(F)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)CC(F)(F)F)nc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine (0.033 g, 0.00020 mol) was dissolved in dichloromethane (3.0 mL) and N,N-diisopropylethylamine (0.070 mL, 0.00040 mol) was added. The reaction was cooled to 0° C. and 3,3,3-trifluoropropionyl chloride (29 uL, 0.00024 mol) was added. The mixture was warmed to room temperature and was stirred for 1 hour. Solvent removed and residue was chromatographed on silca (70% ethyl acetate/hexanes) to give 3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamide Rf 0.43, 70% ethyl acetate/hexanes; MS m/z 276 (M+H). SH-SY5Y_EC50 (μM): 10.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70842.3 %

Procedure:
2-Chloroquinoline (0.12 moles, 20.0 g), 4-nitrothiophenol (0.13 mmoles, 20.8 g), and potassium carbonate (0.13 moles, 18.5 g) were dissolved in 800 ml ethanol and stirred at room temperature for 1.5 hr. The mixture was filtered and the solid washed with ethanol. The solid was dissolved with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to yield 2-(4-nitrophenylthio)quinoline 26.0 g, 77%. Mass Spec (FD) 282. Calculated for C15H10N2O2S: C, 63.82, H 3.57; N, 9.92. Found: C, 63.55, H 3.59; N, 9.71.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[NH3:10]>C(O)C>[NH2:10][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1
Reactant: N
Reactant: Nc1cnc(Br)c(Cl)n1
Solvent: CCO
Product: Nc1cnc(Br)c(N)n1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
A suspension of 2-chloro-3-bromo-6-aminopyrazine (15 g, 0.072 mole) in absolute ethanol (150 ml) and 0.880 ammonia (375 ml) was stirred and heated in an autoclave at 160° C. and 20 atm. for 16 hrs. The cooled mixture was evaporated in vacuo and extracted with hot methanol (3×100 ml). The combined methanol extracts were evaporated in vacuo. The residue was dissolved in hot chloroform, dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered, and dried in vacuo. Yield 5.51 g (40%), M.p. 176-178° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[CH3:2].[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][NH2:16].N[C@H](C(O)=O)CC(O)=O>C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C@@H:6]([C:7]([OH:9])=[O:8])[NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH3:17])[CH3:11])[CH3:2]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)/C=C\C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NCCCN(C)C)C(=O)O

Procedure:
In a manner analogous to that of Example 1, 360.3 g (2.5 mols) of maleic acid monoethyl ester are placed into the glass flask and, with cooling, 500 ml of triethylamine are added dropwise. 306.5 g (2.5 mols+20% excess) of 3-dimethylaminopropylamine are subsequently added, and the reaction mixture is reacted at 64°-90° C. for 50 minutes. The crude product is processed according to Example 1, and the yield is 568.2 g (92.3% of theory) of a white crystalline aspartic acid derivative having a melting point of 168°-169° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:26]=[CH:25][C:19]3[O:20][C:21]([F:24])([F:23])[O:22][C:18]=3[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.FC1(F)OC2C=CC(NCC3CCCCC3)=CC=2O1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:26]=[CH:25][C:19]3[O:20][C:21]([F:23])([F:24])[O:22][C:18]=3[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)OC(F)(F)O3)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: FC1(F)Oc2ccc(NCC3CCCCC3)cc2O1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)OC(F)(F)O3)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 2,2-difluoro-benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1CC[CH2:5][C:4](=[O:8])[CH:3]=1.C([Al]([CH2:14][CH3:15])CC)C.C[Si](Cl)(C)C.Cl.[C:22]1(C)C=CC=C[CH:23]=1>C1COCC1>[CH2:22]([C:14]1([CH3:15])[CH2:1][CH2:2][CH2:3][C:4](=[O:8])[CH2:5]1)[CH3:23]
Reactant: CC1=CC(=O)CCC1
Reactant: CC[Al](CC)CC
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCC1(C)CCCC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
1.1 g (10 mmol) of 3-methyl-cyclohex-2-en-1-one and 14 mg (0.2 mmol) of CuBr are introduced into 15 ml of THF. 5.78 ml (11 mmol) of a 1.6 molar triethylaluminum solution in toluene and 2.16 g (20 mmol) of trimethylsilyl chloride are added at 0° C. and stirred for 3 hours at room temperature. It is hydrolyzed with 10 ml of 1N hydrochloric acid, extracted with ethyl acetate and the solvent is evaporated. After chromatography on silica gel, 1.26 g (90% of theory) of 3-ethyl-3-methyl-cyclohexanone is obtained.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:9]3([O:29][C@@H:10]3[C@@H:11]([Cl:28])[C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[C@@H:14]3[CH2:27][C@@H:15]3[C:16]2=[O:26])[CH2:8]1)(C)(C)C.[CH3:32]O.S(=O)(=O)(O)O>O1CCCC1.CCOCC>[CH:10]([O:29][CH:9]([CH3:8])[CH3:22])([CH3:11])[CH3:32].[Cl:28][C@@H:11]1[C@H:10]2[O:29][C@:9]32[C@:22]([CH3:25])([CH2:23][CH2:24][C@H:7]([OH:6])[CH2:8]3)[C@@H:21]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][CH2:20]2)([CH3:18])[C:16](=[O:26])[C@H:15]2[CH2:27][C@@H:14]12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)OC(C)C
Product: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
142 g of 3β-(tert.-butyldimethylsilyloxy)-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstan-17-one is dissolved in 400 ml of tetrahydrofuran and 400 ml of methanol and stirred with 1,000 ml of 8% strength sulfuric acid for 1.5 hours at room temperature. The mixture is then diluted with ether, washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate, and concentrated under vacuum. By trituration of the resultant solid with diisopropyl ether, 108 g of 7α-chloro-5,6β-epoxy-3β-hydroxy-15β,16β- methylene-5β-androstan-17-one is obtained, mp 173° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH2:17]([NH2:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>COC(C)(C)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8]([C:10]([O-:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[CH2:17]([NH3+:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Reactant: CCCCCCCCCCCCN
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCC[NH3+]
Product: O=C([O-])c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
A mixture of 300 mg of 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, 238 mg of laurylamine and 10 ml of tert-butyl methyl ether was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 538 mg of laurylammonium 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter referred to as “the present compounds 8”).
Reaction SMILES: [CH3:1][CH:2]1[C:15](=O)O[C:12](=O)[C@@H:4]([NH:5]C(=O)C(F)(F)F)[CH2:3]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18]1.CC(C(O)=O)C[C@@H](C(O)=O)N>>[NH2:5][CH:4]1[CH2:12][C:23]2=[CH:22][C:21]3[O:17][CH2:18][CH2:19][C:20]=3[CH:25]=[C:24]2[CH2:15][CH:2]([CH3:1])[CH2:3]1
Reactant: CC1C[C@H](NC(=O)C(F)(F)F)C(=O)OC1=O
Reactant: c1ccc2c(c1)CCO2
Agent: CC(C[C@H](N)C(=O)O)C(=O)O
Product: CC1Cc2cc3c(cc2CC(N)C1)OCC3

Procedure:
This compound may be prepared by condensing 4-methyl-N-trifluoroacetylglutamic anhydride with 2,3-dihydrobenzofuran according to the process described in Example 2. The synthesis of 4-methylglutamic acid is known (J. Pharm. Scien., (1975), 64, No. 11, p. 1855-1858).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A stirred solution of 14.2 grams (0.090 mole) of 1,4-dioxaspiro[4.5]decan-8-ol and 10.0 grams (0.099 mole) of triethylamine in 100 mL of methylene chloride is cooled to 0° C., and a solution of 7.7 mL (0.099 mole) of methanesulfonyl chloride in 25 mL of methylene chloride is added drop-wise at a rate to maintain the reaction mixture temperature at 0° C. to 5° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature. The reaction mixture is then washed with two 75 mL portions of an aqueous 5% sodium bicarbonate solution and then with 75 mL of an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.C([O-])(=O)C.[Na+].[C:13]([C:15]1[CH:23]=[CH:22]C(C(N)=O)=[CH:17][CH:16]=1)#[N:14].[N+]([O-])([N+]([O-])=O)=O>C(O)(=O)C>[C:13]([C:15]1[CH:23]=[CH:22][C:6]([C:5]([OH:4])=[O:7])=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 96 %

Procedure:
Acetic acid (30 ml), acetic anhydride (70 ml), sodium acetate (6.2 g), and p-cyanobenzamide (5.0 g) were mixed with stirring under cooling with ice, to thereby obtain a mixture. The mixture was allowed to react while dinitrogen tetroxide gas was introduced thereto at 381 N ml/minute for three hours. The residual solvent was removed through distillation in vacuum, and water was added to the residue, to thereby form crystals. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 4.83 g of p-cyanobenzoic acid (yield 96%, based on p-cyanobenzamide). The p-cyanobenzoic acid obtained had a purity of 97%.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:32])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:32])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 37.4 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.500 g), KOH (0.200 g), water (5 mL) and THF (10.0 mL) to afford 0.150 g of desired product.
Reaction SMILES: CO[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO.O1CCCC1>[OH:28][CH2:27][CH2:29][NH:30][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: NCCO
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 53.6 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (10 mL) was treated with ethanolamine (0.094 g) and the mixture was refluxed for 48 hours. The solvents were removed by evaporation and the residue was purified by HPLC (ethyl acetate-methanoltriethylamine; 95:5:2) followed by crystallization from tetrahydrofuran-ethyl alcohol to give 0.29 g of N-(2-hydroxyethyl)-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 138°-140° C.
Reaction SMILES: C(O)C.Cl.[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]([OH:19])=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=1)=[O:21]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
Ethanol (75 ml) was cooled to 15° C and saturated with hydrogen chloride gas. This solution was diluted by addition of another 400 ml of ethanol. To this alcoholic solution was added 82.4 grams of 2,6-di-tert-butylphenol. After it was dissolved, a solution of 30.4 grams of sodium nitrite in 40 ml of water was added at 15°-20° C over a period of one hour with stirring. Stirring was continued for another two hours with the temperature allowed to rise to room temperature. The solution was diluted with 200 ml of water, and the product formed was collected by filtration and washed well with water. The filter cake was then slurried in 300 ml of petroleum ether, filtered, washed with another 100 ml of petroleum ether and dried in a vacuum oven at 70°-80° C to yield the desired intermediate 4-nitroso-2,6-di-tert-butylphenol, melting at 219° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:10]=[C:11]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH:12]=[CH:13][CH:14]=4)[CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH2:24][CH2:25]1
Reactant: C=CC(=O)Nc1cccc(Sc2ccnc(Cl)n2)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: C=CC(=O)Nc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 42.2 %

Procedure:
In a procedure analogous to Example 8, reaction of N-(3-(2-chloropyrimidin-4-ylthio)phenyl)acrylamide (1.10 g, 3.77 mmol) and 4-morpholinoaniline (806 mg, 4.52 mmol) furnished the product (690 mg, 43%).